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Information on EC 4.2.1.22 - cystathionine beta-synthase and Organism(s) Saccharomyces cerevisiae and UniProt Accession P32582
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4.2.1.22 cystathionine beta-synthaseIUBMB Comments
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.
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Word Map
- 4.2.1.22
- h2s
- sulfide
- homocystinuria
- hyperhomocysteinemia
- artery
-
spacer
-
corticobasal
- candida
- mthfr
-
carotid
- folate
-
transsulfuration
- conidia
-
cajal
- nahs
- dextrose
- methylenetetrahydrofolate
-
bismuth
- hallucinations
-
anamorphic
- palsy
-
supranuclear
-
charles
-
remethylation
-
reisolated
-
conidiophore
-
gamma-lyase
-
biodiversity
-
hyaline
-
chemoreceptor
-
gasotransmitter
- 3-mercaptopyruvate
-
frontotemporal
- sulfurtransferase
-
thromboembolic
- ascospore
-
rinsed
-
aminooxyacetic
- apraxia
-
snrnps
-
symptomless
- hydrosulfide
- marxianus
-
visuospatial
- 5,10-methylenetetrahydrofolate
-
voxel-based
-
appressoria
- naocl
- medicine
- diagnostics
- ascus
-
phytopathological
- analysis
The taxonomic range for the selected organisms is: Saccharomyces cerevisiae
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Synonyms
cbs, cystathionine beta-synthase, cystathionine-beta-synthase, cnnm2, cystathionine beta synthase, serine sulfhydrylase, ytcbs, serine sulfhydrase, hemoprotein h-450, cdcp2, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Beta-thionase
-
-
-
-
CBS
Cysteine synthase
-
-
-
-
Hemoprotein H-450
-
-
-
-
Methylcysteine synthase
-
-
-
-
Serine sulfhydrase
-
-
-
-
Serine sulfhydrylase
-
-
-
-
Serine sulphhydrase
-
-
-
-
ytCBS
-
a truncated form of CBS comprising the catalytic core is used for mutational analysis
CBS
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
L-serine + L-homocysteine = L-cystathionine + H2O
mechanism
-
L-serine + L-homocysteine = L-cystathionine + H2O
ping-pong mechanism
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
elimination
-
-
-
-
C-S bond formation
-
-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
KEGG
-
-, -, -, -
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.
CAS REGISTRY NUMBER
COMMENTARY
9023-99-8
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
L-serine + H2O
NH3 + pyruvate
-
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
-
hydroxylgroup of serine is replaced by the thiol of homocysteine
-
r
L-Serine + homocysteine
Cystathionine + H2O
-
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
additional information
?
-
-
no substrates: D-, L-allo- and D-allo-cystathionine
-
?
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
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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
additional information
-
yeast cystathionine beta-synthase does not have a heme cofactor
-
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
S-adenosyl-L-methionine does not activate
-
additional information
-
S-adenosyl-L-methionine does not activate
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
pre-steady-state kinetic analysis of enzyme-monitored turnover during cystathionine beta-synthase-catalyzed H2S generation, overview
-
0.14
L-cystathionine
-
reverse reaction (L-cystathionine hydrolysis), wild-type
0.9
L-cystathionine
-
reverse reaction (L-cystathionine hydrolysis), mutant S289A
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
the kcat for the generation of H2S by cystathionine beta-synthase of 55/s at 37°C, via the condensation of cysteine and homocysteine is 18fold faster than that for the beta-elimination and rehydration to form serine of 3/s-
-
0.0045
L-cystathionine
-
reverse reaction (L-cystathionine hydrolysis), mutant S289A
1.03
L-cystathionine
-
reverse reaction (L-cystathionine hydrolysis), wild-type
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.005
L-cystathionine
-
reverse reaction (L-cystathionine hydrolysis), mutant S289A
7.5
L-cystathionine
-
reverse reaction (L-cystathionine hydrolysis), wild-type
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
CBS is involved in the cysteine pathway of bacteria and plants, overview
evolution
-
cystathionine beta-synthase belongs to the fold II family of pyridoxal 5'-phosphate enzymes
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
physiological function
-
comparison of human, fruit fly and yeast enzymes. Truncation of human CBS and yeast CBS, i.e. deletion of the regulatory domains, results in enzyme activation and formation of dimers compared to native tetramers The fruit fly CBS and yeast CBS are not regulated by the allosteric activator of human CBS, S-adenosyl-L-methionine. compared to the yeast CBS, the heme-containing Drosophila melanogaster CBS and human CBS show increased thermal stability and retention of the enzyme's catalytic activity
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
55000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
octamer
tetramer
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystallization of truncated enzyme, lacking amino acids 345-507, leads to two different crystal forms belonging to space groups P41212 and P212121, to 2.7 and 3.1 A resolution, respectively
structure of the catalytic core, residues 1-353, to 1.5 A resolution, and structures with pyridoxal 5'-phosphate-L-serine external aldimine, aminoacrylate intermediate, cycloserine and hydrazine. Two monomers form a tight dimer. The monomer contains two structurally conserved salt bridges, residues E174/K42 and E44/R55, on the si side of the pyridoxal 5'-phosphate cofactor
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
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
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
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
additional information
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
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
the CBS domain contributes only very little to the thermal stabilization of the enzyme. In the presence of 1 mM cycloserine, the full-length and catalytic-core enzymes are destabilized by 12 and 14.5°C, respectively
additional information
-
the CBS domain contributes only very little to the thermal stabilization of the enzyme. In the presence of 1 mM cycloserine, the full-length and catalytic-core enzymes are destabilized by 12 and 14.5°C, respectively
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant cystathionine beta-synthase from Escherichia coli strain BL21(DE3) by anion exchange and hydroxyapatite chromatography
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
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)
-
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Schlossmann, K.; Brueggemann, J.; Lynen, F.
Biosynthese des Cysteins. I. Nachweis und Isolierung der Serinsulfhydrase aus Bckerhefe
Biochem. Z.
336
258-273
1962
Saccharomyces cerevisiae
-
Ono, B.I.; Kijima, K.; Inoue, T.; Miyoshi, A.I.; Matsuda, A.; Shinoda, S.
Purification and properties of Saccharomyces cerevisiae cystathionine beta-synthase
Yeast
10
333-339
1994
Saccharomyces cerevisiae
Jhee, K.H.; McPhie, P.; Miles, E.W.
Domain architecture of the heme-independent yeast cystathionine beta-synthase provides insights into mechanisms of catalysis and regulation
Biochemistry
39
10548-10556
2000
Saccharomyces cerevisiae
Jhee, K.H.; Niks, D.; McPhie, P.; Dunn, M.F.; Miles, E.W.
The reaction of yeast cystathionine beta-synthase is rate-limited by the conversion of aminoacrylate to cystathionine
Biochemistry
40
10873-10880
2001
Saccharomyces cerevisiae
Jhee, K.H.; Niks, D.; McPhie, P.; Dunn, M.F.; Miles, E.W.
Yeast cystathionine beta-synthase reacts with L-allothreonine, a non-natural substrate, and L-homocysteine to form a new amino acid, 3-methyl-L-cystathionine
Biochemistry
41
1828-1835
2002
Saccharomyces cerevisiae
Aitken, S.M.; Kirsch, J.F.
Kinetics of the yeast cystathionine beta-synthase forward and reverse reactions: continuous assays and the equilibrium constant for the reaction
Biochemistry
42
571-578
2003
Saccharomyces cerevisiae
Aitken, S.M.; Kirsch, J.F.
Role of active-site residues Thr81, Ser82, Thr85, Gln157, and Tyr158 in yeast cystathionine beta-synthase catalysis and reaction specificity
Biochemistry
43
1963-1971
2004
Saccharomyces cerevisiae
Banerjee, R.; Evande, R.; Kabil, O.; Ojha, S.; Taoka, S.
Reaction mechanism and regulation of cystathionine beta-synthase
Biochim. Biophys. Acta
1647
30-35
2003
Saccharomyces cerevisiae, Homo sapiens, Mammalia
Kabil, O.; Toaka, S.; LoBrutto, R.; Shoemaker, R.; Banerjee, R.
Pyridoxal phosphate binding sites are similar in human heme-dependent and yeast heme-independent cystathionine beta-synthases. Evidence from 31P NMR and pulsed EPR spectroscopy that heme and PLP cofactors are not proximal in the human enzyme
J. Biol. Chem.
276
19350-19355
2001
Saccharomyces cerevisiae, Homo sapiens
Taoka, S.; Banerjee, R.
Stopped-flow kinetic analysis of the reaction catalyzed by the full-length yeast cystathionine beta-synthase
J. Biol. Chem.
277
22421-22425
2002
Saccharomyces cerevisiae
Miles, E.W.; Kraus, J.P.
Cystathionine {beta}-synthase: structure, function, regulation and location of homocystinuria-causing mutations
J. Biol. Chem.
279
29871-29874
2004
Saccharomyces cerevisiae, Trypanosoma cruzi, Homo sapiens (P35520)
Maclean, K.N.; Janosik, M.; Oliveriusova, J.; Kery, V.; Kraus, J.P.
Transsulfuration in Saccharomyces cerevisiae is not dependent on heme: purification and characterization of recombinant yeast cystathionine beta-synthase
J. Inorg. Biochem.
81
161-171
2000
Saccharomyces cerevisiae (P32582), Saccharomyces cerevisiae
Lodha, P.H.; Shadnia, H.; Woodhouse, C.M.; Wright, J.S.; Aitken, S.M.
Investigation of residues Lys112, Glu136, His138, Gly247, Tyr248, and Asp249 in the active site of yeast cystathionine beta-synthase
Biochem. Cell Biol.
87
531-540
2009
Saccharomyces cerevisiae
Quazi, F.; Aitken, S.M.
Characterization of the S289A,D mutants of yeast cystathionine beta-synthase
Biochim. Biophys. Acta
1794
892-897
2009
Saccharomyces cerevisiae
Ishikawa, K.; Mino, K.; Nakamura, T.
New function and application of the cysteine synthase from archaea
Biochem. Eng. J.
48
315-322
2010
Saccharomyces cerevisiae (P32582), Homo sapiens (P35520), Aeropyrum pernix (Q9YCN5)
-
Singh, S.; Ballou, D.; Banerjee, R.
Pre-steady-state kinetic analysis of enzyme-monitored turnover during cystathionine beta-synthase-catalyzed H2S generation
Biochemistry
50
419-425
2011
Saccharomyces cerevisiae
Ereno-Orbea, J.; Majtan, T.; Oyenarte, I.; Kraus, J.P.; Martinez-Cruz, L.A.
Purification, crystallization and preliminary crystallographic analysis of the catalytic core of cystathionine beta-synthase from Saccharomyces cerevisiae
Acta Crystallogr. Sect. F
70
320-325
2014
Saccharomyces cerevisiae (P32582), Saccharomyces cerevisiae, Saccharomyces cerevisiae ATCC 204508 (P32582)
Tu, Y.; Kreinbring, C.A.; Hill, M.; Liu, C.; Petsko, G.A.; McCune, C.D.; Berkowitz, D.B.; Liu, D.; Ringe, D.
Crystal structures of cystathionine beta-synthase from Saccharomyces cerevisiae One enzymatic step at a time
Biochemistry
57
3134-3145
2018
Saccharomyces cerevisiae (P32582), Saccharomyces cerevisiae
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