Information on EC 4.4.1.17 - Holocytochrome-c synthase

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

EC NUMBER
COMMENTARY hide
4.4.1.17
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RECOMMENDED NAME
GeneOntology No.
Holocytochrome-c synthase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
Holocytochrome c = apocytochrome c + heme
show the reaction diagram
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
covalent attachment of heme
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
Porphyrin and chlorophyll metabolism
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SYSTEMATIC NAME
IUBMB Comments
holocytochrome-c apocytochrome-c-lyase (heme-forming)
In the reverse direction, the enzyme catalyses the attachment of heme to two cysteine residues in the protein, forming thioether links.
CAS REGISTRY NUMBER
COMMENTARY hide
75139-03-6
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
gene CaCYC3, 45% homology to the gene CYC3 of Saccharomyces cerevisiae
SwissProt
Manually annotated by BRENDA team
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
at least five heme c maturation systems have been identified: Systems I, II, III, IV, and V. System I, the cytochrome c maturation (CCM) system, involves genes ccmA-H5 and is found in various bacteria and in plant mitochondria. System I matures cytochromes c in the periplasmic space of bacteria. System II, cytochrome c synthesis (CCS), consists of four modular components and occurs in various bacteria as well as the thylakoid membranes of plants and algae. System III, also called cytochrome c heme lyase (CCHL), is a single enzyme found in the mitochondria of fungi, vertebrates and invertebrates
metabolism
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the enzyme is the primary component of the eukaryotic cytochrome c biogenesis pathway, known as System III
physiological function
additional information
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
apo-iso-1 cytochrome c + heme
holocytochrome c
show the reaction diagram
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single residue variants of five conserved N-terminal residues G6A, K10A, G11A, F15A and R18A of Saccharomyces cerevisiae iso-1 cytochrome c. F15A replacement, corresponding to F10 in the horse cytochrome c, is not matured at all. G6A, K10A, G11A, and R18A variants are matured
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?
apo-MccA + heme
holo-MccA
show the reaction diagram
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MccA contains seven conventional heme-binding motifs and a CX15CH sequence involved in binding of an additional heme catalyzed by a specific lyase enzyme
octaheme protein
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?
Apocytochrome c + heme
?
show the reaction diagram
Apocytochrome c + heme
Holocytochrome c
show the reaction diagram
apocytochrome c1 + heme
holocytochrome c1
show the reaction diagram
additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
Apocytochrome c + heme
?
show the reaction diagram
Apocytochrome c + heme
Holocytochrome c
show the reaction diagram
additional information
?
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during apoptotic stimuli, enzyme translocates to outside the mitochondria, and binds to and suppresses the X-linked inhibitor of apoptosis protein XIAP, leading to activation of caspase-3. The N-terminus of the neuronal glutamate transporter excitatory amino-acid carrier 1 EAAC1 can bind to enzyme which interferes with the enzyme-XIAP association
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
NADH
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activation
NADPH
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activation
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
Deuterohemin
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r; reversible inhibition
Hemin
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at concentrations higher than 0.002 mM; at higher concentrations
Holocytochrome c
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competitive inhibition
N-ethylmaleimide
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kinetics, in vivo; pretreatment of reticulocyte lysates with N-ethylmaleimide results in nearly complete inactivation
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
Cytosolic factor
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requirement
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glutathione
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activation
NADH
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10fold activation between 1 and 10 mM of NADH
NADPH
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about half of the activation observed with NADH
additional information
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independent of a potential across the inner mitochondrial membrane generated by N,N,N',N'-tetramethyl-p-phenylenediamine/ascorbate
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
additional information
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Km values for holocytochrome c using mitochondria and mitoplasts from several yeast strains
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.096
Holocytochrome c
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pH 7.4, 30°C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5.5 - 8.5
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about half-maximal activity at pH 5.5 and 8.5
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
30080
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predicted from gene sequence
33000
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SDS-PAGE
57000
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x * 57000, recombinant GST-tagged enzyme, SDS-PAGE
additional information
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comparison of amino acid sequence of Saccharomyces cerevisiae and Neurospora crassa enzymes to that of Saccharomyces cerevisiae cytochrome-c1-heme lyase
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
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x * 57000, recombinant GST-tagged enzyme, SDS-PAGE
additional information
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the N-terminus of the neuronal glutamate transporter excitatory amino-acid carrier 1 EAAC1 can bind to enzyme
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
partial, solubilization by Triton X-100
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partial; partial, subfractionation of mitochondria with digitonin
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recombinant GST-tagged enzyme and cytochrome c mutants from Escherichia coli strain RK103 membranes by ultracentrifugation, glutahione affinity chromatographyand ultrafiltration
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recombinant GST-tagged wild-type and mutant enzymes and cytochrome c from Escherichia coli strain RK103 membranes by ultracentrifugation, glutahione affinity chromatographyand ultrafiltration
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wild-type membrane-bound human GST-tagged enzyme with endogenous heme and in complex with its cognate human apocytochrome c and mutants from Escherichia coli
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
; Neurospora crassa
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; Saccharomyces cerevisiae gene CYC3
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cloning in Escherichia coli
cloning of the gene CaCYC3 in Escherichia coli
coexpression of N-terminally GST-tagged wild-type enzyme with endogenous heme and in complex with its cognate human apocytochrome c and mutants in Escherichia coli
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coexpression of the wild-type enzyme with periplasmic targeting sequence and addition of the Pseudomonas aeruginosa cytochrome c551/552 pre-sequence, and mutant enzymes with Equus caballus heart cytochrome c or Strep-tagged Saccharomyces cerevisiaecytochrome c in Escherichia coli strain BL21(DE3)
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expression in Escherichia coli
expression of the enzyme in Escherichia coli cytosplasm, coexpression with several mutant variants of holocytochrome c552 from Hydrogenobacter thermophilus, the latter are expressed in the periplasm, or several cytochrome c variants from Equus caballus
heterologous expression in a multicopy yeast vector
recombinant coexpression of GST-tagged wild-type and mutant enzymes with cytochrome c in Escherichia coli strain RK103 membranes
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recombinant coexpression of the GST-tagged enzyme with cytochrome c mutants, containing individual cysteine, histidine, double cysteine, and triple cysteine/histidine substitutions of conserved motif CXXCH, in Escherichia coli strain RK103 membranes, single and double mutants form a complex with the enzyme but not the triple mutant
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recombinant expression of His-tagged wild-type enzyme and mutants in Escherichia coli strain BL21(DE3) cytoplasm, coexpression with Equus caballus cytochrome c
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C15S
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the HCCS:cyt c C15S and C18A mutants support the formation of single thioether cross-links between the heme and cyt c at the vinyl position alternate to the mutation
C18A
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the HCCS:cyt c C15S and C18A mutants support the formation of single thioether cross-links between the heme and cyt c at the vinyl position alternate to the mutation
DELTA197-268
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mutation identified in female patient with microphthalmia with linear skin defects syndrome. In contrast to wild-type, mutant protein is unable to complement a Saccharomyces cerevisiae mutant deficient in the yeast enzyme ortholog. Upon expression in CHO-K1 cells, mutant protein fails to be sorted to mitochondria. Mutation results in disturbance of both oxidative phosphorylation and the balance between apoptosis and necrosis
E159A
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site-directed mutagenesis of a domain II residue, the mutant shows altered heme binding compared to the wild-type enzyme
E159D
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site-directed mutagenesis of a domain II residue, the mutant shows altered heme binding compared to the wild-type enzyme
E159K
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site-directed mutagenesis of a domain II residue, the mutant shows altered heme binding compared to the wild-type enzyme
M130A
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site-directed mutagenesis of a domain I residue, the mutant shows altered heme binding compared to the wild-type enzyme
N128A
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site-directed mutagenesis of a domain I residue, the mutant shows altered heme binding compared to the wild-type enzyme
N128A/M130A
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site-directed mutagenesis of domain I residues, the mutant shows altered heme binding compared to the wild-type enzyme
N155A
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site-directed mutagenesis of a domain II residue, the mutant shows altered heme binding compared to the wild-type enzyme
P121A
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site-directed mutagenesis of a domain I residue, the mutant shows altered heme binding compared to the wild-type enzyme
R217C
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mutation identified in female patient with microphthalmia with linear skin defects syndrome. In contrast to wild-type, mutant protein is unable to complement a Saccharomyces cerevisiae mutant deficient in the yeast enzyme ortholog. Mutation results in disturbance of both oxidative phosphorylation and the balance between apoptosis and necrosis
W118A
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site-directed mutagenesis of a domain I residue, the mutant shows altered heme binding compared to the wild-type enzyme
Y120A
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site-directed mutagenesis of a domain I residue, the mutant shows altered heme binding compared to the wild-type enzyme
Y120A/P121A
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site-directed mutagenesis of domain I residues, the mutant shows altered heme binding compared to the wild-type enzyme
C15A
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site-directed mutagenesis, cytoplasm-targeted mutant, the mutant is matured and undergoes heme attachment like the wild-type enzyme
C18A
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site-directed mutagenesis, cytoplasm-targeted mutant, the mutant does not undergo heme attachment
C26A
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site-directed mutagenesis of CP-motif 1 of the enzyme, the mutant shows activity similar to the wild-type enzyme
C26A/C42A
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site-directed mutagenesis of both CP-motifs of the enzyme, the mutant shows activity similar to the wild-type enzyme
C26A/P27A
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site-directed mutagenesis of CP-motif 1 of the enzyme, the mutant shows activity similar to the wild-type enzyme
C42A
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site-directed mutagenesis of CP-motif 2 of the enzyme, the mutant shows activity similar to the wild-type enzyme
C42A/P43A
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site-directed mutagenesis of CP-motif 2 of the enzyme, the mutant shows activity similar to the wild-type enzyme
E133A
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site-directed mutagenesis, the mutant shows highly reduced activity compared with the wild-type enzyme
E133K
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site-directed mutagenesis, the mutant shows highly reduced activity compared with the wild-type enzyme
F15A
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site-directed mutagenesis, periplasm-targeted mutant, the mutant variant does not produce holocytochrome c
F15E
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site-directed mutagenesis, periplasm-targeted mutant, the mutant variant does not produce holocytochrome c
F15I
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site-directed mutagenesis, periplasm-targeted mutant, the mutant shows reduced holocytochrome c production compared to the wild-type enzyme
F15W
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site-directed mutagenesis, periplasm-targeted mutant, the mutant shows reduced holocytochrome c production compared to the wild-type enzyme
F15Y
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site-directed mutagenesis, periplasm-targeted mutant, the mutant shows unaltered holocytochrome c production like the wild-type enzyme
H19K
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site-directed mutagenesis, cytoplasm-targeted mutant, the mutant does not undergo heme attachment
H19M
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site-directed mutagenesis, cytoplasm-targeted mutant, the mutant does not undergo heme attachment
H19R
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site-directed mutagenesis, cytoplasm-targeted mutant, the mutant does not undergo heme attachment
R199A
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site-directed mutagenesis, almost inactive mutant
R199C
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site-directed mutagenesis, almost inactive mutant
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
molecular biology
system III, cytochrome c heme lyase, is an enzyme found in the mitochondria of many eukaryotes, which is used for heterologous expression of mitochondrial holocytochromes c
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