Information on EC 4.2.1.22 - cystathionine beta-synthase

New: Word Map on EC 4.2.1.22
Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
Specify your search results
Mark a special word or phrase in this record:
Select one or more organisms in this record:
Show additional data
Do not include text mining results
Include (text mining) results (more...)
Include results (AMENDA + additional results, but less precise; more...)


The expected taxonomic range for this enzyme is: Archaea, Eukaryota, Bacteria

EC NUMBER
COMMENTARY
4.2.1.22
-
RECOMMENDED NAME
GeneOntology No.
cystathionine beta-synthase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
L-serine + L-homocysteine = L-cystathionine + H2O
show the reaction diagram
mechanism
-
L-serine + L-homocysteine = L-cystathionine + H2O
show the reaction diagram
mechanism
-
L-serine + L-homocysteine = L-cystathionine + H2O
show the reaction diagram
ping-pong mechanism
-
L-serine + L-homocysteine = L-cystathionine + H2O
show the reaction diagram
ping-pong mechanism
-
L-serine + L-homocysteine = L-cystathionine + H2O
show the reaction diagram
sequential bisubstrate mechanism in which no product release occurs until both substrates are bound to the enzyme to form a ternary complex
Trichostrongylus colubriformis, Steinernema bibionis
-
L-serine + L-homocysteine = L-cystathionine + H2O
show the reaction diagram
carbanion and aminacrylate intermediates in the CBS-catalyzed reaction, arrangement of the protein residues and pyridoxal 5'-phosphate cofactor in the active site pocket, and reaction mechanism, overview
Q9VRD9
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C-S bond formation
-
-
-
-
elimination
-
-
-
-
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
Biosynthesis of antibiotics
-
-
Cysteine and methionine metabolism
-
-
cysteine metabolism
-
-
Glycine, serine and threonine metabolism
-
-
L-cysteine biosynthesis III (from L-homocysteine)
-
-
L-homocysteine and L-cysteine interconversion
-
-
Metabolic pathways
-
-
SYSTEMATIC NAME
IUBMB Comments
L-serine hydro-lyase (adding homocysteine; L-cystathionine-forming)
A pyridoxal-phosphate protein. A multifunctional enzyme: catalyses beta-replacement reactions between L-serine, L-cysteine, cysteine thioethers, or some other beta-substituted alpha-L-amino acids, and a variety of mercaptans.
SYNONYMS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Beta-thionase
-
-
-
-
CBS
-
-
-
-
Cysteine synthase
-
-
-
-
Hemoprotein H-450
-
-
-
-
Methylcysteine synthase
-
-
-
-
Serine sulfhydrase
-
-
-
-
Serine sulfhydrylase
-
-
-
-
Serine sulphhydrase
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
9023-99-8
-
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
cystathionine beta-synthase
UniProt
Manually annotated by BRENDA team
vervet monkey
-
-
Manually annotated by BRENDA team
a cobalt-substituted variant of hCBS, i.e. Co hCBS, in which CoPPIX replaces FePPIX, i.e. heme
-
-
Manually annotated by BRENDA team
Down's syndrome patients
-
-
Manually annotated by BRENDA team
gene mutations in Venezuelan patients: G85R, T191M, D234N, D444N and Q243X. The mutations present in each country differ from each other depending on the demographic profile
-
-
Manually annotated by BRENDA team
patients with homocystinuria
-
-
Manually annotated by BRENDA team
recombinant
-
-
Manually annotated by BRENDA team
stump-tailed macaque
-
-
Manually annotated by BRENDA team
long-tailed macaque
-
-
Manually annotated by BRENDA team
japanese macaque
-
-
Manually annotated by BRENDA team
Balb/c and F1 (C57BLBalb/c) specific pathogen-free female
-
-
Manually annotated by BRENDA team
moderate to intermediate murine model of hyperhomocysteinaemia. Using wild type and heterozygous cystathionine beta-synthase deficient mice fed a methionine enriched diet or a control diet
-
-
Manually annotated by BRENDA team
mouse model for spontaneous steatohepatitis in which the gene for the MAT1A isoenzyme encoding AdoMet synthetase has been disrupted
-
-
Manually annotated by BRENDA team
strain C57BL/6J, strain BALB/c, strain Black Swiss
-
-
Manually annotated by BRENDA team
crested gibbon
-
-
Manually annotated by BRENDA team
Northern white-cheeked gibbon
-
-
Manually annotated by BRENDA team
Bonobo-pygmy chimpanzee
-
-
Manually annotated by BRENDA team
common chimpanzee
-
-
Manually annotated by BRENDA team
Hamadryas baboon
-
-
Manually annotated by BRENDA team
orang utan
-
-
Manually annotated by BRENDA team
male Sprague-Dawley
-
-
Manually annotated by BRENDA team
Steinernema bibionis
-
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
-
cystathionine beta-synthase belongs to the fold II family of pyridoxal 5'-phosphate enzymes
malfunction
-
hemizygous (+/-) CBS knockout mice are analysed: Significantly higher plasma total homocysteine concentrations occurr in the CBS (+/-) mice than in wild-type cohorts. Female mice of both genotypes have significantly higher plasma total homocysteine concentrations and lower relative CBS mRNA levels than did male mice. During vitamin B6 deficiency, plasma total homocysteine concentrations are significantly elevated. CBS (+/-) mice have a lower plasma cholesterol concentration, and during a taurine- and cysteine-deficient diet, CBS mRNA levels in CBS (+/-) mice are reduced only 13%
malfunction
-
the effects of endogenous elevation of homocysteine on the retina using the cystathionine beta-synthase mutant mouse is determined. Increased retinal homocysteine alters inner and outer retinal layers in cbs homozygous mice and older cbs heterozygous mice, and it primarily affects the cells of the ganglion cell layer in younger heterozygous mice. Elevated retinal homocysteine alters expression of genes involved in endoplasmic reticular stress, N-methyl-D-aspartate (NMDA) receptor activation, cell cycle, and apoptosis
malfunction
-
CBS deficiency due to missense mutations in the CBS gene is the most common cause of inherited homocystinuria, a treatable multisystemic disease affecting to various extent vasculature, connective tissues, and central nervous system
malfunction
-
cystathionine beta-synthase deficiency is a well-known genetic disease affecting the first step in the conversion of homocysteine to cysteine and ultimately to inorganic sulfur. The disease occurs in a mild and a severe form, phenotypes, overview. Cystathionine beta-synthase activities in wild-type individuals, and in hetero-, and homozygote cystathionine beta-synthase mutants, overview
malfunction
-
misfolding of mutant enzymes may play an important role in the pathogenesis of cystathionine beta-synthase deficiency, identification of mutant variants in patients with homocystinuria due to CBS deficiency and phenotypes, the topology of mutations predicts in part the behavior of mutant CBS, pathogenic mechanism in CBS deficiency, molecular dynamics simulations, overview
malfunction
-
depletion of cystathionine beta synthase induces premature senescence in human endothelial cells, induces mild mitochondrial dysfunction and increases the sensitivity of endothelial cells to homocysteine, a known inducer of endothelial cell senescence and an established risk factor for vascular disease
metabolism
-
involved in homocystein metabolism
metabolism
-
CBS is a key enzyme in the trans-sulfuration pathway and catalyzes the condensation of serine with homocysteine to produce cystathionine
metabolism
-
CBS is involved in the cysteine pathway of bacteria and plants, overview
metabolism
-
cystathionine beta-synthase catalyzes the first step in the transsulfuration pathway in mammals, i.e. the condensation of serine and homocysteine to produce cystathionine and water
metabolism
-
cystathionine beta-synthase is a pivotal enzyme in the metabolism of homocysteine, and is a pyridoxal 5'-phosphate-dependent enzyme that also contains heme as a second cofactor
metabolism
-
cystathionine beta-synthase is a pyridoxal 5'-phosphate-dependent enzyme, which catalyzes the first step of the transsulfuration pathway, namely, the condensation of serine with homocysteine to cystathionine
physiological function
-
CBS activity may contribute to butyrate-stimulated H2S production in WiDr cells
physiological function
-
CBS activity partially regulates endogenous H2S in mice. It contributes significantly to endogenous H2S production in mice, adenovirus-mediated overexpression of CBS in the liver significantly increases circulating levels of H2S, whereas CBS deficiency results in reduced levels. irculating H2S levels are increased by pharmacological activation of CBS in vivo; i.e. in the presence of the endogenous activator
physiological function
-
regulation mechanisms, overview
physiological function
-
Cystathionine beta synthase (CBS) is the main contributor to the production of hydrogen sulfide (H2S) in the brain. The CBS/H2S pathway plays an important role in the protection of learning and memory functions in the brain at the level of the hippocampus
physiological function
-
cystathionine beta-synthase contributes to advanced ovarian cancer progression and drug resistance. The enzyme also regulates bioenergetics of ovarian cancer cells by regulating mitochondrial reactive oxygen species production, oxygen consumption and ATP generation
physiological function
-
enzyme overexpression extends lifespan of human endothelial cells
metabolism
Q9YCN5
cystathionine beta-synthase is involved in the cysteine pathway of bacteria and plants, overview
additional information
-
CBS is a modular enzyme, cross-talk between the catalytic core and the regulatory domain in cystathionine beta-synthase: study by differential covalent labeling and computational modeling, overview
additional information
-
increased immunoreactivity is evident in liver homogenates from mice treated with adenovirus carrying human CBS compared to mice treated with the Ad-lacZ virus
additional information
-
increased immunoreactivity is evident in liver homogenates from mice treated with adenovirus carrying human CBS compared to mice treated with the Ad-lacZ virus. Overexpression of hCBS reduces homocysteine levels significantly by 5.3fold compared to Ad-lacZ treated mice
additional information
Q9VRD9
structural basis for substrate activation and regulation by cystathionine beta-synthase domains in cystathionine beta-synthase, allosteric regulation via the CBS domains, mechanism, overview
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
beta-Chloro-DL-alanine + DL-homocysteine
?
show the reaction diagram
-
-
-
-
-
beta-Cyano-DL-alanine + DL-homocysteine
?
show the reaction diagram
-
-
-
-
-
cysteine + ?
H2S + ?
show the reaction diagram
-
-
-
-
?
DL-Serine-O-sulfate + DL-homocysteine
?
show the reaction diagram
-
-
-
-
-
L-allothreonine + homocysteine
? + H2O
show the reaction diagram
-
-
-
?
L-Cysteine + 1-butanethiol
?
show the reaction diagram
-
-
-
-
-
L-Cysteine + 1-mercapto-2-propanol
HOOC-CH(NH2)-CH2-S-CH2-CH(OH)-CH3 + H2S
show the reaction diagram
-
-
-
-
-
L-Cysteine + 1-mercapto-2-propanol
HOOC-CH(NH2)-CH2-S-CH2-CH(OH)-CH3 + H2S
show the reaction diagram
-
-
-
-
-
L-Cysteine + 1-mercapto-2-propanol
HOOC-CH(NH2)-CH2-S-CH2-CH(OH)-CH3 + H2S
show the reaction diagram
-
-
-
-
-
L-Cysteine + 1-mercapto-2-propanol
HOOC-CH(NH2)-CH2-S-CH2-CH(OH)-CH3 + H2S
show the reaction diagram
-
activated L-serine sulfhydrase
-
-
L-Cysteine + 1-pentanethiol
?
show the reaction diagram
-
-
-
-
-
L-Cysteine + 2-mercaptoethanol
HOOC-CH(NH2)-CH2-S-CH2-CH2OH + H2S
show the reaction diagram
-
-
-
-
-
L-Cysteine + 2-mercaptoethanol
HOOC-CH(NH2)-CH2-S-CH2-CH2OH + H2S
show the reaction diagram
-
-
-
-
L-Cysteine + 2-mercaptoethanol
HOOC-CH(NH2)-CH2-S-CH2-CH2OH + H2S
show the reaction diagram
-
-
-
-
-
L-Cysteine + 2-mercaptoethanol
HOOC-CH(NH2)-CH2-S-CH2-CH2OH + H2S
show the reaction diagram
-
-
-
-
L-Cysteine + 2-mercaptoethanol
HOOC-CH(NH2)-CH2-S-CH2-CH2OH + H2S
show the reaction diagram
-
-
-
-
-
L-Cysteine + 2-mercaptoethanol
HOOC-CH(NH2)-CH2-S-CH2-CH2OH + H2S
show the reaction diagram
Steinernema bibionis
-
-
-
-
-
L-cysteine + 2-mercaptoethanol
S-hydroxyethyl-L-cysteine + H2S
show the reaction diagram
-
-
-
?
L-Cysteine + cysteamine
?
show the reaction diagram
-
-
-
-
-
L-Cysteine + dithioerythritol
?
show the reaction diagram
-
-
-
-
-
L-Cysteine + dithiothreitol
?
show the reaction diagram
-
-
-
-
-
L-Cysteine + DL-homocysteine
Cystathionine + H2S
show the reaction diagram
-
-
-
-
L-Cysteine + DL-homocysteine
Cystathionine + H2S
show the reaction diagram
-
-
-
-
L-Cysteine + DL-homocysteine
Cystathionine + H2S
show the reaction diagram
-
-
-
-
-
L-Cysteine + DL-homocysteine
Cystathionine + H2S
show the reaction diagram
-
-
-
-
-
L-Cysteine + DL-homocysteine
Cystathionine + H2S
show the reaction diagram
-
-
-
-
-
L-Cysteine + DL-homocysteine
Cystathionine + H2S
show the reaction diagram
-
full-length enzyme and truncated enzyme form lacking the C-terminal regulatory domain
-
-
?
L-cysteine + L-homocysteine
L-cystathionine + H2S
show the reaction diagram
-
-
-
-
r
L-cysteine + L-homocysteine
L-cystathionine + H2S
show the reaction diagram
-
-
-
-
r
L-Cysteine + monothioglycerol
?
show the reaction diagram
-
-
-
-
-
L-Cysteine + monothioglycerol
?
show the reaction diagram
-
-
-
-
-
L-Cysteine + monothioglycerol
?
show the reaction diagram
-
-
-
-
-
L-serine + cysteamine
L-thialysine
show the reaction diagram
-
-
-
-
?
L-serine + H2O
NH3 + pyruvate
show the reaction diagram
-
wild-type enzyme shows no beta-elimination reaction, beta elimination is only detectable in the following mutants: T81A, S82A, T85A, Q157A, Q157E, Q157H, Y158F
-
?
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
r
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
?
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
?
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
?
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
?
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
?
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
?
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
?
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
?
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
?
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
?
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
?
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
?
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
?
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
r
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
r
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
r
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
r
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
r
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
?
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
?
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
?
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
r
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
r
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
r
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
r
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
r
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
r
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
r
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
Steinernema bibionis
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
Steinernema bibionis
-
-
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
ir
-
-
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
P35520
beta-replacement reaction
-
?
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
catalyzes a beta-replacement reaction in which an electronegative substituent in the beta-position of the amino acid substrate is replaced by a nucleophile, binding of L-serine as the external aldimine is faster than formation of the aminoacrylate intermediate, the rate-limiting step is the reaction of aminoacrylate with L-homocysteine to form L-cystathione, rate of the forward reaction is 38fold greater than the reverse reaction
-
r
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
hydroxylgroup of serine is replaced by the thiol of homocysteine
-
r
L-Serine + homocysteine
Cystathionine + H2O
show the reaction diagram
-
in the forward direction an external aldimine of serine and an aminoacrylate intermediate are formed, the aminoacrylate binds to homocysteine and converts to cystathione, in the reverse reaction cystathione binds to the enzyme and is rapidly converted to the aminoacrylate without accumulation of the external aldimine
-
r
L-Serine + homocysteine
?
show the reaction diagram
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
Steinernema bibionis
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
initial step in transsulfuration forming cysteine. Homocysteine is a relatively toxic amino acid, which levels have to be kept low
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
synthesis of cystathionine
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
reverse trans-sulfuration pathway
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
irreversible step in transsulfuration pathway
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
reduced activity of EC 4.2.1.22 in patients with homocystinuria due to mutations in the CBS gene
-
-
-
L-Serine + HS-
Cysteine + OH-
show the reaction diagram
-
-
-
-
L-Serine + HS-
Cysteine + OH-
show the reaction diagram
-
-
-
-
L-Serine + HS-
Cysteine + OH-
show the reaction diagram
-
-
-
-
L-Serine + HS-
Cysteine + OH-
show the reaction diagram
-
-
-
-
L-serine + L-cysteine
?
show the reaction diagram
-
-
-
-
?
L-serine + L-homocysteine
cystathionine + H2O
show the reaction diagram
-
-
-
-
?
L-serine + L-homocysteine
cystathionine + H2O
show the reaction diagram
-
-
-
-
?
L-serine + L-homocysteine
cystathionine + H2O
show the reaction diagram
-
-
-
-
?
L-serine + L-homocysteine
cystathionine + H2O
show the reaction diagram
Q91WT9
the enzyme participates in the process of oocyte maturation
-
-
?
L-serine + L-homocysteine
L-cystathionine + H2O
show the reaction diagram
-
-
-
-
?
L-serine + L-homocysteine
L-cystathionine + H2O
show the reaction diagram
-
-
-
-
?
L-serine + L-homocysteine
L-cystathionine + H2O
show the reaction diagram
-
-
-
-
ir
L-serine + L-homocysteine
L-cystathionine + H2O
show the reaction diagram
-
-
-
-
?
L-serine + L-homocysteine
L-cystathionine + H2O
show the reaction diagram
-
-
-
-
?
L-serine + L-homocysteine
L-cystathionine + H2O
show the reaction diagram
Q9VRD9
-
-
-
?
L-serine + L-homocysteine
L-cystathionine + H2O
show the reaction diagram
Q9YCN5
-
-
-
?
L-serine + L-homocysteine
L-cystathionine + H2O
show the reaction diagram
-
-
-
-
?
L-serine + L-homocysteine
L-cystathionine + H2O
show the reaction diagram
-
-
-
-
?
L-serine + L-homocysteine
L-cystathionine + H2O
show the reaction diagram
Q9VRD9
electrostatic stabilization of the zwitterionic carbanion intermediate is afforded by the close positioning of an active site lysine residue that is initially used for Schiff base formation in the internal aldimine and later as a general base, and additional stabilizing interactions between active site residues and the catalytic intermediates
-
-
?
O-acetyl-L-serine + L-homocysteine
?
show the reaction diagram
-
poor substrate for both the wild type and the N- and C-terminally truncated enzyme 71400 CBS
-
-
?
S-Methyl-L-cysteine + DL-homocysteine
?
show the reaction diagram
-
-
-
-
-
L-serine + L-homocysteine
?
show the reaction diagram
-
-
-
-
r
additional information
?
-
-
no L-serine sulfhydrase activity
-
-
-
additional information
?
-
-
no substrate: L-threonine
-
?
additional information
?
-
-
no substrates: D-, L-allo- and D-allo-cystathionine
-
?
additional information
?
-
-
first step in transsulfuration pathway
-
?
additional information
?
-
-
key enzyme involved in intracellular metabolism of homocysteine
-
?
additional information
?
-
-
cystathionine beta-synthase is a key enzyme for homocysteine metabolism, it is associated with the generation and/or differentiation of the radial glia/astrocyte linage cells in the developing central nervous system
-
-
-
additional information
?
-
-
elevated total plasma homocysteine is an independent risk factor in the development of vascular disease in humans. Elevating cystathionine beta-synthase level is an effective method to lower plasma homocysteine levels
-
-
-
additional information
?
-
-
plasma albumin cysteinylation is regulated by cystathionine beta-synthase
-
-
-
additional information
?
-
-
the enzyme may have additional in vivo functions beyond its role as a homocysteine metabolizing enzyme
-
-
-
additional information
?
-
-
the overexpression of cystathionine beta-synthase may cause the developmental abnormality in cognition in Down's syndrome children and may lead to Alzheimer type of disease in Down's syndrom adults
-
-
-
additional information
?
-
-
cystathionine-beta-synthase domains in the ATP-binding component of OpuC are required for transporter function
-
-
-
additional information
?
-
-
hyperhomocysteinaemia is a metabolic disorder associated with the development of premature atherosclerosis. Cystathionine beta-synthase activity is significantly decreased in mice with a plasma homocysteine value greater than 0.015 mg
-
-
-
additional information
?
-
-
key enzyme in the trans-sulfuration pathway. Cystathionine beta-synthase may be an oxidative defense enzyme in the eye tissue, in particular in the segments of the eye where constant environmental oxidative stress is imposed
-
-
-
additional information
?
-
-
role for CBS as a mediator in interactions between oocyte and granulosa cells
-
-
-
additional information
?
-
-
the cystathionine beta-synthase variant c.844_845ins68 protects against CNS demyelination in X-linked adrenoleukodystrophy
-
-
-
additional information
?
-
-
the oxidation of CBS by dioxygen appears to proceed directly from the ferrous to the ferric state, presumably via an outer sphere electron transfer reaction
-
-
-
additional information
?
-
-
CBS also catalyze H2S production in vitro
-
-
-
additional information
?
-
-
cystathionine beta-synthase also catalyze H2S production. The most efficient route for H2S generation by cystathionine beta-synthase is the beta-replacement of the cysteine thiol with homocysteine. In this reaction, cystathionine beta-synthase first reacts with cysteine to release H2S and forms an aminoacrylate intermediate. Homocysteine binds to the E 3 aminoacrylate intermediate with a bimolecular rate constant of 142 mM/s and rapidly condenses to form the enzyme-bound external aldimine of cystathionine. The reactions could be partially rate limited by release of the products, cystathionine and H2S
-
-
-
additional information
?
-
Q9YCN5
O-acetylserine sulfhydrylase isozyme A, OASSAp, EC 2.5.1.65, exhibits both O-acetylserine sulfhydrylase and cystathionine beta-synthase activities
-
-
-
additional information
?
-
-
the enzyme performs L-cysteine sythesis from L-serine
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
L-Serine + homocysteine
?
show the reaction diagram
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
Steinernema bibionis
-
-
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
initial step in transsulfuration forming cysteine. Homocysteine is a relatively toxic amino acid, which levels have to be kept low
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
synthesis of cystathionine
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
reverse trans-sulfuration pathway
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
irreversible step in transsulfuration pathway
-
-
-
L-Serine + homocysteine
?
show the reaction diagram
-
reduced activity of EC 4.2.1.22 in patients with homocystinuria due to mutations in the CBS gene
-
-
-
L-serine + L-homocysteine
cystathionine + H2O
show the reaction diagram
-
-
-
-
?
L-serine + L-homocysteine
cystathionine + H2O
show the reaction diagram
Q91WT9
the enzyme participates in the process of oocyte maturation
-
-
?
L-serine + L-homocysteine
L-cystathionine + H2O
show the reaction diagram
-
-
-
-
?
L-serine + L-homocysteine
L-cystathionine + H2O
show the reaction diagram
-
-
-
-
?
L-serine + L-homocysteine
L-cystathionine + H2O
show the reaction diagram
-
-
-
-
?
L-serine + L-homocysteine
L-cystathionine + H2O
show the reaction diagram
-
-
-
-
?
L-serine + L-homocysteine
L-cystathionine + H2O
show the reaction diagram
Q9VRD9
-
-
-
?
L-serine + L-homocysteine
L-cystathionine + H2O
show the reaction diagram
Q9YCN5
-
-
-
?
L-serine + L-homocysteine
L-cystathionine + H2O
show the reaction diagram
-
-
-
-
?
L-serine + L-homocysteine
L-cystathionine + H2O
show the reaction diagram
-
-
-
-
?
additional information
?
-
-
first step in transsulfuration pathway
-
?
additional information
?
-
-
key enzyme involved in intracellular metabolism of homocysteine
-
?
additional information
?
-
-
cystathionine beta-synthase is a key enzyme for homocysteine metabolism, it is associated with the generation and/or differentiation of the radial glia/astrocyte linage cells in the developing central nervous system
-
-
-
additional information
?
-
-
elevated total plasma homocysteine is an independent risk factor in the development of vascular disease in humans. Elevating cystathionine beta-synthase level is an effective method to lower plasma homocysteine levels
-
-
-
additional information
?
-
-
plasma albumin cysteinylation is regulated by cystathionine beta-synthase
-
-
-
additional information
?
-
-
the enzyme may have additional in vivo functions beyond its role as a homocysteine metabolizing enzyme
-
-
-
additional information
?
-
-
the overexpression of cystathionine beta-synthase may cause the developmental abnormality in cognition in Down's syndrome children and may lead to Alzheimer type of disease in Down's syndrom adults
-
-
-
additional information
?
-
-
cystathionine-beta-synthase domains in the ATP-binding component of OpuC are required for transporter function
-
-
-
additional information
?
-
-
hyperhomocysteinaemia is a metabolic disorder associated with the development of premature atherosclerosis. Cystathionine beta-synthase activity is significantly decreased in mice with a plasma homocysteine value greater than 0.015 mg
-
-
-
additional information
?
-
-
key enzyme in the trans-sulfuration pathway. Cystathionine beta-synthase may be an oxidative defense enzyme in the eye tissue, in particular in the segments of the eye where constant environmental oxidative stress is imposed
-
-
-
additional information
?
-
-
role for CBS as a mediator in interactions between oocyte and granulosa cells
-
-
-
additional information
?
-
-
the cystathionine beta-synthase variant c.844_845ins68 protects against CNS demyelination in X-linked adrenoleukodystrophy
-
-
-
additional information
?
-
-
the oxidation of CBS by dioxygen appears to proceed directly from the ferrous to the ferric state, presumably via an outer sphere electron transfer reaction
-
-
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
heme
-
2 mol per mol of tetrameric enzyme
heme
-
ferrous CBS can form a complex with isonitriles
heme
-
ferruous CBS can form a complex with isonitriles
heme
-
b-type heme
heme
-
iron protoporphyrin IX
heme
-
dependent
heme
-
the heme favors the ferric state at lower pH and, in the presence of reductants, attains the ferric state via transient formation of the ferrous state. Fe(II)-enzyme and Fe(III)-enzyme are apparently interconverted by a proton-controlled internal electron transfer process
heme
-
cystathionine beta-synthase binds one mole of heme per subunit
heme
-
carbon monoxide or nitric oxide can bind to the cofactor, resulting in enzyme inhibition
heme
-
the in vitro activity of cystathionine beta-synthase is sensitive to the redox state of the heme and is higher in the ferric form. Both carbon monoxide and nitric oxide bind to ferrous heme and inhibit the enzyme. The crystal structure of the protein reveals that the heme is about 20 A away from the active site
heme
-
heme in CBS is six-coordinate, low spin, and contains cysteine and histidine as axial ligands, the unusual heme in CBS represents a potential source of cytosolic superoxide radical
heme
-
the specific activity of CBS improves 1.8-2.8fold under truncation of R51A and R224A when the heme iron is in the ferric state
heme
-
the specific activity of the alkaline form is approximately 25% of that for the intact CBS enzyme when the heme iron is in the ferric state
heme
-
requires a heme cofactor for maximal activity, heme plays a key role in proper CBS folding and assembly
heme
-
CO binding displaces Cys52 from the heme
heme
-
vibrational coherence spectroscopy is used to probe the low-frequency vibrational motions of the heme and how they depend on structural distortions that are induced by the CBS protein environment
heme
-
role of heme in cystathionine beta-synthase folding
pyridoxal 5'-phosphate
-
requirement
pyridoxal 5'-phosphate
-
requirement
pyridoxal 5'-phosphate
-
requirement
pyridoxal 5'-phosphate
-
requirement
pyridoxal 5'-phosphate
-
2 mol per mol of tetrameric enzyme
pyridoxal 5'-phosphate
-
Lys119 is eesential for the formation of the internal aldimine with pyridoxal 5'-phosphate
pyridoxal 5'-phosphate
-
4 pyridoxal phosphate molecules per tetramer
pyridoxal 5'-phosphate
-
forms a series of intermediates during the reaction, gem-diamine and external aldimine of aminoacrylate are the primary intermediates in the forward half-reaction with L-serine and the external aldimine of aminoacrylate or its complex with L-homocysteine is the primary intermediate in the reverse half-reaction with L-cystathionine
pyridoxal 5'-phosphate
-
reacts with L-allothreonine to form a stable 3-methyl aminoacrylate intermediate
pyridoxal 5'-phosphate
-
dependent
pyridoxal 5'-phosphate
-
-
pyridoxal 5'-phosphate
-
dependent
pyridoxal 5'-phosphate
-
dependent
pyridoxal 5'-phosphate
-
Km-value for wild-type enzyme: 0.00118 mM, KM-value for mutant enzyme I278T: 0.00084 mM, KM-value for mutant enzyme R266K: 0.00339 mM
pyridoxal 5'-phosphate
-
CBS is a pyridoxal 5'-phosphate-dependent enzyme
pyridoxal 5'-phosphate
-
i.e. PLP, serves in the catalytic chemistry of CBS via a well-established mechanism
pyridoxal 5'-phosphate
Q9YCN5
-
pyridoxal 5'-phosphate
-
-
pyridoxal 5'-phosphate
Q9VRD9
-
pyridoxal 5'-phosphate
-
dependent on
S-adenosyl-L-methionine
-
activation
S-adenosyl-L-methionine
-
allosterical regulation, increase of the enzyme's affinity for homocysteine
S-adenosyl-L-methionine
-
stimulates
S-adenosyl-L-methionine
-
-
additional information
-
heme is no cofactor
-
additional information
-
no dependence on heme
-
additional information
-
yeast cystathionine beta-synthase does not have a heme cofactor
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
-
contains 0.38 Ca atoms/subunit
Co2+
-
97.1% Fe2+ and 2.9% Co2+ in wild-type FeCBS enzyme, 8% Fe2+ and 92% Co2+ in the CoCBS enzyme variant
Co3+
-
cobalt-substituted variant of hCBS, i.e. Co hCBS, in which CoPPIX replaces FePPIX, i.e. heme. Co(III) hCBS is a unique Co-substituted heme protein: the Co(III) ion is 6-coordinate, low-spin, diamagnetic, and bears a cysteine(thiolate) as one of its axial ligands. Electronic absorption and MCD spectra of the Co-substituted heme protein, overview. Co(III) hCBS is slowly reduced to Co(II) hCBS, which contains a 5-coordinate, low-spin, S = 1/2 Co-porphyrin that does not retain the cysteine(thiolate) ligand. This form of Co(II)hCBS binds NO but not CO. Co(II) hCBS is reoxidized in the air to form a new Co(III) form, which does not contain a cysteine(thiolate) ligand. Maintaining the native heme ligation motif of wild-type Fe hCBS (Cys/His) is essential in maintaining maximal activity in Co hCBS
Fe
-
contains 0.67 Fe atoms/subunit, in minimal medium
Fe
-
contains 0.13 Fe atoms/subunit
Fe2+
-
ferrous human cystathionine beta-synthase loses activity during enzyme assay due to a ligand switch process
Fe2+
-
contains 0.16 Fe atoms/subunit
Fe2+
-
heme enzyme, 97.1% Fe2+ and 2.9% Co2+ in wild-type FeCBS enzyme, 8% Fe2+ and 92% Co2+ in the CoCBS enzyme variant
Fe2+
-
wild-type FePPIX, i.e. heme
Zn
-
contains 0.17 Zn atoms/subunit, in minimal medium
Zn
-
contains 0.25 Zn atoms/subunit
Zn2+
-
contains 0.35 Zn atoms/subunit
Fe3+
-
-
additional information
-
Na+, K+, Li+, Ca2+, Mg2+, Zn2+, Co2+, no effect on activity
additional information
-
construction of a cobalt CBS, CoCBS, by metalloporphyrin replacement, which results in a high yield of fully active, high purity enzyme, in which heme is substituted by Co-protoporphyrin IX, CoPPIX. the enzyme contains 92% cobalt and 8% iron. CoCBS is indistinguishable from wild-type FeCBS in its activity, tetrameric oligomerization, PLP saturation and responsiveness to the allosteric activator, S-adenosyl-L-methionine
additional information
-
maintaining the native heme ligation motif of wild-type Fe hCBS (Cys/His) is essential in maintaining maximal activity in Co hCBS
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Amino-oxyacetate
-
complete inhibition at 0.05 mM
aminooxyacetic acid
-
-
beta-chloro-L-alanine
-
-
Bithionol
-
-
carbon monoxide
-
-
carbon monoxide
-
binds to the prosthetic heme, stabilizing 6-coordinated CO-Fe(II)-histidine complex to block the activity
CO
-
reversible competitive with respect to homocysteine, complete loss of activity at 0.06 mM
CO
-
can bind to the cofactor heme, resulting in enzyme inhibition. CBS exhibits strong anticooperativity in CO binding
CO
-
CO binding is found to induce a tautomeric shift of the pyridoxal 5'-phosphate from the ketoenamine to the enolimine form. The ketoenamine is key to pyridoxal 5'-phosphate reactivity because its imine C-N bond is protonated, facilitating attack by the nucleophilic substrate, serine
Co3+
-
Co3+ has 30-60% of the specific activity of Fe3+-CBS
cyanide
-
-
Dichlorophene
-
-
Dithionite
-
2fold decrease in enzyme activity due to altered oxidation state of the heme
Hexachlorophene
-
-
Hg2+
-
reactivity of Co(III) hCBS with HgCl2 is consistent with a loss of the cysteine(thiolate) ligand. 2-Mercaptoethanol is unable to reverse the Hg-induced ligand switch, in contrast to some other heme-thiolate proteins
HgCl2
-
inhibits enzyme activity by interacting with the heme
HgCl2
-
-
hydroxylamine
-
-
hydroxylamine
-
-
hydroxylamine
-
-
hydroxylamine
-
complete inhibition at 1 mM
iodoacetate
-
-
L-cystathione
-
product inhibition
L-homocysteine
-
substrate inhibition
nitric oxide
-
-
nitric oxide
-
irreversible inhibition
NO
-
inhibits full length enzyme
p-chloromercuribenzoate
-
-
peroxynitrite
-
exposure to peroxynitrite does not modify bound pyridoxal 5'-phosphate but leads to nitration of Trp208, Trp43 and Tyr223 and alterations in the heme environment including loss of thiolate coordination, conversion to high-spin and bleaching, with no detectable formation of oxoferryl compounds nor promotion of one-electron processes
regulatory domain
-
exerts an inhibitory effect on the enzyme, deletion is correlated with a 1fold increase in catalytic activity
-
titanium citrate
-
2fold decrease in enzyme activity due to altered oxidation state of the heme
-
Mn3+
-
Mn3+ has 30-60% of the specific activity of Fe3+-CBS
additional information
-
the CBS activity is significantly reduced in kidneys subjected to ischemia alone (15-60 min) or subjected to ischemia followed by reperfusion for 1-24 h, injection of alkaline solution into the kidney partially restores the CBS activity during ischemia, reduction of CBS activity during reperfusion is accompanied by an elevation of nitrate and nitrite in the kidney tissue, injection of 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide restores the CBS activity in the kidneys subjected to ischemia-reperfusion
-
additional information
-
the alternation of heme environment inactivates the enzyme
-
additional information
-
not inhibited by nitric oxide
-
additional information
-
taurine activates some cystathionine beta-synthase mutants slightly, while it slightly inhibits the wild-type enzyme and other cystathionine beta-synthase mutants
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
AdoMet
-
allosteric regulator, 1mol per mole of monomeric subunit activates the enzyme 2fold
betaine
-
activates, effects on wild-type and mutant enzymes, overview
delta-aminolevulinic acid
-
activates, effects on wild-type and mutant enzymes, overview
Ethionine
-
i.e. 2-amino-4-(ethylthio)butyric acid, an methionine analogue, which is converted to S-adenosyl-ethionine in vivo and activates CBS, treatment increased liver CBS activity 4.0fold in wild-type mice
glycerol
-
activates, effects on wild-type and mutant enzymes, overview
pyridoxal 5'-phosphate
-
-
S-adenosyl-L-methionine
-
activates full length enzyme, but not the truncated core, 4 S-adenosyl-L-methionine molecules per tetramer
S-adenosyl-L-methionine
-
induces conformational change
S-adenosyl-L-methionine
-
activates 2fold
S-adenosyl-L-methionine
-
2fold activation, allosteric regulator
S-adenosyl-L-methionine
-
3fold activation, allosteric regulator of the full length enzyme, does not activate the truncated enzyme
S-adenosyl-L-methionine
-
3fold activation, allosteric regulator
S-adenosyl-L-methionine
-
stimulates
S-adenosyl-L-methionine
-
activates
S-adenosyl-L-methionine
-
the enzyme is allosterically activated by S-adenosyl-L-methionine under normal conditions but is destabilized under pathological conditions
S-adenosyl-L-methionine
-
about 4fold increase of specific activity in the presence of 0.25 mM S-adenosyl-L-methionine
S-adenosyl-L-methionine
-
allosteric activation
S-adenosyl-L-methionine
-
activity increases in the presence of
S-adenosyl-L-methionine
-
allosteric activator
S-adenosyl-L-methionine
-
-
S-adenosyl-L-methionine
-
allosteric activator. Binding of AdoMet to wild-type CBS moderately increases the protein stability toward urea, while it does not influence the unfolding cooperativity
S-adenosyl-L-methionine
-
activates CBS by 13.6fold in Hep-G2 cell lysate
S-adenosyl-L-methionine
-
-
S-adenosyl-L-methionine
-
an allosteric activator
S-adenosyl-L-methionine
Q9VRD9
structure of the regulatory, energy-sensing CBS domains and mechanism for allosteric activation by S-adenoyl-L-methionine, overview
S-adenosyl-L-methionine
-
the addition of S-adenosyl-L-methionine nearly doubles enzyme activity
S-adenosyl-L-methionine
-
-
S-adenosyl-L-methionine
-
the enzyme is allosterically activated (2-3fold) by S-adenosyl-L-methionine
S-adenosylhomocysteine
-
stimulates activity 1.1fold at 0.48 mM
sinefungin
-
stimulates activity 1.28fold at 1 mM
sodium nitroprusside
-
enhances activity by interacting with cysteine residues, N-ethylmaleimide abolishes this effect
tumor necrosis factor-alpha
-
leads to cleavage of the enzyme to a truncated form and therefore increases the activity, 50% increase of activity after treatment of HepG2 cells for 16 h
-
heme
-
regulatory role
additional information
-
enzyme is more active under oxidizing conditions
-
additional information
-
oxidizing conditions increase the enzyme activity by 2fold
-
additional information
-
enzyme is not dependent on heme
-
additional information
-
enzyme can not be activated by S-adenosyl-L-methionine
-
additional information
-
S-adenosyl-L-methionine does not activate
-
additional information
-
treatment with 0.2 M trimethylamine-N-oxide results in rescuing expression as well as activity of CBS to 82% of human wild type CBS produced in a yeast heme-deficient strain
-
additional information
-
taurine activates some cystathionine beta-synthase mutants slightly, while it slightly inhibits the wild-type enzyme and other cystathionine beta-synthase mutants
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1.72
2-mercaptoethanol
-
-
5.58
2-mercaptoethanol
-
-
24
2-mercaptoethanol
-
-
24
2-mercaptoethanol
-
cosubstrate L-Cys
5.6
cysteamine
-
pH 8.0, 37C, UV assay
6.6
cysteamine
-
pH 8.0, 37C, Mudd assay
68
DL-homocysteine
-
cosubstrate L-Ser
0.05
homocysteine
-
S466L mutant, 37C, absence of S-adenosyl-L-methionine
0.08
homocysteine
-
wild-type enzyme, 37C, presence of S-adenosyl-L-methionine
0.1
homocysteine
-
I435T mutant, 37C, absence of S-adenosyl-L-methionine
0.17
homocysteine
-
wild-type enzyme, 37C, absence of S-adenosyl-L-methionine
0.2
homocysteine
-
I435T mutant, 37C, presence of S-adenosyl-L-methionine
0.59
homocysteine
-
-
0.8
homocysteine
-
enzyme composed of MW 48000 subunits
1.1
homocysteine
-
absence of S-adenosyl-L-methionine
1.2
homocysteine
-
37C, L-serine pre-treatment
2
homocysteine
-
37C, pH 8.6, mutant enzyme I278T
2.2
homocysteine
-
37C
2.25
homocysteine
-
-
2.3
homocysteine
-
37C, homocysteine pre-treatment
3.41
homocysteine
-
enzyme form beta
3.98
homocysteine
-
enzyme form alpha
4.8
homocysteine
-
absence of S-adenosyl-L-methionine, recombinant enzyme
5
homocysteine
-
presence of S-adenosyl-L-methionine, recombinant enzyme
5
homocysteine
-
pH 6.8, 37C, full length enzyme after L-serine pre-treatment
7.17
homocysteine
-
37C, pH 8.6, mutant enzyme R266K; 37C, pH 8.6, wild-type enzyme
9.7
homocysteine
-
pH 6.8, 37C, deltaC143 mutant after L-serine pre-treatment
15
homocysteine
-
pH 6.8, 37C, full length enzyme after homocysteine pre-treatment
18
homocysteine
-
-
18
homocysteine
-
cosubstrate L-Ser
25
homocysteine
-
enzyme composed of MW 68000 subunits
67
homocysteine
-
pH 6.8, 37C, deltaC143 mutant after homocysteine pre-treatment
0.13
L-Cys
-
-
0.21
L-Cys
-
-
36
L-Cys
-
cosubstrate 2-mercaptoethanol
0.083
L-cystathionine
-
pH 8.6, 37C, reverse reaction
0.13
L-cystathionine
-
recombinant 6-His-tagged enzyme, in 50 mM Tris (pH 8.6), at 25C
0.14
L-cystathionine
-
reverse reaction (L-cystathionine hydrolysis), wild-type
0.9
L-cystathionine
-
reverse reaction (L-cystathionine hydrolysis), mutant S289A
2
L-cysteine
-
wild-type
3.59
L-cysteine
-
37C, pH 8.6, mutant enzyme I278T
4.3
L-cysteine
-
37C, pH 8.6, mutant enzyme R266K
4.4
L-cysteine
-
mutant R266K
5.4
L-cysteine
-
mutant H67A
5.5
L-cysteine
-
mutant R266K
6.11
L-cysteine
-
pH 8.6
6.11
L-cysteine
-
37C, pH 8.6, wild-type enzyme
0.16
L-homocysteine
-
mutant S289A
0.21
L-homocysteine
-
wild-type
0.3
L-homocysteine
-
pH 8.6, 37C
0.43
L-homocysteine
-
recombinant 6-His-tagged enzyme, in 50 mM Tris (pH 8.6), at 25C
1
L-homocysteine
-
37C, pH 8.0, wild-type enzyme, with S-adenosyl-L-methionine
1.04
L-homocysteine
-
37C, pH 8.0, wild-type enzyme, without S-adenosyl-L-methionine
1.1
L-homocysteine
-
mutant enzyme S466L, in the presence of 0.25 mM S-adenosyl-L-methionine
1.3
L-homocysteine
-
mutant R266K
1.6
L-homocysteine
-
mutant R266K
2.5
L-homocysteine
-
wild type enzyme, in the presence of 0.25 mM S-adenosyl-L-methionine
3.4
L-homocysteine
-
mutant H67A
3.7
L-homocysteine
-
pH 8.0, 37C
5
L-homocysteine
-
wild-type
0.91
L-Ser
-
-
1.15
L-Ser
-
-
1.6
L-Ser
-
-
2
L-Ser
-
no influence of S-adenosyl-L-methionine, recombinant enzyme
3.1
L-Ser
-
absence of S-adenosyl-L-methionine
4
L-Ser
-
-
6
L-Ser
-
value is reduced 8fold by S-adenosyl-L-methionine
8
L-Ser
-
-
0.7
L-serine
-
wild-type
0.77
L-serine
-
mutant enzyme S466L, in the presence of 0.25 mM S-adenosyl-L-methionine
0.78
L-serine
-
wild type enzyme, in the presence of 0.25 mM S-adenosyl-L-methionine
1.2
L-serine
-
pH 8.6, 37C
1.2
L-serine
-
pH 8.0, 37C, reaction with cysteamine, continous UV assay
1.41
L-serine
-
37C, pH 8.0, wild-type enzyme, without -adenosyl-L-methionine
1.41
L-serine
-
37C, pH 8.6, mutant enzyme I278T
1.74
L-serine
-
pH 8.6
1.74
L-serine
-
37C, pH 8.6, wild-type enzyme
2
L-serine
-
pH 6.8, 37C, full length enzyme after L-serine pre-treatment
2.13
L-serine
-
37C, pH 8.0, wild-type enzyme, with S-adenosyl-L-methionine
2.2
L-serine
-
37C
2.2
L-serine
-
pH 8.0, 37C, reaction with cysteamine, Mudd assay
2.76
L-serine
-
37C, pH 8.6, mutant enzyme R266K
3.5
L-serine
-
37C, homocysteine pre-treatment
3.6
L-serine
-
wild-type enzyme, 37C, presence of S-adenosyl-L-methionine
4.2
L-serine
-
I435T mutant, 37C, absence of S-adenosyl-L-methionine
4.5
L-serine
-
I435T mutant, 37C, presence of S-adenosyl-L-methionine
4.9
L-serine
-
wild-type enzyme, 37C, absence of S-adenosyl-L-methionine
4.9
L-serine
-
37C, L-serine pre-treatment
4.9
L-serine
-
pH 8.0, 37C, reaction with L-homocysteine
5
L-serine
-
recombinant 6-His-tagged enzyme, in 50 mM Tris (pH 8.6), at 25C
5.5
L-serine
-
pH 6.8, 37C, full length enzyme after homocysteine pre-treatment
7.2
L-serine
-
S466L mutant, 37C, absence of S-adenosyl-L-methionine
14
L-serine
-
pH 6.8, 37C, deltaC143 mutant after homocysteine pre-treatment
18
L-serine
-
pH 6.8, 37C, deltaC143 mutant after L-serine pre-treatment
27.1
L-serine
-
mutant S289A
additional information
additional information
-
pre-steady-state kinetic analysis of enzyme-monitored turnover during cystathionine beta-synthase-catalyzed H2S generation, overview
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
5.9
homocysteine
-
I435T mutant, 37C, absence of S-adenosyl-L-methionine
6.2
homocysteine
-
wild-type enzyme, 37C, absence of S-adenosyl-L-methionine
7.38
homocysteine
-
-
15.5
homocysteine
-
S466L mutant, 37C, absence of S-adenosyl-L-methionine
32.1
homocysteine
-
I435T mutant, 37C, presence of S-adenosyl-L-methionine
34
homocysteine
-
wild-type enzyme, 37C, presence of S-adenosyl-L-methionine
0.0045
L-cystathionine
-
reverse reaction (L-cystathionine hydrolysis), mutant S289A
0.083
L-cystathionine
-
S82A mutant, pH 8.6, 37C
0.133
L-cystathionine
-
T85A mutant, pH 8.6, 37C
0.418
L-cystathionine
-
Y158F mutant, pH 8.6, 37C
0.56
L-cystathionine
-
pH 8.6, 37C
0.56
L-cystathionine
-
wild-type enzyme, pH 8.6, 37C
1.03
L-cystathionine
-
reverse reaction (L-cystathionine hydrolysis), wild-type
6.08
L-cystathionine
-
pH 8.6, 37C
6.08
L-cystathionine
-
wild-type enzyme, pH 8.6, 37C
0.04
L-cysteine
-
37C, pH 8.6, mutant enzyme I278T
1.95
L-cysteine
-
37C, pH 8.6, mutant enzyme R266K
3.13
L-cysteine
-
pH 8.6
3.13
L-cysteine
-
37C, pH 8.6, wild-type enzyme
4.39
L-cysteine
-
pH 8.6
4.39
L-cysteine
-
37C, pH 8.6, wild-type enzyme
0.024
L-homocysteine
-
recombinant 6-His-tagged enzyme, in 50 mM Tris (pH 8.6), at 25C
0.031 - 0.51
L-homocysteine
-
37C, pH 8.6, wild-type enzyme
0.04 - 1.97
L-homocysteine
-
37C, pH 8.6, mutant enzyme R266K
0.09
L-homocysteine
-
37C, pH 8.6, mutant enzyme I278T
0.85
L-homocysteine
-
cosubstrate: L-serine, mutant S289A
3.3
L-homocysteine
-
37C, pH 8.0, wild-type enzyme, without S-adenosyl-L-methionine
4.66
L-homocysteine
-
37C, pH 8.0, wild-type enzyme, without S-adenosyl-L-methionine
7.93
L-homocysteine
-
37C, pH 8.6, wild-type enzyme
9.06
L-homocysteine
-
37C, pH 8.6, mutant enzyme R266K
12.7
L-homocysteine
-
37C, pH 8.0, wild-type enzyme, with S-adenosyl-L-methionine
17
L-homocysteine
-
cosubstrate: L-serine, wild-type
21.5
L-homocysteine
-
pH 8.6, 37C
0.052 - 2.1
L-serine
-
37C, pH 8.6, wild-type enzyme
0.082
L-serine
-
Q157H mutant, pH 8.6, 37C
0.15
L-serine
-
37C, pH 8.6, mutant enzyme I278T
0.45
L-serine
-
T81A mutant, pH 8.6, 37C
0.52
L-serine
-
37C, pH 8.0, wild-type enzyme, with S-adenosyl-L-methionine
0.85
L-serine
-
cosubstrate: L-homocysteine, mutant S289A
1.3
L-serine
-
pH 8.0, 37C, reaction with cysteamine, continous UV assay
1.67
L-serine
-
recombinant 6-His-tagged enzyme, in 50 mM Tris (pH 8.6), at 25C
2.5
L-serine
-
pH 8.0, 37C, reaction with cysteamine, Mudd assay
2.9
L-serine
-
37C, pH 8.6, mutant enzyme R266K
3.67
L-serine
-
37C, pH 8.0, wild-type enzyme, without S-adenosyl-L-methionine
5.3
L-serine
-
S82A mutant, pH 8.6, 37C
5.4
L-serine
-
wild-type enzyme, 37C, absence of S-adenosyl-L-methionine
5.9
L-serine
-
I435T mutant, 37C, absence of S-adenosyl-L-methionine
7.5
L-serine
-
pH 8.0, 37C, reaction with L-homocysteine
7.6
L-serine
-
37C
8.2
L-serine
-
Y158F mutant, pH 8.6, 37C
10.19
L-serine
-
37C, pH 8.6, wild-type enzyme
10.2
L-serine
-
pH 8.6
13.2
L-serine
-
T85A mutant, pH 8.6, 37C
14.01
L-serine
-
37C, pH 8.0, wild-type enzyme, with S-adenosyl-L-methionine
14.6
L-serine
-
S466L mutant, 37C, absence of S-adenosyl-L-methionine
14.7
L-serine
-
37C, L-serine pre-treatment
15.8
L-serine
-
I435T mutant, 37C, presence of S-adenosyl-L-methionine
16.8
L-serine
-
37C, homocysteine pre-treatment
17
L-serine
-
cosubstrate: L-homocysteine, wild-type
19
L-serine
-
pH 6.8, 37C, deltaC143 mutant after L-serine pre-treatment
19.7
L-serine
-
wild-type enzyme, 37C, presence of S-adenosyl-L-methionine
21
L-serine
-
pH 6.8, 37C, full length enzyme after L-serine pre-treatment
21.5
L-serine
-
wild-type enzyme, pH 8.6, 37C
39
L-serine
-
pH 6.8, 37C, full length enzyme after homocysteine pre-treatment
45
L-serine
-
pH 6.8, 37C, deltaC143 mutant after homocysteine pre-treatment
additional information
additional information
-
the kcat for the generation of H2S by cystathionine beta-synthase of 55/s at 37C, via the condensation of cysteine and homocysteine is 18fold faster than that for the beta-elimination and rehydration to form serine of 3/s-
-
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.005
L-cystathionine
-
reverse reaction (L-cystathionine hydrolysis), mutant S289A
585
7.5
L-cystathionine
-
reverse reaction (L-cystathionine hydrolysis), wild-type
585
6.3
L-homocysteine
-
mutant S289A
305
80
L-homocysteine
-
wild-type
305
0.031
L-serine
-
mutant S289A
95
25
L-serine
-
wild-type
95
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
5.6
CO
-
37C under anaerobic conditions
2.3
cyanide
-
37C
2.1
L-homocysteine
-
recombinant 6-His-tagged enzyme, in 50 mM Tris (pH 8.6), at 25C
0.32
NO
-
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.15
peroxynitrite
-
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.045
-
recombinant 6-His-tagged enzyme from crude extract, in 50 mM Tris (pH 8.6), at 25C
0.68
-
without pyridoxal 5'-phosphate, without S-adenosyl-L-methionine, mutant R266M
1.2
-
truncated ferrous mutant enzyme R51A, at 37C and pH 8
1.3
-
full-length ferrous mutant enzyme R224A, at 37C and pH 8; full-length ferrous mutant enzyme R51A, at 37C and pH 8
1.91
-
without pyridoxal 5'-phosphate, without S-adenosyl-L-methionine, mutant R266K
2.2
-
full-length ferric mutant enzyme R224A, at 37C and pH 8; full-length ferric mutant enzyme R51A, at 37C and pH 8
2.3
-
wild-type enzyme
2.31
-
without pyridoxal 5'-phosphate, without S-adenosyl-L-methionine, mutant H67A
2.6
-
-
2.65
-
wild-type enzyme in the presence of S-adenosyl-L-methionine
2.8
-
full-length ferrous wild type enzyme, at 37C and pH 8
3.17
-
recombinant 6-His-tagged enzyme after purification, in 50 mM Tris (pH 8.6), at 25C
3.5
-
-
3.6
-
without pyridoxal 5'-phosphate, without S-adenosyl-L-methionine, wild-type
3.8
-
truncated ferrous mutant enzyme R224A, at 37C and pH 8
3.9
-
with pyridoxal 5'-phosphate, with S-adenosyl-L-methionine, mutant R266M
3.95
-
D144N mutant in the presence of S-adenosyl-L-methionine
4
-
truncated ferric mutant enzyme R51A, at 37C and pH 8
4.6
-
recombinant enzyme
5.2
-
truncated ferric wild type enzyme, at 37C and pH 8
5.2
-
with pyridoxal 5'-phosphate, with S-adenosyl-L-methionine, mutant H67A; with pyridoxal 5'-phosphate, with S-adenosyl-L-methionine, wild-type
5.6
-
-
5.71
-
with pyridoxal 5'-phosphate, with S-adenosyl-L-methionine, mutant R266K
6
-
truncated ferric mutant enzyme R224A, at 37C and pH 8
8
-
truncated ferrous wild type enzyme, at 37C and pH 8
10.3
-
full-length ferric wild type enzyme, at 37C and pH 8
105.2
-
purified recombinant CoCBS, pH 8.6, 37C
additional information
-
continous spectrometric assay for cystathionine beta-synthase
additional information
-
cystathionine synthesis activity of FeCBS and CoCBS
additional information
-
specific activities of wild-type and mutants in presence of activators, overview
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
-
cystathionine beta-synthase assay at
7.9 - 8.3
-
enzyme form alpha
8.3
-
enzyme form beta
8.3
-
wild-type enzyme
8.3
-
assay at
8.4 - 9
-
-
8.5
-
recombinant enzyme
8.5
-
full-length Fe(III)-enzyme and truncated Fe(III) CBS-45
8.5
-
broad, full-length and the C-terminally truncated enzyme (CBS 1-413)
8.6
-
around pH 8.6
9
-
sharp, N- and C-terminally truncated enzyme (BS 71-400)
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
6.5 - 10
-
-
6.5 - 10
-
-
6.5 - 10.5
-
-
6.5 - 9.5
-
activity increases with increasing pH, C52S and H65R mutant
7.2 - 9.3
-
pH 7.2: about 45% of maximal activity, pH 9.3: about 75% of maximal activity, full-length Fe(III)-enzyme and truncated Fe(III) CBS-45
7.3 - 9.5
-
pH 7.3: about 45% of maximal activity, pH 9.5: about 80% of maximal activity, full-length and the C-terminally truncated enzyme (CBS 1-413)
8.3 - 9.5
-
pH 8.3: about 45% of maximal activity, pH 9.5: about 85% of maximal activity N- and C-terminally truncated enzyme (BS 71-400)
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
-
assay at
37
-
assay at
37
-
cystathionine beta-synthase assay at
37
-
assay at
additional information
-
wild-type CBS is therminally activated at 55C
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
cystathionine beta-synthase is associated with the generation and/or differentiation of the radial glia/astrocyte lineage cells in the developing central nervous system
Manually annotated by BRENDA team
-
hyperhomocysteinaemia is a metabolic disorder associated with the development of premature atherosclerosis. Cystathionine beta-synthase activity is significantly decreased in mice with a plasma homocysteine value greater than 0.015 mg
Manually annotated by BRENDA team
-
cystathionine beta-synthase is enriched in the brains of Down's syndrome patients
Manually annotated by BRENDA team
-
cystathionine beta-synthase is associated with the generation and/or differentiation of the radial glia/astrocyte lineage cells in the developing central nervous system
Manually annotated by BRENDA team
-
highest cystathionine beta-synthase protein presence in cornea, conjunctiva and iris, followed by retina and optic nerve. Cystathionine beta-synthase may be a oxidative defense enzyme in the eye tissue, in particular in the segments of the eye where constant environmental oxidative stress is imposed
Manually annotated by BRENDA team
-
reduced cystathionine beta-synthase
Manually annotated by BRENDA team
-
cystathionine beta-synthase activity is indistinguishable in females and males
Manually annotated by BRENDA team
-
higher cystathionine beta-synthase activity in females versus males
Manually annotated by BRENDA team
-
higher cystathionine beta-synthase activity in males versus females
Manually annotated by BRENDA team
-
ubiquitously expressed in the ovary with the strongest expression in follicular cells at all stages. In late antral follicles, cystathionine beta-synthase expression is markedly higher in granulosa cells located close to the antrum and in cumulus cells around the oocyte
Manually annotated by BRENDA team
-
cystathionine beta-synthase activities in wild-type individuals, and in hetero-, and homozygote cystathionine beta-synthase mutants, overview
Manually annotated by BRENDA team
-
found in somas in the inner nuclear layer and as punctate staining in the inner and outer plexiform layers in the salamander retina
Manually annotated by BRENDA team
-
highest activity
Manually annotated by BRENDA team
additional information
-
absent in the oocytes
Manually annotated by BRENDA team
additional information
-
no cystathionine beta-synthase activity in retina
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
sumoylated CBS is present in the nucleus where it is associated with the nuclear scaffold
Manually annotated by BRENDA team
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
36800
-
gel filtration
681468
38000
-
gel filtration
681468
45000
-
the protein is an active and stable dimer of 45 kDa subunits
701929
45000
-
molecular weight of the truncated protein lacking the C-terminal domain
704177
50000 - 130000
-
existence in multiple molecular forms of MW 50000-130000, 235000, 500000, gel filtration
5588
62800
-
gel filtration
681468
63000
-
His-tagged enzyme, SDS-PAGE
701064
70000
-
gel filtration, truncated enzyme, dimer
649915
94000
-
gel filtration
5587
100000
-
aged enzyme extract, gel filtration
5585
115000
-
aged enzyme extract, gel filtration
5598
119000
-
fresh enzyme extract, gel filtration
5598
235000
-
existence in multiple molecular forms of MW 50000-130000, 235000, 500000, gel filtration
5588
235000
-
gel filtration
5599
250000
-
fresh enzyme extract, gel filtration
5585
250000
-
gel filtration
5591
250000
-
fresh enzyme extract, gel filtration
5594
288000
-
fresh and aged enzyme extract, gel filtration
5598
290000
-
fresh enzyme extract, gel filtration
5598
400000
-
gel filtration, truncated enzyme, octamer
649915
486000
-
octamer, gel filtration
650017
500000
-
existence in multiple molecular forms of MW 50000-130000, 235000, 500000, gel filtration
5588
1330000
-
multimer, gel filtration
650017
additional information
-
high tendency for aggregation
5600
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
?
-
x * 55000, SDS-PAGE
?
-
x * 55000, SDS-PAGE
?
-
x * 63000, SDS-PAGE
?
-
x * 65000, SDS-PAGE
?
-
x * 68000, SDS-PAGE
dimer
-
-
dimer
-
2 * 48000, proteolytically activated enzyme, derived from 4 * 68000 enzyme, SDS-PAGE
dimer
-
2 * 48000, proteolytically activated enzyme, derived from 4 * 68000 enzyme, SDS-PAGE
dimer
-
after deletion of the C-terminal regulatory domain
dimer
-
truncated catalytic core
dimer
-
truncated enzyme
dimer
-
truncated form of the enzyme
dimer
-
2 * 19700, calculated from sequence
dimer
-
2 * 20300, calculated from sequence
dimer
-
2 * 45000 Da, truncated human CBS lacking 143 amino acids at the C-terminus
homodimer
-
truncated CBS, X-ray crystallography
homotetramer
-
-
homotetramer
-
4 * 61000
multimer
-
wild-type enzyme and I435T mutant, gel filtration
octamer
-
full-length enzyme is a mixture of tetramer and octamer
octamer
-
homooctamer
octamer
-
wild-type enzyme and I435T mutant, gel filtration
oligomer
-
full length subunits for tetramers and higher oligomers
tetramer
-
-
tetramer
-
SDS-PAGE
tetramer
-
4 * 55000, SDS-PAGE
tetramer
-
4 * 68000, enzyme from fresh liver extract, SDS-PAGE
tetramer
-
4 * 68000, enzyme from fresh liver extract, SDS-PAGE
tetramer
-
alpha4 homotetramer
tetramer
-
full length subunits for tetramers and higher oligomers
tetramer
-
full-length enzyme is a mixture of tetramer and octamer
tetramer
-
native enzyme
tetramer
-
native gel Western blot
trimer
-
3 * 20200, calculated from sequence
homotetramer
-
4 * 63000
additional information
-
mutant enzymes K102N and P78R/K102N behaves like wild-type enzyme by native gel chromatography and exist as a mixture of higher-order quaternary states
additional information
-
CBS protein comprises three regions: the N-terminal heme-binding domain, residues 1-69, a highly conserved catalytic core, residues 70-413, and the C-terminal regulatory domain, resdiues 414-551, and an autoinhibitory module with binding site for the allosteric activator, S-adenosyl-L-methionine. Computational modeling of CBS structure, the enzyme has a regulatory dimer-dimer interface, homology modeling and protein-protein docking, overview. Model of wild-type CBS dimer by docking of a single C-terminal regulatory domain to mutant 45CBS dimer, PDB ID 1JBQ, and surface mapping of wild-type CBS and mutant 45CBS with diverse differentially reactive amino acid residues involved in conformational changes and thermal activation, overview
additional information
-
each subunit has a modular structure consisting of three domains: an N-terminal heme binding domain, a highly conserved pyridoxal 5'-phosphate-binding catalytic core, and a S-adenosyl-L-methionine-binding C-terminal regulatory domain
additional information
-
three-dimensional CBS structure and molecular dynamics simulation of folding process in CBS wild-type and mutants, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
proteolytic modification
-
trypsinolyis occurs initially at Lys30, Lys36, Lys39, then at Arg413 and transforms the tetrameric enzyme to a dimer of MW 85000 which is twice as active as the tetramer
sumoylation
-
CBS is modified by the small ubiquitin-like modifier-1 protein (SUMO-I) under both in vitro and in vivo conditions. Deletion analysis of CBS indicates that the C-terminal regulatory domain is required for interaction with proteins in the sumoylation machinery. Sumoylated CBS is present in the nucleus where it is associated with the nuclear scaffold
proteolytic modification
-
the tetrameric enzyme, MW 4 * 68000, is processed to a dimeric (2 * 48000) enzyme by proteolysis, 60fold increase of activity
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
hanging drop vapour diffusion method, 100 mM phosphate-acetate pH 4.2, 200 mM NaCl and 20% (w/v) PEG 8000
-
enzyme free or in complex with a carbanion and an aminoacrylate intermediate, X-ray diffraction structure determination and analysis at 1.70 A and 1.55 A resolution, respectively
Q9VRD9
catalytic core, hanging drop vapor diffusion method
-
mutant lacking the S-adenosyl-L-methionine binding site and heme-free crystals, hanging drop vapor diffusion method
-
truncated form
-
with heme and pyridoxal 5'-phosphate, hanging drop vapor diffusion method
-
crystal structures of both mercury- and iron-bound TA0289 (1.52.0 A resolution) reveals a dimeric protein whose intersubunit contacts are formed exclusively by the alpha-helices of two cystathionine beta-synthase subdomains, whereas the C-terminal domain has a classical Zn ribbon planar architecture
-
nanodropletvapor diffusion method, crystal structure of a tandem cystathionine-beta-synthase domain protein (TM0935) from Thermotoga maritima at 1.87 A resolution
-
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
48
-
stable up to
650105
55
-
melting point of wild type and S466L mutant
650017
additional information
-
dissociation of tetrameric enzyme to dimeric form, initiated by proteolysis decreases thermostability
5604
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
2-mercaptoethanol stabilizes
-
binding of S-adenosyl-L-methionine stabilizes cystathionine beta-synthase against degradation. Under pathological conditions with reduced levels of S-adenosyl-L-methionine (human hepatocellular carcinoma), level of cystathionine beta-synthase is diminished. This decrease in cystathionine beta-synthase level correlates with reduced glutathione that is, in turn, associated with increased vulnerability to oxidative stress. Posttranslational regulation of cystathionine beta-synthase stability by S-adenosyl-L-methionine provides a mechanism for achieving coordinate changes in cellular methylation and antioxidant status that is observed in a number of disease states
-
high protein concentration stabilizes
-
lyophilization inactivates
-
binding of S-adenosyl-L-methionine stabilizes cystathionine beta-synthase against degradation. Under pathological conditions with reduced levels of S-adenosyl-L-methionine (mouse model for chronic steatohepatitis), level of cystathionine beta-synthase is diminished. This decrease in cystathionine beta-synthase level correlates with reduced glutathione that is, in turn, associated with increased vulnerability to oxidative stress. Posttranslational regulation of cystathionine beta-synthase stability by S-adenosyl-L-methionine provides a mechanism for achieving coordinate changes in cellular methylation and antioxidant status that is observed in a number of disease states
-
inactivation by aging
-
2-mercaptoethanol stabilizes
-
high protein concentration stabilizes
-
lyophilization inactivates
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-15C, 40% glycerol, 5 weeks stable
-
-20C, 0.1 M Tris-HCl buffer, pH 7.5, 0.1 mM pyridoxal 5'-phosphate
-
-80C, potassium phosphate buffer, pH 6.5, 1 mM 2-mercaptoethanol, 3 years, no loss of activity
-
-20C, 0.02 M potassium phosphate buffer, pH 7.8, 1 mM EDTA, 1 month stable
-
-20C, potassium phosphate buffer, pH 7.8, EDTA
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
glutathione-linked resin chromatography, HiTrap Q Fast Flow column chromatography, GST-Sepharose column chromatography, and Superose 12 gel-filtration
-
CBSdeltaC143
-
full length enzyme exhibits a strong tendency toward aggregation during the course of purification as well as in the purified state
-
full length protein and truncated variant lacking 143 amino acid residues at the C-terminus
-
glutathione-Sepharose column chromatography
-
GST Trap FF column chromatography and Mono Q column chromatography
-
Ni-NTA column chromatography
-
recombinant GST-tagged wild-type and Co-subsituted CBS from Escherichia coli strain Rosetta 2 (DE3) by glutathione affinity and anion exchange chromatography
-
recombinant mutant 45CBS and wild-type CBS from Escherichia coli to homogeneity
-
truncated human CBS lacking 143 amino acids at the C-terminus is purified as a fusion protein with glutathione S-transferase using the Escherichia coli expression vector pGEXCBSN. The protein is purified through affinity chromatography with glutathione sepharose and anion exchange chromatography. The glutathione Stransferase tag was cleaved by limited proteolysis using thrombin
-
two patient-derived forms S466L and I435T, 95% purity
-
using a glutathione sepharose column
-
wild type and truncated human cystathionine beta-synthase expressed in Escherichia coli
-
N-terminal cystathionine beta-synthase domain fused to the C-terminal Zn ribbon domain overexpressed in Escherichia coli
-
recombinant cystathionine beta-synthase from Escherichia coli strain BL21(DE3) by anion exchange and hydroxyapatite chromatography
-
using Ni-NTA chromatography
-
N-terminal cystathionine beta-synthase domain fused to the C-terminal Zn ribbon domain overexpressed in Escherichia coli
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
CDCP2 is expressed in Escherichia coli BL21 (DE3) cells, selenomethionine-substituted CDCP2 is expressed using B834 (DE3) cells
-
a mutant form of the human cystathionine beta-synthase protein, I278T, is expressed in Saccharomyces cerevisiae
-
eight CBS mutants are expressed in Escherichia coli in the presence of chemical chaperones such as ethanol, dimethyl sulfoxide, or trimethylamine-N-oxide
-
expressed as a GST-fusion protein in Escherichia coli
-
expressed in Escherichia coli
-
expressed in Escherichia coli BL21(DE3) cells
-
expressed in Escherichia coli strain DH10B
-
expressed in heme-deficient strains of Saccharomyces cerevisiae and Escherichia coli
-
expression in Escherichia coli
-
expression in yeast or in Escherichia coli
-
expression of human mutant CBS proteins in Saccharomyces cerevisiae reveals that the disease causing mutation severely inhibits enzyme activity and cannot support growth of yeast on cysteine-free media. The osmolyte chemical chaperones glycerol, trimethylamine-N-oxide, dimethylsulfoxide, proline or sorbitol, when added to yeast media, allows growth on cysteine-free media and causes increased enzyme activity from I278T mutant protein. The increase in enzyme activity is associated with stabilization of the tetramer form of the enzyme. This effect is not specific to yeast, as addition of the chaperone glycerol results in increased I278T activity when the enzyme is produced either in Escherichia coli or in a coupled in vitro transcription/translation reaction. No stimulation of specific activity is observed when chaperones are added directly to purified I278T indicating that the presence of chemical chaperones is required during translation
-
expression of mutant 45CBS and wild-type CBS in Escherichia coli
-
expression of wild type and truncated human cystathionine beta-synthase enzyme in Escherichia coli
-
expression of wild-type and Co-subsituted CBS as GST-tagged enzymes in Escherichia coli strain Rosetta 2 (DE3)
-
full-length CBS and truncated enzyme containing residues 1-397 are expressed in Escherichia coli BL21 cells
-
fusion protein with glutathione S-transferase
-
genotyping of wild-type and mutant CBSs, determination of mutations in patients with homocystinuria due to CBS deficiency, overview
-
in a recombinant expression system (pGEX4T1/hCBSDELTAC143) that produces a fusion protein with glutathione S-transferase
-
mutant enzymes K102N, P78R and P78R/K102N are expressed in Escherichia coli and purified as glutathione S-transferase fusion proteins using recombinant expression
-
the truncated human CBS enzyme consisting of residue 1-397 is expressed in the glutathione S-transferase fusion expression system
-
transgenic mice that contain the human cystathionine beta-synthase cDNA under control of the zinc-inducible metallothionein promoter (Tg-CBS). In the presence of zinc, Tg-CBS mice have a 2fold to 4fold increase in liver and kidney cystathionine beta-synthase activity compared with nontransgenic littermates
-
truncated form fused with glutathione S-transferase
-
truncated human CBS lacking 143 amino acids at the C-terminus is expressed as a fusion protein with glutathione S-transferase in the Escherichia coli
-
truncated protein lacking the C-terminal domain is expressed
-
wild type enzyme is expressed in Mus musculus and mutant enzyme S466L is expressed in Saccharomyces cerevisiae strain WY35 and in Mus musculus
-
N-terminal cystathionine beta-synthase domain fused to the C-terminal Zn ribbon domain is overexpressed in Escherichia coli
-
expression in CHO/duk- cell line
-
a truncated form of CBS comprising the catalytic core is used for mutational analysis
-
CBS gene encoding the truncated yCBS (residues 1-353), lacking the regulatory domain, is expressed with a C-terminal, 6-His affinity tag in Escherichia coli
-
expression of cystathionine beta-synthase in Escherichia coli strain BL21(DE3)
-
N-terminal cystathionine beta-synthase domain fused to the C-terminal Zn ribbon domain is overexpressed in Escherichia coli
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
decreased expression after exogenous addition alltrans-retinoic acid
-
expression level of CBS in 120 hepatocellular carcinoma specimens evaluated by RT-PCR is markedly lower than in surrounding non-cancerous liver. Reduced CBS expression is significantly correlated with high tumor stage. A survival analysis shows that a significantly shorter overall survival time is observed in patients with reduced CBS expression
-
butyrate significantly increases CBS protein expression, butyrate-stimulated CBS expression is not changed by trichostatin A
-
protein level and activity increase with incubation time, upon stimulation, and similar to intracellular homocysteine, depending on intra- and extracellular homocysteine and glutathione concentrations
-
the enzyme is overexpressed in primary epithelial ovarian cancer and ovarian cancer cell lines
-
in hemizygous (+/-) CBS knockout mice the remaining CBS monoallele is up-regulated in mice when fed a taurine-deficient diet to produce additional CBS mRNA
-
mice at the unusual age of 28 months even have a higher hippocampal enzyme expression than young mice
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A114V
-
mutation in dimer interface of patients with homocystinurea, variable amounts of residual activity, mutation in the heme binding site of patients with homocystinurea
A114V
-
the presence of a chemical chaperone (ethanol, dimethyl sulfoxide, or trimethylamine-N-oxide) in the medium during expression increases the mutant CBS activity in Escherichia coli crude extracts at least equal to wild-type, mutants show significant change in the level of active CBS tetramers in the presence of chaperones, mutant responds to a S-adenosyl-L-methionine stimulation or heating to 53C with an increased activity
A114V
-
naturally occuring mutant involved in CBS deficiency, three-dimensional CBS structure compared to the wild-type enzyme
A114V
-
site-directed mutagenesis, mutation at the dimer-dimer interface, the mutant shows a decrease in specific activity compared to the wild-type enzyme
A114V
-
the mutant in the active core has slightly increased urea unfolding with decreased stability and shows 76.9% activity compared to the wild type enzyme
A226T
-
mutation in the connecting loop between the N- and C-terminal domain between beta-strand 7 and alpha-helix 6, patients respond to vitamin B6 treatment
A226T
-
mutant exhibits slight rescue with trimethylamine N-oxide and proline, but not glycerol, DMSO, or sorbitol
A331V
-
mutation effects can be suppressed in a yeast assay by the deletion of the regulatory domain of the protein
C15S
-
mutagenesis does not affect catalysis or S-adenosyl-L-methionine activation but significantly reduces aggregation of the purified enzyme in vitro
C165Y
-
the mutation is associated with homocystinuria
C165Y
-
site-directed mutagenesis, the mutant shows an increase in specific activity compared to the wild-type enzyme
C272A
-
2fold lower heme content, 2fold lower specific activity, 2fold higher activity in the presence of S-adenosyl-L-methionine
C274S
-
2fold lower heme content, 2fold lower specific activity, 2fold higher activity in the presence of S-adenosyl-L-methionine
C431S
-
mutagenesis results in a constitutively activated form of CBS that can not be further activated by either S-adenosyl-L-methionine or thermal activation
C52A
-
reduced heme content, pyridoxal phosphate content comparable to wild-type enzyme, low catalytic activity
C52S
-
reduced heme content, pyridoxal phosphate content comparable to wild-type enzyme, low catalytic activity
D234N
-
the mutation is associated with Venezuelan homocystinuria responsive to vitamin B6. The mutant shows 43% activity compared to the wild type enzyme
D376N
-
mutant is not rescuable by any of the chemical chaperones
D444N
-
high level of enzyme activity
D444N
-
mutant is unresponsive to physiological S-adenosyl-L-methionine concentrations, but can be activated in the presence of supraphysiological concentrations
D444N
-
basal activity of the recombinant D444N mutant is 1.5fold higher than that of wild-type enzyme under similar conditions but 1.3fold lower than wild-type enzyme in the presence of S-adenosyl-L-methionine. D444N mutant retains the ability to bind AdoMet albeit with reduced affinity
D444N
-
the mutation is associated with homocystinuria
D444N
-
naturally occuring mutant involved in CBS deficiency, three-dimensional CBS structure compared to the wild-type enzyme
D444N
-
site-directed mutagenesis, the mutant shows altered activity compared to the wild-type enzyme
D444N
-
the mutant shows 97% activity compared to the wild type enzyme when expressed in Escherichia coli
D444N
-
the mutant with substitution in the C-terminal regulatory domain shows increased global stability with decreased flexibility and shows 163.8% activity compared to the wild type enzyme
DELAT143
-
truncated human CBS lacking 143 amino acids at the C-terminus is purified from a recombinant expression system and is used for vibrational coherence spectroscopy
DELTAC
-
studies are carried out using a truncated protein lacking the C-terminal domain. kcat increases by a factor of 4 and the responsiveness to S-adenosyl-L-methionine is lost. The C-terminal domain is involved in the aggregation of the full-length protein, which exists as a mixture of tetramer and higher oligomers, while the 45 kDa truncated form lacking the C-terminal domain is a dimer
DELTAC143
-
a truncated human CBS lacking 143 amino acids at the C-terminus is used to study the inactivation of cystathionine beta-synthase by peroxynitrite
E144K
-
site-directed mutagenesis, inactive mutant
E144K
-
naturally occuring mutant involved in CBS deficiency, three-dimensional CBS structure compared to the wild-type enzyme
E176K
-
mutation in dimer interface of patients with homocystinurea, mutation in dimer interface of patients with homocystinurea, patients do not respond to vitamin B6 treatment, mutant forms high molecular wight aggregates devoid of heme after expression in Escherichia coli
E176K
-
the presence of a chemical chaperone (ethanol, dimethyl sulfoxide, or trimethylamine-N-oxide) in the medium during expression increases the mutant CBS activity in Escherichia coli crude extracts at least equal to wild-type, mutants show significant change in the level of active CBS tetramers in the presence of chaperones, mutant does not respond to a S-adenosyl-L-methionine stimulation or heating to 53C with an increased activity
E176K
-
site-directed mutagenesis, the mutant shows a decrease in specific activity compared to the wild-type enzyme
E302K
-
site-directed mutagenesis, the mutant shows altered activity compared to the wild-type enzyme
E302K
-
the mutant in the active core has slightly increased urea unfolding with decreased stability and shows 95.4% activity compared to the wild type enzyme
G116R
-
mutation in dimer interface of patients with homocystinurea
G148R
-
active site mutation in patients with homocystinurea
G148R
-
site-directed mutagenesis, inactive mutant
G259S
-
active site mutation in patients with homocystinurea
G305R
-
active site mutation in patients with homocystinurea
G305R
-
site-directed mutagenesis, inactive mutant
G307S
-
active site mutation in patients with homocystinurea
G307S
-
site-directed mutagenesis, inactive mutant
G307S
-
mutant is not rescuable by any of the chemical chaperones
G307S
-
naturally occuring mutant involved in CBS deficiency, three-dimensional CBS structure compared to the wild-type enzyme
G307S
-
the mutant in the active core has slightly increased urea unfolding with decreased stability and shows 0.2% activity compared to the wild type enzyme
H65R
-
reduced heme and pyridoxal phosphate content, low catalytic activity
H65R
-
site-directed mutagenesis, inactive mutant
H65R
-
the mutant in the active core has extensive urea unfolding with decreased stability and shows 3.9% activity compared to the wild type enzyme
H67A
-
mutant is comparable to wild-type, specific activity and Km values for L-Ser, L-homocysteine comparable to wild-type
I152M
-
the mutation is associated with homocystinuria
I278T
-
located in the middle of beta-strand 9 and the beta-sheet of the C-terminal domain, effects of this mutation can be suppressed when expressed in yeast by certain point mutations in the regulatory domain or by complete deletion of the C-terminal region
I278T
-
site-directed mutagenesis, inactive mutant
I278T
-
mutant enzyme is inactive, although transgenic mouse line that expresses I278T possess the ability to rescue the neonatal lethality associated with homozygosity for the Cbs- allele
I278T
-
1-5% of the specific activity of the wild-type enzyme. Decreased activity is due to reduced turnover rate and not substrate binding. Mutant enzyme does not have altered affinity for 5'-pyridoxal phosphate. KM-value for pyridoxal 5'-phosphate is 1.4fold lower than wild-type value. KM-value for L-serine is 1.2fold lower than wild-type value. KM-value for L-homocysteine is 3.6fold higher than wild-type value. KM-value for L-cysteine is 1.7 fold lower than wild-type value
I278T
-
expression of human mutant CBS proteins in Saccharomyces cerevisiae reveals that the disease causing mutation severely inhibits enzyme activity and cannot support growth of yeast on cysteine-free media. The osmolyte chemical chaperones glycerol, trimethylamine-N-oxide, dimethylsulfoxide, proline or sorbitol, when added to yeast media, allows growth on cysteine-free media and causes increased enzyme activity from I278T mutant protein. The increase in enzyme activity is associated with stabilization of the tetramer form of the enzyme. This effect is not specific to yeast, as addition of the chaperone glycerol results in increased I278T activity when the enzyme is produced either in Escherichia coli or in a coupled in vitro transcription/translation reaction. No stimulation of specific activity is observed when chaperones are added directly to purified I278T indicating that the presence of chemical chaperones is required during translation
I278T
-
the mutation is associated with homocystinuria
I278T
-
I278T mutant is expressed in Saccharomyces cerevisiae. By manipulation of the cellular chaperone environment the enzymatic function is resuced. Ethanol treatment induces Hsp70 and causes increased activity and steady-state levels of I278T. Exposure of I278T yeast to a 45C heat shock for 3 h results in a 312% increase in steady-state CBS and a 511% increase in CBS activity. Hsp70 and Hsp26 bind specifically to I278T. Deletion of the SSA2 gene, which encodes a cytoplasmic isoform of Hsp70, eliminates the ability of ethanol to restore function, indicating that Hsp70 plays a positive role in proper I278T folding. In contrast, deletion of HSP26 results in increased I278T protein and activity, whereas overexpression of Hsp26 results in reduced I278T protein. The Hsp26-I278T complex is degraded via a ubiquitin/proteosome-dependent mechanism
I278T
-
naturally occuring mutant involved in CBS deficiency, three-dimensional CBS structure compared to the wild-type enzyme
I278T
-
the mutant in the active core has extensive urea unfolding with decreased stability and shows 0.3% activity compared to the wild type enzyme
I278T
-
the mutant shows 0.7% activity compared to the wild type enzyme when expressed in Escherichia coli
I278T/T424N
-
mutant enzyme is inactive, although transgenic mouse line that expresses I278T/T424N possess the ability to rescue the neonatal lethality associated with homozygosity for the Cbs- allele
I435T
-
inducible by S-adenosyl-L-methionine, but less responsive than wild-type enzyme to physiologically relevant concentrations
I435T
-
the presence of a chemical chaperone (ethanol, dimethyl sulfoxide, or trimethylamine-N-oxide) in the medium during expression increases the mutant CBS activity in Escherichia coli crude extracts at least equal to wild-type, mutants show significant change in the level of active CBS tetramers in the presence of chaperones, mutant responds to a S-adenosyl-L-methionine stimulation or heating to 53C with an increased activity
I435T
-
site-directed mutagenesis, the mutant shows an increase in specific activity compared to the wild-type enzyme
I437T
-
mutation results in loss of S-adenosyl-L-methionine-dependent activation but exhibits basal activity that is comparable to that of wild-type enzyme expressed under the same conditions. Purified recombinant I435T shows a two to 3fold higher basal activity compared to wild-type enzyme but is unresponsive to the allosteric activator S-adenosyl-L-methionine
K102N
-
KM for L-serine is about 2fold higher than wild-type value. KM for L-homocysteine is 2fold higher than wild-type value
K102N
-
site-directed mutagenesis, the mutant shows a decrease in specific activity compared to the wild-type enzyme
N228K
-
active site mutation in patients with homocystinurea
N228K
-
site-directed mutagenesis, inactive mutant
N228S
-
active site mutation in patients with homocystinurea
N228S
-
mutant is not rescuable by any of the chemical chaperones
P422L
-
the presence of a chemical chaperone (ethanol, dimethyl sulfoxide, or trimethylamine-N-oxide) in the medium during expression increases the mutant CBS activity in Escherichia coli crude extracts at least equal to wild-type, mutants show significant change in the level of active CBS tetramers in the presence of chaperones, mutant responds to a S-adenosyl-L-methionine stimulation or heating to 53C with an increased activity
P422L
-
site-directed mutagenesis, mutation in the regulatory domain, the mutant shows an increase in specific activity compared to the wild-type enzyme
P427L/S500L
-
the mutant is almost not activated by S-adenosyl-L-methionine
P49L
-
site-directed mutagenesis
P49L
-
the presence of a chemical chaperone (ethanol, dimethyl sulfoxide, or trimethylamine-N-oxide) in the medium during expression increases the mutant CBS activity in Escherichia coli crude extracts at least equal to wild-type, mutants show significant change in the level of active CBS tetramers in the presence of chaperones, mutant responds to a S-adenosyl-L-methionine stimulation or heating to 53C with an increased activity
P49L
-
the mutant shows 39% activity compared to the wild type enzyme when expressed in Escherichia coli
P78R
-
mutation in dimer interface of patients with homocystinurea
P78R
-
KM for L-serine is about 4fold higher than wild-type value. KM for L-homocysteine is comparable to wild-type value
P78R
-
the presence of a chemical chaperone (ethanol, dimethyl sulfoxide, or trimethylamine-N-oxide) in the medium during expression increases the mutant CBS activity in Escherichia coli crude extracts at least equal to wild-type, mutants show significant change in the level of active CBS tetramers in the presence of chaperones, mutant responds to a S-adenosyl-L-methionine stimulation or heating to 53C with an increased activity
P78R
-
site-directed mutagenesis, mutation at the dimer-dimer interface
P78R/K102N
-
KM for L-serine is about 2fold higher than wild-type value. Mutant enzyme is insensitive to allosteric regulation and unresponsive to S-adenosyl-L-methionine
P88S
-
mutation in dimer interface of patients with homocystinurea
Q222X
-
mutagenesis studies reveal that Gln-222 is involved in interactions with substrates
Q526K
-
mutant is not rescuable by any of the chemical chaperones
R125Q
-
the presence of a chemical chaperone (ethanol, dimethyl sulfoxide, or trimethylamine-N-oxide) in the medium during expression increases the mutant CBS activity in Escherichia coli crude extracts at least equal to wild-type, mutants show significant change in the level of active CBS tetramers in the presence of chaperones, mutant does not respond to a S-adenosyl-L-methionine stimulation or heating to 53C with an increased activity
R125Q
-
naturally occuring mutant involved in CBS deficiency, three-dimensional CBS structure compared to the wild-type enzyme
R125Q
-
site-directed mutagenesis, the mutant shows a decrease in specific activity compared to the wild-type enzyme
R125W
-
the mutation is associated with homocystinuria
R224A
-
the mutation decreases CBS activity by approximately 50%
R224H
-
mutation in the connecting loop between the N- and C-terminal domain between beta-strand 7 and alpha-helix 6, patients respond to vitamin B6 treatment
R266G
-
patient mutation , mutant protein shows instability and extensive degradation during thrombin treatment. A GST-R266G fusion protein does not exhibit any detectable activity unlike the GST-tagged wild-type CBS
R266K
-
site-directed mutagenesis, inactive mutant
R266K
-
30-100% of the specific activity of the wild-type enzyme. Decreased activity is due to reduced turnover rate and not substrate binding. Reduced affinity for 5'-pyridoxal phosphate compared to the wild type enzyme. KM-value for pyridoxal 5'-phosphate is 2.9fold higher than wild-type value. KM-value for L-serine is 1.6fold lower than wild-type value. KM-value for L-homocysteine is identical to wild-type value. KM-value for L-cysteine is 1.4 fold lower than wild-type value
R266K
-
mutant is moderately pyridoxal 5'-phosphate responsive, Km value for serine is slightly elevated compared to wild-type CBS, Km value for homocysteine slightly lower compared to wild-type
R266K
-
naturally occuring mutant involved in CBS deficiency, three-dimensional CBS structure compared to the wild-type enzyme
R266M
-
enzyme is inactivated, pyridoxal 5'-phosphate is displaced by breaking the salt bridge between Cys52 and Arg266
R266M
-
R266M mutant shows a significantly lower basal activity, Km value for serine is slightly elevated compared to wild-type CBS, Km value for homocysteine slightly lower compared to wild-type, R266M mutant shows dramatic differences in the ferrous state. The electrostatic interaction between C52 and R266 is critical for stabilizing the ferrous heme and its disruption leads to the facile formation of a 424 nm (C-424) absorbing ferrous species, which is inactive, compared to the active 449 nm ferrous species for wild-type CBS. Resonance Raman studies on the R266M mutant reveal that the kinetics of C52 rebinding after Fe-CO photolysis are comparable to that of wild-type CBS
R266X
-
mutagenesis studies reveal that Arg-266 is important to sense structural changes in heme-binding site
R336C
-
mutation causes a mild disease type, mutation in dimer interface of patients with homocystinurea
R336H
-
mutation causes a mild disease type, mutation in dimer interface of patients with homocystinurea
R336H
-
the mutant shows 0.43% activity compared to the wild type enzyme when expressed in Escherichia coli
R369C
-
the mutation is associated with homocystinuria
R369C
-
site-directed mutagenesis, the mutant shows a decrease in specific activity compared to the wild-type enzyme
R369C
-
the mutant in the active core has extensive urea unfolding with decreased stability and shows 1.8% activity compared to the wild type enzyme
R439Q
-
site-directed mutagenesis, the mutant shows altered activity compared to the wild-type enzyme
R439Q
-
the mutant with substitution in the C-terminal regulatory domain shows increased global stability with decreased flexibility and shows 117.2% activity compared to the wild type enzyme
R491C
-
the mutation is associated with homocystinuria
R51A
-
the mutation decreases CBS activity by approximately 50%
R58W
-
mutation in the heme binding site of patients with homocystinurea, reduced ability to bind heme
S352N
-
patients with this mutation are not vitamin B6 responsive
S466L
-
enzyme is constitutively activated, does bind S-adenosyl-L-methionine, but is not activated by it
S466L
-
not inducible by S-adenosyl-L-methionine
S466L
-
mutant exhibits a higher basal activity than wild-type enzyme but cannot be further activated by the allosteric effecto S-adenosyl-L-methionine
S466L
-
the mutation causes hyperhomocysteinemia by affecting both the steady state level of CBS protein and by reducing the efficiency of the enzyme in vivo, S466L is enzymatically active, forms tetramers, and lacks S-adenosyl-L-methionine inducibility
S466L
-
the presence of a chemical chaperone (ethanol, dimethyl sulfoxide, or trimethylamine-N-oxide) in the medium during expression increases the mutant CBS activity in Escherichia coli crude extracts at least equal to wild-type, mutants show significant change in the level of active CBS tetramers in the presence of chaperones, mutant responds to a S-adenosyl-L-methionine stimulation or heating to 53C with an increased activity
S466L
-
site-directed mutagenesis, mutation in the regulatory domain, the mutant shows an increase in specific activity compared to the wild-type enzyme
T191M
-
site-directed mutagenesis, inactive mutant
T191M
-
naturally occuring mutant involved in CBS deficiency, three-dimensional CBS structure compared to the wild-type enzyme
T191M
-
the mutant in the active core has extensive urea unfolding with decreased stability and shows 0.3% activity compared to the wild type enzyme
T223X
-
mutagenesis studies reveal that Tyr-223 is involved in interactions with substrates
T257M
-
active site mutation in patients with homocystinurea
T262M
-
expression of human mutant CBS proteins in Saccharomyces cerevisiae reveals that the disease causing mutation severely inhibits enzyme activity and cannot support growth of yeast on cysteine-free media. The osmolyte chemical chaperones glycerol, trimethylamine-N-oxide, dimethylsulfoxide, proline or sorbitol, when added to yeast media, allows growth on cysteine-free media and causes increased enzyme activity from I278T mutant protein. The increase in enzyme activity is associated with stabilization of the tetramer form of the enzyme. This effect is not specific to yeast, as addition of the chaperone glycerol results in increased I278T activity when the enzyme is produced either in Escherichia coli or in a coupled in vitro transcription/translation reaction. No stimulation of specific activity is observed when chaperones are added directly to purified I278T indicating that the presence of chemical chaperones is required during translation
T262R
-
site-directed mutagenesis, inactive mutant
T353M
-
mutation effects can be suppressed in a yeast assay by the deletion of the regulatory domain of the protein, patients with this mutation are not vitamin B6 responsive
T353M
-
expression of human mutant CBS proteins in Saccharomyces cerevisiae reveals that the disease causing mutation severely inhibits enzyme activity and cannot support growth of yeast on cysteine-free media. The osmolyte chemical chaperones glycerol, trimethylamine-N-oxide, dimethylsulfoxide, proline or sorbitol, when added to yeast media, allows growth on cysteine-free media and causes increased enzyme activity from I278T mutant protein. The increase in enzyme activity is associated with stabilization of the tetramer form of the enzyme. This effect is not specific to yeast, as addition of the chaperone glycerol results in increased I278T activity when the enzyme is produced either in Escherichia coli or in a coupled in vitro transcription/translation reaction. No stimulation of specific activity is observed when chaperones are added directly to purified I278T indicating that the presence of chemical chaperones is required during translation
T434N
-
the mutation is associated with homocystinuria
T87N
-
the mutation is associated with Venezuelan homocystinuria nonresponsive to vitamin B6. The mutant shows 3.5% activity compared to the wild type enzyme
V180A
-
mutation in dimer interface of patients with homocystinurea
V180A
-
the mutation is associated with homocystinuria
V180A
-
site-directed mutagenesis, mutation at the dimer-dimer interface, the mutant shows a decrease in specific activity compared to the wild-type enzyme
V354M
-
patients with this mutation are not vitamin B6 responsive
V371M
-
the mutation is associated with homocystinuria
W409_G453del
-
site-directed mutagenesis, inactive mutant
W409_G453del
-
naturally occuring mutant involved in CBS deficiency, three-dimensional CBS structure compared to the wild-type enzyme
C272A
-
spectroscopic properties similar to wild-type enzyme
C162S
-
activity can be enhanced by sodium nitroprusside
C367S
-
activity can be enhanced by sodium nitroprusside
C476S
-
activity can be enhanced by sodium nitroprusside
C49S
-
activity can be enhanced by sodium nitroprusside
D249A
-
a series of 8 site-directed mutants is constructed, and their order of impact on the ability of ytCBS to catalyze the beta-replacement reaction is G247S asymptotically equal to K112Q bigger than K112L asymptotically equal to K112R bigger than Y248F bigger D249A asymptotically equal to H138F bigger than E136A
E136A
-
a series of 8 site-directed mutants is constructed, and their order of impact on the ability of ytCBS to catalyze the beta-replacement reaction is G247S asymptotically equal to K112Q bigger than K112L asymptotically equal to K112R bigger than Y248F bigger D249A asymptotically equal to H138F bigger than E136A
G247A
-
undetectable beta-replacement activity
H138F
-
a series of 8 site-directed mutants is constructed, and their order of impact on the ability of ytCBS to catalyze the beta-replacement reaction is G247S asymptotically equal to K112Q bigger than K112L asymptotically equal to K112R bigger than Y248F bigger D249A asymptotically equal to H138F bigger than E136A. Km (L-homocysteine) increased by 8fold
K112L
-
a series of 8 site-directed mutants is constructed, and their order of impact on the ability of ytCBS to catalyze the beta-replacement reaction is G247S asymptotically equal to K112Q bigger than K112L asymptotically equal to K112R bigger than Y248F bigger D249A asymptotically equal to H138F bigger than E136A. Km (L-Ser) increased by 50fold, Km (L-homocysteine) increased by 2fold
K112Q
-
a series of 8 site-directed mutants is constructed, and their order of impact on the ability of ytCBS to catalyze the beta-replacement reaction is G247S asymptotically equal to K112Q bigger than K112L asymptotically equal to K112R bigger than Y248F bigger D249A asymptotically equal to H138F bigger than E136A
Q157A
-
no detectable beta-replacement activity, catalyzes a competing beta-elimination reaction, in which L-Ser is hydrolyzed to NH3 and pyruvate
Q157E
-
no detectable beta-replacement activity, catalyzes a competing beta-elimination reaction, in which L-Ser is hydrolyzed to NH3 and pyruvate
Q157H
-
enzyme suffers suicide inhibition via a mechanism in which the released aminoacrylate intermediate covalently attacks the internal aldimine of the enzyme, catalyzes a competing beta-elimination reaction, in which L-Ser is hydrolyzed to NH3 and pyruvate
S289A
-
kcat/Km (L-serine) is reduced by 800fold compared to wild-type. Km (L-homocysteine) equal to wild-type, Km (L-serine) increased compared to wild-type. The reverse-reaction (L-cystathionine hydrolysis) shows a 1400fold reduction of kcat/Km (L-cystathionine) for mutant S289A which is dominated by a 230fold decrease in kcat. Residue S289 is essential in maintaining the properties and orientation of the pyridine ring of the pyridoxal 5'-phosphate cofactor. The reduction in activity of mutant S289A suggests that yeast CBS catalyzes the alpha, beta-elimination of L-Ser via an E1cB mechanism
S289D
-
mutant shows no beta-replacement activity. Fluorescence energy transfer between tryptophan residue(s) of the enzyme and the pyridoxal 5'-phosphate cofactor, observed in the wild-type enzyme and diminished in the S289A mutant, is absent in S289D
S82A
-
catalyzes a competing beta-elimination reaction, in which L-Ser is hydrolyzed to NH3 and pyruvate
T81A
-
catalyzes a competing beta-elimination reaction, in which L-Ser is hydrolyzed to NH3 and pyruvate
T85A
-
catalyzes a competing beta-elimination reaction, in which L-Ser is hydrolyzed to NH3 and pyruvate
Y158F
-
3fold decreased beta-replacement activity, enzyme suffers suicide inhibition via a mechanism in which the released aminoacrylate intermediate covalently attacks the internal aldimine of the enzyme, catalyzes a competing beta-elimination reaction, in which L-Ser is hydrolyzed to NH3 and pyruvate
Y248F
-
a series of 8 site-directed mutants is constructed, and their order of impact on the ability of ytCBS to catalyze the beta-replacement reaction is G247S asymptotically equal to K112Q bigger than K112L asymptotically equal to K112R bigger than Y248F bigger D249A asymptotically equal to H138F bigger than E136A. Km (L-homocysteine) increased by 18fold
L539S
-
site-directed mutagenesis, inactive mutant, the mutant shows altered activity compared to the wild-type enzyme
additional information
-
C-terminal regulatory domain deletion leads to formation of highly active dimeric enzyme
additional information
-
CBSdeltaC143, truncated catalytic core in which the C-terminal 143 amino acid residues are deleted, higher Km for the substrates
additional information
-
deletion mutant CBSdeltaN43/deltaC143 lacking C-terminal and N-terminal amino acids
additional information
-
deletion of 70 N-terminal residues results in a heme-free protein retaining 20% activity, additional deletion of 151 C-terminal residues results in an inactive enzyme, deletion of 8 C-terminal residues results in increased enzyme activity and abolishes any further activation by S-adenosyl-L-methionine
additional information
-
c.833T4C transition (p.I278 T) in the cystathionine beta synthase gene represents the most common cause of pyridoxine-responsive homocystinuria in Western Eurasians. The frequency of the pathogenic c.833C allele, as observed in healthy newborns from several European countries, is about 20fold higher than expected on the basis of the observed number of symptomatic homocystinuria patients carrying this mutation, implying clinical underascertainment. The c.833C mutation is also present in combination with a 68-bp insertion, c.[833C, 844_845ins68], in a substantial proportion of chromosomes from nonhomocystinuric individuals worldwide
additional information
-
structural insights into pathogenic mutations
additional information
-
a 68 bp CBS insertion polymorphism in exon 8 is associated with decreased enzyme activity
additional information
-
homocysteine levels in 5,10-methylenetetrahydrofolate reductase 677TT homozygotes who carry the cystathionine beta-synthase 844ins68 allele are significantly lower than in those who do not
additional information
-
mutations in the cystathionine beta-synthase gene lead to markedly elevated levels of circulating plasma homocysteine-thiolactone
additional information
-
construction of a cobalt CBS, CoCBS, by metalloporphyrin replacement, which results in a high yield of fully active, high purity enzyme, in which heme is substituted by Co-protoporphyrin IX, CoPPIX. The enzyme contains 92% cobalt and 8% iron. CoCBS is indistinguishable from wild-type FeCBS in its activity, tetrameric oligomerization, PLP saturation and responsiveness to the allosteric activator, S-adenosyl-L-methionine
additional information
-
effects of delta-aminolevulinic acid, betaine, glycerol and taurine on amounts of tetramers/oligomers of the cystathionine beta-synthase mutants, overview
additional information
-
generation of a truncated 45 kDa CBS, 45CBS, enzyme lacking the C-terminal regulatory domain, amino acids 1-413. The wild-type CBS exhibits lower resistance to urea-induced denaturation and lower degree of unfolding cooperativity compared to 45CBS. Proteolytic kinetics by thermolysin under native conditions reveals slower cleavage of wild-type CBS compared to the mutant 45CBS
C275S
-
spectroscopic properties similar to wild-type enzyme
additional information
-
CBS activity in liver homogenates is reduced and plasma homocysteine levels are elevated in the CBS heterozygous knockout , CBS-/+ animals compared to wild-type littermate control mice. H2S is also significantly reduced by 30% and 46% compared to wild type in male and female CBS-/+ animals respectively
K112R
-
a series of 8 site-directed mutants is constructed, and their order of impact on the ability of ytCBS to catalyze the beta-replacement reaction is G247S asymptotically equal to K112Q bigger than K112L asymptotically equal to K112R bigger than Y248F bigger D249A asymptotically equal to H138F bigger than E136A. Km (L-Ser) increased by 90fold, Km (L-homocysteine) increased by 4fold
additional information
-
C-terminal regulatory domain deletion leads to formation of highly active dimeric enzyme
additional information
-
truncated version residues 1-353 is catalytically active and binds pyridoxal phosphate, removal of residues 354-507 increases the specific activity and alters steady-state kinetic parameters
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
diagnostics
-
the mutations present in each country differ from each other depending on the demographic profile. Therefore, specific mutations scanning must be performed in each population for diagnosis and prognosis purposes
diagnostics
-
evaluation of plasma cystathionine beta-synthase activity in cystathionine beta-synthase-deficient patients for utilization of the assay in diagnosis and study of cystathionine beta-synthase deficiency
medicine
-
inherited deficiency leads to homocystinura, a disease of sulfur metabolism
medicine
-
inherited deficiency leads to homocystinura, a disease of sulfur metabolism characterized by increased levels of homocysteine and methionine and decreased levels of cysteine
medicine
-
inherited deficiency leads to homocystinuria, an autosomal recessivlely inherited disease of sulfur metabolism
medicine
-
inherited dysfunction of the enzyme leads to homocystinurea, mutations can occur at the dimer interface, the active site, the heme-binding site and the predicted interface region between the catalytic domain and the missing regulatory domain of the truncated enzyme
medicine
-
CBS-deficient patients have significantly elevated plasma levels of prothrombotic N-homocysteine-fibrinogen
medicine
-
there is no association between the CBS (844ins68) insertion polymorphism and cancer of the upper gastrointestinal tract
medicine
-
a deficiency of cystathionine beta-synthase causes various neurodevelopmental defects which result in complex neuropathological features associated with abnormal homocysteine metabolism, and also suggest that radial glia/astrocyte lineage cells might be a new therapeutic target for preventing and treating them
analysis
-
usefulness of the CBS domains as predictors of osmoregulatory activity