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Information on EC 1.17.99.9 - heme a synthase
for references in articles please use BRENDA:EC1.17.99.9
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EC Tree 1 Oxidoreductases
1.17 Acting on CH or CH2 groups
1.17.99 With unknown physiological acceptors
1.17.99.9 heme a synthase
IUBMB Comments
Contains a heme b cofactor. The enzyme catalyses the conversion of heme o to heme a by two successive hydroxylations of the methyl group at C-8, using water as the oxygen source. The first hydroxylation forms heme i, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group of heme a [2,4]. The electrons produced by the reaction are transferred to a heme b cofactor . However, the electron acceptor that is used to restore the heme b cofactor to its oxidized state is still not known (both a thioredoxin-like protein and menaquinol have been proposed).
The expected taxonomic range for this enzyme is: Bacteria, Archaea, Eukaryota
Reaction Schemes
show+
+
2
=
+
2
Synonyms
cox15, heme a synthase, cox15p, cctaa, ctaa protein, tccox15, ape1694, more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
ape1694
BCAH187_A4064
BsHAS
cCtaA
COA89_14165
COX15
COX15p
ctaA
HAS
heme A synthase
heme A-containing proton pumping cytochrome oxidase
TcCox15
COX15
-
-
-
-
ctaA
-
-
-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ferroheme i + H2O + acceptor = hydroxyferroheme i + reduced acceptor
(1b)
-
-
-
ferroheme o + H2O + acceptor = ferroheme i + reduced acceptor
(1a)
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-
-
hydroxyferroheme i = ferroheme a + H2O
(1c), spontaneous
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-
-
ferroheme o + H2O + 2 acceptor = ferroheme a + 2 reduced acceptor
(overall reaction)
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-
-
ferroheme o + H2O + 2 acceptor = ferroheme a + 2 reduced acceptor
catalytic mechanism analysis. HAS oxidizes the methyl group of pyrrole ring D to an aldehyde. It uses a catalytic mechanism that is more similar to that of peroxidases, in which the high-valent iron-oxo species oxidizes the substrate via electron transfer instead of hydrogen atom abstraction
ferroheme o + H2O + 2 acceptor = ferroheme a + 2 reduced acceptor
catalytic mechanism analysis. HAS oxidizes the methyl group of pyrrole ring D to an aldehyde. It uses a catalytic mechanism that is more similar to that of peroxidases, in which the high-valent iron-oxo species oxidizes the substrate via electron transfer instead of hydrogen atom abstraction
ferroheme o + H2O + 2 acceptor = ferroheme a + 2 reduced acceptor
catalytic mechanism analysis. HAS oxidizes the methyl group of pyrrole ring D to an aldehyde. It uses a catalytic mechanism that is more similar to that of peroxidases, in which the high-valent iron-oxo species oxidizes the substrate via electron transfer instead of hydrogen atom abstraction
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PATHWAY SOURCE
PATHWAYS
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SYSTEMATIC NAME
IUBMB Comments
ferroheme o:acceptor C-81-oxidoreductase (heme a-forming)
Contains a heme b cofactor. The enzyme catalyses the conversion of heme o to heme a by two successive hydroxylations of the methyl group at C-8, using water as the oxygen source. The first hydroxylation forms heme i, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group of heme a [2,4]. The electrons produced by the reaction are transferred to a heme b cofactor [6]. However, the electron acceptor that is used to restore the heme b cofactor to its oxidized state is still not known (both a thioredoxin-like protein and menaquinol have been proposed).
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ferroheme o + H2O + 2 NAD(P)+
ferroheme a + 2 NAD(P)H + 2 H+
A0A2G2K2S2
Substrates: overall reaction
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?
ferroheme i + H2O + acceptor
hydroxyferroheme i + reduced acceptor
Substrates: the enzyme catalyses the conversion of heme o to heme a by two successive hydroxylations of the methyl group at C-8, using water as the oxygen source. The first hydroxylation forms heme i, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group
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ferroheme i + H2O + acceptor
hydroxyferroheme i + reduced acceptor
Substrates: -
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ferroheme i + H2O + acceptor
hydroxyferroheme i + reduced acceptor
Substrates: the enzyme catalyses the conversion of heme o to heme a by two successive hydroxylations of the methyl group at C-8, using water as the oxygen source. The first hydroxylation forms heme i, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group
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ferroheme i + H2O + acceptor
hydroxyferroheme i + reduced acceptor
Substrates: -
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ferroheme i + H2O + acceptor
hydroxyferroheme i + reduced acceptor
Substrates: -
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
-
Substrates: overall reaction
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: overall reaction
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Aeropyrum pernix ATCC 700893
Substrates: overall reaction
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?
ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: overall reaction. The enzyme is involved in biosynthesis of heme A, an obligatory cofactor in eukaryotic cytochrome c oxidase. The enzyme catalyses the conversion of heme o to heme a by two successive hydroxylations of the methyl group at C-8, using water as the oxygen source. The first hydroxylation forms heme i, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group of heme a
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: overall reaction. The enzyme catalyses the conversion of heme o to heme a by two successive hydroxylations of the methyl group at C-8, using water as the oxygen source. The first hydroxylation forms heme i, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group of heme a
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: overall reaction
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?
ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: -
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?
ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: overall reaction. The enzyme is involved in biosynthesis of heme A, an obligatory cofactor in eukaryotic cytochrome c oxidase. The enzyme catalyses the conversion of heme o to heme a by two successive hydroxylations of the methyl group at C-8, using water as the oxygen source. The first hydroxylation forms heme i, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group of heme a
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: overall reaction. The enzyme catalyses the conversion of heme o to heme a by two successive hydroxylations of the methyl group at C-8, using water as the oxygen source. The first hydroxylation forms heme i, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group of heme a
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: overall reaction. The enzyme is involved in biosynthesis of heme A, an obligatory cofactor in eukaryotic cytochrome c oxidase. The enzyme catalyses the conversion of heme o to heme a by two successive hydroxylations of the methyl group at C-8, using water as the oxygen source. The first hydroxylation forms heme i, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group of heme a
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: overall reaction. The enzyme catalyses the conversion of heme o to heme a by two successive hydroxylations of the methyl group at C-8, using water as the oxygen source. The first hydroxylation forms heme i, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group of heme a
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: overall reaction. The enzyme is involved in biosynthesis of heme A, an obligatory cofactor in eukaryotic cytochrome c oxidase. The enzyme catalyses the conversion of heme o to heme a by two successive hydroxylations of the methyl group at C-8, using water as the oxygen source. The first hydroxylation forms heme i, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group of heme a
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: overall reaction. The enzyme catalyses the conversion of heme o to heme a by two successive hydroxylations of the methyl group at C-8, using water as the oxygen source. The first hydroxylation forms heme i, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group of heme a
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: overall reaction
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?
ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: -
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: overall reaction
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: -
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor + H+
Substrates: overall reaction
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor + H+
Substrates: overall reaction
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ferroheme o + H2O + acceptor
ferroheme a + 2 reduced acceptor + H+
Substrates: overall reaction
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?
ferroheme o + H2O + acceptor
ferroheme a + 2 reduced acceptor + H+
Substrates: overall reaction
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?
ferroheme o + H2O + acceptor
ferroheme a + 2 reduced acceptor + H+
Substrates: overall reaction
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?
ferroheme o + H2O + acceptor
ferroheme i + reduced acceptor
Substrates: the enzyme catalyses the conversion of heme o to heme a by two successive hydroxylations of the methyl group at C-8, using water as the oxygen source. The first hydroxylation forms heme i, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group
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ferroheme o + H2O + acceptor
ferroheme i + reduced acceptor
Substrates: -
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ferroheme o + H2O + acceptor
ferroheme i + reduced acceptor
Substrates: the enzyme catalyses the conversion of heme o to heme a by two successive hydroxylations of the methyl group at C-8, using water as the oxygen source. The first hydroxylation forms heme i, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group
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ferroheme o + H2O + acceptor
ferroheme i + reduced acceptor
Substrates: -
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?
ferroheme o + H2O + acceptor
ferroheme i + reduced acceptor
Substrates: -
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?
hydroxyferroheme i
ferroheme a + H2O
Substrates: spontaneous
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hydroxyferroheme i
ferroheme a + H2O
Substrates: spontaneous
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hydroxyferroheme i
ferroheme a + H2O
Substrates: spontaneous
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?
additional information
?
-
Substrates: single-turnover in vitro activity assay with membranes isolated from Escherichia coli overexpressing HAS shows that HAS can convert heme o to heme a in the presence of reductant, the enzyme can catalyze the successive oxidation of the C8 methyl group of heme o to an alcohol, aldehyde, and carboxylate. The aldehyde product is heme a, and the alcohol and carboxylate products are an intermediate (heme I) and an overoxidized product (heme II), respectively
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?
additional information
?
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Substrates: single-turnover in vitro activity assay with membranes isolated from Escherichia coli overexpressing HAS shows that HAS can convert heme o to heme a in the presence of reductant, the enzyme can catalyze the successive oxidation of the C8 methyl group of heme o to an alcohol, aldehyde, and carboxylate. The aldehyde product is heme a, and the alcohol and carboxylate products are an intermediate (heme I) and an overoxidized product (heme II), respectively
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?
additional information
?
-
Substrates: single-turnover in vitro activity assay with membranes isolated from Escherichia coli overexpressing HAS shows that HAS can convert heme o to heme a in the presence of reductant, the enzyme can catalyze the successive oxidation of the C8 methyl group of heme o to an alcohol, aldehyde, and carboxylate. The aldehyde product is heme a, and the alcohol and carboxylate products are an intermediate (heme I) and an overoxidized product (heme II), respectively
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ferroheme o + H2O + 2 NAD(P)+
ferroheme a + 2 NAD(P)H + 2 H+
A0A2G2K2S2
Substrates: overall reaction
Products: -
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?
ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
-
Substrates: overall reaction
Products: -
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?
ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: overall reaction. The enzyme is involved in biosynthesis of heme A, an obligatory cofactor in eukaryotic cytochrome c oxidase. The enzyme catalyses the conversion of heme o to heme a by two successive hydroxylations of the methyl group at C-8, using water as the oxygen source. The first hydroxylation forms heme i, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group of heme a
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: overall reaction
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?
ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: -
Products: -
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: overall reaction. The enzyme is involved in biosynthesis of heme A, an obligatory cofactor in eukaryotic cytochrome c oxidase. The enzyme catalyses the conversion of heme o to heme a by two successive hydroxylations of the methyl group at C-8, using water as the oxygen source. The first hydroxylation forms heme i, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group of heme a
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: overall reaction
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: -
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: overall reaction
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ferroheme o + H2O + 2 acceptor
ferroheme a + 2 reduced acceptor
Substrates: -
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ferroheme o + H2O + acceptor
ferroheme a + 2 reduced acceptor + H+
Substrates: overall reaction
Products: -
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ferroheme o + H2O + acceptor
ferroheme a + 2 reduced acceptor + H+
Substrates: overall reaction
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ferroheme o + H2O + acceptor
ferroheme a + 2 reduced acceptor + H+
Substrates: overall reaction
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?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ferredoxin
-
requirement of ferredoxin and indirectly of ferredoxin reductase in hydroxylation of heme O
-
heme a
between 0.2 and 1.95 mol heme B per mol CtaA polypeptide and up to 0.2 mol heme A per mol enzyme (CtaA)
heme
-
contains 0.2 mol of heme B per mol of polypeptide, and a small amounts of heme A
heme
a stoichiometry of 1.1 hemes (heme Bx02O) to 1 AaHAS monomer is found, pyridine hemochrome assay
heme b
between 0.2 and 1.95 mol heme B per mol CtaA polypeptide and up to 0.2 mol heme A per mol enzyme (CtaA)
heme b
two molecules of heme B are bound to the enzyme. Wild-type enzyme contains 54.6 nmol/mg protein. Heme composition of wild-type enzyme hemeB:hemeO:hemeOX:hemeOY is 1.95:0.02:0.03:0. Substitutions of His60 and His126 do not affect heme binding, while His216 and His278 in the carboxy-halves are essential in heme binding
heme b
cofactor heme-binding domain structure and mechanism, overview
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
intracellular copper levels do not affect the activity of the enzyme
additional information
intracellular copper levels do not affect the activity of the enzyme
additional information
-
intracellular copper levels do not affect the activity of the enzyme
additional information
-
intracellular copper levels do not affect the activity of the enzyme
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Brain Diseases
Phenotypic variability and mutation hotspot in COX15-related Leigh syndrome.
Cardiomyopathies
Novel mutations in COX15 in a long surviving Leigh syndrome patient with cytochrome c oxidase deficiency.
Cardiomyopathy, Hypertrophic
Analysis of Oligomerization Properties of Heme a Synthase Provides Insights into its Function in Eukaryotes.
Cardiomyopathy, Hypertrophic
Leigh syndrome associated with a novel mutation in the COX15 gene.
Cardiomyopathy, Hypertrophic
Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.
Cardiomyopathy, Hypertrophic
Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy.
Cytochrome-c Oxidase Deficiency
Defects in the biosynthesis of mitochondrial heme c and heme a in yeast and mammals.
Cytochrome-c Oxidase Deficiency
Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy.
Cytochrome-c Oxidase Deficiency
Novel mutations in COX15 in a long surviving Leigh syndrome patient with cytochrome c oxidase deficiency.
Leigh Disease
Analysis of Oligomerization Properties of Heme a Synthase Provides Insights into its Function in Eukaryotes.
Leigh Disease
Functional and genetic studies demonstrate that mutation in the COX15 gene can cause Leigh syndrome.
Leigh Disease
Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.
Leigh Disease
Novel mutations in COX15 in a long surviving Leigh syndrome patient with cytochrome c oxidase deficiency.
Mitochondrial Diseases
Phenotypic variability and mutation hotspot in COX15-related Leigh syndrome.
Neoplasms
Systematic expression analysis of the mitochondrial respiratory chain protein subunits identifies COX5B as a prognostic marker in clear cell renal cell carcinoma.
Nervous System Diseases
Analysis of Oligomerization Properties of Heme a Synthase Provides Insights into its Function in Eukaryotes.
Osteoporosis
Identification of B cells participated in the mechanism of postmenopausal women osteoporosis using microarray analysis.
Pulmonary Disease, Chronic Obstructive
Effects of exercise training on quadriceps muscle gene expression in chronic obstructive pulmonary disease.
Starvation
CtaA of Staphylococcus aureus is required for starvation survival, recovery, and cytochrome biosynthesis.
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
SwissProt
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
the replicative life stages (epimastigotes and amastigotes) show higher TcCox15 levels than the infective and non-replicative stage (trypomastigotes). Two times higher level in epimastigotes than in amastigotes and five times higher level than in trypomastigotes
brenda
the amount of mRNA is significantly lower compared with the other life stages
brenda
-
the replicative life stages (epimastigotes and amastigotes) show higher TcCox15 levels than the infective and non-replicative stage (trypomastigotes). Two times higher level in epimastigotes than in amastigotes and five times higher level than in trypomastigotes
-
brenda
the replicative life stages (epimastigotes and amastigotes) show higher TcCox15 levels than the infective and non-replicative stage (trypomastigotes). Two times higher level in epimastigotes than in amastigotes and five times higher level than in trypomastigotes
brenda
-
the replicative life stages (epimastigotes and amastigotes) show higher TcCox15 levels than the infective and non-replicative stage (trypomastigotes). Two times higher level in epimastigotes than in amastigotes and five times higher level than in trypomastigotes
-
brenda
the replicative life stages (epimastigotes and amastigotes) show higher TcCox15 levels than the infective and non-replicative stage (trypomastigotes). Two times higher level in epimastigotes than in amastigotes and five times higher level than in trypomastigotes
brenda
-
the replicative life stages (epimastigotes and amastigotes) show higher TcCox15 levels than the infective and non-replicative stage (trypomastigotes). Two times higher level in epimastigotes than in amastigotes and five times higher level than in trypomastigotes
-
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
the enzyme is an integral membrane protein
-
brenda
membrane protein with 8 transmembrane segments
brenda
the deduced protein sequence indicates that the enzyme is a 35-kDa intrinsic membrane protein with seven hydrophobic segments
brenda
Cox15p is a constituent of the mitochondrial inner membrane
brenda
the enzyme is an integral membrane protein
brenda
additional information
BsHAS has eight transmembrane helices (TM1-TM8) and two long extracellular loop regions (ECL1 and ECL3)
-
brenda
additional information
-
BsHAS has eight transmembrane helices (TM1-TM8) and two long extracellular loop regions (ECL1 and ECL3)
-
-
brenda
Highest Expressing Human Cell Lines
Cell Line LinksPlease wait a moment until the data is sorted. This message will disappear when the data is sorted.
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
evolution
A0A2G2K2S2
cytochrome oxidase containing heme A (COX) is a common terminal oxidase in aerobic bacteria and is the only one in mammalian mitochondria. The synthesis of heme A is catalyzed by heme A synthase (CtaA/Cox15), an enzyme that most likely co-evolved with COX. The ancestral type of heme A synthases is present in iron-oxidizing Proteobacteria such as Acidithiobacillus spp. These bacteria also contain a deep branching form of the major COX subunit (COX1) and an ancestral variant of CtaG, a protein that is specifically required for COX biogenesis. Sequence and phylogenetic analysis. The ancestors of extant iron-oxidizers were the first to evolve COX. Acidophilic iron-oxidizing prokaryotes lived on emerged land around the time for which there is the earliest geochemical evidence of aerobic respiration on earth. Hence, ecological niches of iron oxidation have apparently promoted the evolution of aerobic respiration. Heme A-containing proton pumping cytochrome oxidase, COX, of the family A of heme copper oxygen reductases (HCO) is widespread in all kingdoms of life due to extensive lateral gene transfer (LGT). Subsequently bacterial COX became the cytochrome c oxidase of mitochondrial organelles. Synthesis of heme A requires ambient oxygen levels that are attained in primordial earth only after the great oxygenation event (GOE). In bacteria, the genes for COX proteins and those for heme A synthesis and COX assembly factors show modularity, i.e., the genes are frequently clustered in the chromosome. The heme A synthase enzyme protein belongs to the superfamily of Cox15 (CtaA, cl19388) members of which are widespread among prokaryotes. Phylogenetic analyses, phylogeny and evolution of heme A synthase
evolution
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cytochrome oxidase containing heme A (COX) is a common terminal oxidase in aerobic bacteria and is the only one in mammalian mitochondria. The synthesis of heme A is catalyzed by heme A synthase (CtaA/Cox15), an enzyme that most likely co-evolved with COX. The ancestral type of heme A synthases is present in iron-oxidizing Proteobacteria such as Acidithiobacillus spp. These bacteria also contain a deep branching form of the major COX subunit (COX1) and an ancestral variant of CtaG, a protein that is specifically required for COX biogenesis. Sequence and phylogenetic analysis. The ancestors of extant iron-oxidizers were the first to evolve COX. Acidophilic iron-oxidizing prokaryotes lived on emerged land around the time for which there is the earliest geochemical evidence of aerobic respiration on earth. Hence, ecological niches of iron oxidation have apparently promoted the evolution of aerobic respiration. Heme A-containing proton pumping cytochrome oxidase, COX, of the family A of heme copper oxygen reductases (HCO) is widespread in all kingdoms of life due to extensive lateral gene transfer (LGT). Subsequently bacterial COX became the cytochrome c oxidase of mitochondrial organelles. Synthesis of heme A requires ambient oxygen levels that are attained in primordial earth only after the great oxygenation event (GOE). In bacteria, the genes for COX proteins and those for heme A synthesis and COX assembly factors show modularity, i.e., the genes are frequently clustered in the chromosome. The heme A synthase enzyme protein belongs to the superfamily of Cox15 (CtaA, cl19388) members of which are widespread among prokaryotes. Phylogenetic analyses, phylogeny and evolution of heme A synthase
evolution
cytochrome oxidase containing heme A (COX) is a common terminal oxidase in aerobic bacteria and is the only one in mammalian mitochondria. The synthesis of heme A is catalyzed by heme A synthase (CtaA/Cox15), an enzyme that most likely co-evolved with COX. The ancestral type of heme A synthases is present in iron-oxidizing Proteobacteria such as Acidithiobacillus spp. These bacteria also contain a deep branching form of the major COX subunit (COX1) and an ancestral variant of CtaG, a protein that is specifically required for COX biogenesis. Sequence and phylogenetic analysis. The ancestors of extant iron-oxidizers were the first to evolve COX. Acidophilic iron-oxidizing prokaryotes lived on emerged land around the time for which there is the earliest geochemical evidence of aerobic respiration on earth. Hence, ecological niches of iron oxidation have apparently promoted the evolution of aerobic respiration. Heme A-containing proton pumping cytochrome oxidase, COX, of the family A of heme copper oxygen reductases (HCO) is widespread in all kingdoms of life due to extensive lateral gene transfer (LGT). Subsequently bacterial COX became the cytochrome c oxidase of mitochondrial organelles. Synthesis of heme A requires ambient oxygen levels that are attained in primordial earth only after the great oxygenation event (GOE). In bacteria, the genes for COX proteins and those for heme A synthesis and COX assembly factors show modularity, i.e., the genes are frequently clustered in the chromosome. The heme A synthase enzyme protein belongs to the superfamily of Cox15 (CtaA, cl19388) members of which are widespread among prokaryotes. Phylogenetic analyses, phylogeny and evolution of heme A synthase
evolution
enzyme HAS from the hyperthermophilic bacterium Aquifex aeolicus (AaHAS) belongs to class C. HAS can form homooligomeric complexes, which is evolutionary conserved and essential for the biological function of eukaryotic HAS
malfunction
overexpression of a non-functional mutant causes a reduction in heme A content. This hindrance in the heme A synthesis provokes a reduction on CcO activity and, in consequence, an impairment on Trypanosoma cruzi survival, proliferation and infectivity
malfunction
cox15 mutants are blocked in heme A but not heme O biosynthesis
malfunction
deletion of the ctaA gene in Bacillus cereus strain AH187 strain results in loss of cytochrome caa3 activity. Bacillus cereus grown in glucose-containing medium compensates for the loss of cytochrome caa3 activity by remodeling its respiratory metabolism. This remodeling involves upregulation of cytochrome aa3 and several proteins involved in redox stress response to circumvent suboptimal respiratory metabolism. CtaA deletion changes the surface-composition of Bacillus cereus, affecting its motility, autoaggregation phenotype, and the kinetics of biofilm formation. Strikingly, proteome remodeling made the DELTActaA mutant more resistant to cold and exogenous oxidative stresses compared to its parent strain. The ctaA inactivation can improve Bacillus cereus fitness in a nutrient-limited environment. DELTActaA mutant phenotype, overview
malfunction
-
overexpression of a non-functional mutant causes a reduction in heme A content. This hindrance in the heme A synthesis provokes a reduction on CcO activity and, in consequence, an impairment on Trypanosoma cruzi survival, proliferation and infectivity
-
malfunction
-
deletion of the ctaA gene in Bacillus cereus strain AH187 strain results in loss of cytochrome caa3 activity. Bacillus cereus grown in glucose-containing medium compensates for the loss of cytochrome caa3 activity by remodeling its respiratory metabolism. This remodeling involves upregulation of cytochrome aa3 and several proteins involved in redox stress response to circumvent suboptimal respiratory metabolism. CtaA deletion changes the surface-composition of Bacillus cereus, affecting its motility, autoaggregation phenotype, and the kinetics of biofilm formation. Strikingly, proteome remodeling made the DELTActaA mutant more resistant to cold and exogenous oxidative stresses compared to its parent strain. The ctaA inactivation can improve Bacillus cereus fitness in a nutrient-limited environment. DELTActaA mutant phenotype, overview
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metabolism
the enzyme is involved in biosynthesis of heme A, an obligatory cofactor in eukaryotic cytochrome c oxidase. The enzyme catalyses the conversion of heme o to heme a by two successive hydroxylations of the methyl group at C-8, using water as the oxygen source. The first hydroxylation forms heme i, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group of heme a
metabolism
the enzyme is involved in biosynthesis of heme A, an obligatory cofactor in eukaryotic cytochrome c oxidase. The enzyme catalyses the conversion of heme o to heme a by two successive hydroxylations of the methyl group at C-8, using water as the oxygen source. The first hydroxylation forms heme i, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group of heme a
metabolism
the enzyme is required for heme A biosynthesis
metabolism
-
heme O hydroxylation, catalyzed by Cox15p is an important regulatory step
metabolism
A0A2G2K2S2
biosynthesis of COX requires multiple proteins that catalyze the formation of heme A, or are involved in the insertion of the metal cofactors and overall assembly of the enzyme in the membrane. Heme A as a prosthetic group is only found in respiratory oxygen reductases. The biosynthesis of heme A from protoheme IX (heme B) involves two enzymes. First heme O synthase, CtaB/Cox10/CyoE, catalyzes formation of heme O, and then heme A synthase, CtaA/Cox15, converts heme O into heme A. Synthesis of heme A requires ambient oxygen levels
metabolism
-
biosynthesis of COX requires multiple proteins that catalyze the formation of heme A, or are involved in the insertion of the metal cofactors and overall assembly of the enzyme in the membrane. Heme A as a prosthetic group is only found in respiratory oxygen reductases. The biosynthesis of heme A from protoheme IX (heme B) involves two enzymes. First heme O synthase, CtaB/Cox10/CyoE, catalyzes formation of heme O, and then heme A synthase, CtaA/Cox15, converts heme O into heme A. Synthesis of heme A requires ambient oxygen levels
metabolism
biosynthesis of COX requires multiple proteins that catalyze the formation of heme A, or are involved in the insertion of the metal cofactors and overall assembly of the enzyme in the membrane. Heme A as a prosthetic group is only found in respiratory oxygen reductases. The biosynthesis of heme A from protoheme IX (heme B) involves two enzymes. First heme O synthase, CtaB/Cox10/CyoE, catalyzes formation of heme O, and then heme A synthase, CtaA/Cox15, converts heme O into heme A. Synthesis of heme A requires ambient oxygen levels
metabolism
heme a synthase (HAS) catalyzes the oxidation of the C8 methyl group of heme o (pyrrole ring D) to a formyl group. This is the second and final step of the heme a biosynthetic pathway
metabolism
heme a synthase (HAS) catalyzes the oxidation of the C8 methyl group of heme o (pyrrole ring D) to a formyl group. This is the second and final step of the heme a biosynthetic pathway
metabolism
-
the enzyme is involved in biosynthesis of heme A, an obligatory cofactor in eukaryotic cytochrome c oxidase. The enzyme catalyses the conversion of heme o to heme a by two successive hydroxylations of the methyl group at C-8, using water as the oxygen source. The first hydroxylation forms heme i, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group of heme a
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metabolism
-
heme a synthase (HAS) catalyzes the oxidation of the C8 methyl group of heme o (pyrrole ring D) to a formyl group. This is the second and final step of the heme a biosynthetic pathway
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physiological function
the COX15 protein is essential for the assembly of yeast cytochrome oxidase
physiological function
the enzyme is required for starvation survival, recovery, and cytochrome biosynthesis
physiological function
A0A2G2K2S2
heme A synthase is required for the biosynthesis of the characteristic heme prosthetic groups in cytochrome c oxidase, COX
physiological function
-
heme A synthase is required for the biosynthesis of the characteristic heme prosthetic groups in cytochrome c oxidase, COX
physiological function
heme A synthase is required for the biosynthesis of the characteristic heme prosthetic groups in cytochrome c oxidase, COX
physiological function
heme A is an essential cofactor for respiratory terminal oxidases and vital for respiration in aerobic organisms. The final step of heme A biosynthesis is formylation of the C-8 methyl group of heme molecule by heme A synthase (HAS)
physiological function
heme a synthase (HAS) catalyzes the oxidation of the C8 methyl group of heme o (pyrrole ring D) to a formyl group. This is the second and final step of the heme a biosynthetic pathway. The conversion of pyrrole ring D's methyl substituent to an electron-withdrawing formyl group increases the redox potential of heme a relative to hemes b and o. This increase in redox potential is due to a decrease in the binding affinity of ferric (Fe3+) heme a relative to ferrous (Fe2+) heme a. The destabilization of ferric heme a's binding affinity is offset by the presence of the hydroxyethylfarnesyl substituent, which substantially increases the binding affinity of hemes o and a for a heme protein maquette relative to heme b. Functionally, in an aa3 terminal oxidase, the high midpoint reduction potential of heme a (+380 mV) allows it to accept electrons from relatively poor electron donors such as cytochrome c. The two modified porphyrin ring substituents of heme a appear to act in concert to provide a heme cofactor that has a relatively high reduction potential, yet can still bind tightly to a heme-copper oxidase
physiological function
heme a synthase (HAS) catalyzes the oxidation of the C8 methyl group of heme o (pyrrole ring D) to a formyl group. This is the second and final step of the heme a biosynthetic pathway. The conversion of pyrrole ring D's methyl substituent to an electron-withdrawing formyl group increases the redox potential of heme a relative to hemes b and o. This increase in redox potential is due to a decrease in the binding affinity of ferric (Fe3+) heme a relative to ferrous (Fe2+) heme a. The destabilization of ferric heme a's binding affinity is offset by the presence of the hydroxyethylfarnesyl substituent, which substantially increases the binding affinity of hemes o and a for a heme protein maquette relative to heme b. Functionally, in an aa3 terminal oxidase, the high midpoint reduction potential of heme a (+380 mV) allows it to accept electrons from relatively poor electron donors such as cytochrome c. The two modified porphyrin ring substituents of heme a appear to act in concert to provide a heme cofactor that has a relatively high reduction potential, yet can still bind tightly to a heme-copper oxidase
physiological function
the branched aerobic respiratory chain in Bacillus cereus comprises three terminal oxidases: cytochromes aa3, caa3, and bd. Cytochrome caa3 requires heme A for activity, which is produced from heme O by heme A synthase (CtaA). Bacillus cereus CtaA is required for cytochrome aa3 oxidase activity, and optimal growth
physiological function
heme A synthase (HAS) catalyzes the biosynthesis of heme A, which is a prerequisite for cellular respiration in a wide range of aerobic organisms
physiological function
-
heme A is an essential cofactor for respiratory terminal oxidases and vital for respiration in aerobic organisms. The final step of heme A biosynthesis is formylation of the C-8 methyl group of heme molecule by heme A synthase (HAS)
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physiological function
-
heme a synthase (HAS) catalyzes the oxidation of the C8 methyl group of heme o (pyrrole ring D) to a formyl group. This is the second and final step of the heme a biosynthetic pathway. The conversion of pyrrole ring D's methyl substituent to an electron-withdrawing formyl group increases the redox potential of heme a relative to hemes b and o. This increase in redox potential is due to a decrease in the binding affinity of ferric (Fe3+) heme a relative to ferrous (Fe2+) heme a. The destabilization of ferric heme a's binding affinity is offset by the presence of the hydroxyethylfarnesyl substituent, which substantially increases the binding affinity of hemes o and a for a heme protein maquette relative to heme b. Functionally, in an aa3 terminal oxidase, the high midpoint reduction potential of heme a (+380 mV) allows it to accept electrons from relatively poor electron donors such as cytochrome c. The two modified porphyrin ring substituents of heme a appear to act in concert to provide a heme cofactor that has a relatively high reduction potential, yet can still bind tightly to a heme-copper oxidase
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physiological function
-
the enzyme is required for starvation survival, recovery, and cytochrome biosynthesis
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physiological function
-
the branched aerobic respiratory chain in Bacillus cereus comprises three terminal oxidases: cytochromes aa3, caa3, and bd. Cytochrome caa3 requires heme A for activity, which is produced from heme O by heme A synthase (CtaA). Bacillus cereus CtaA is required for cytochrome aa3 oxidase activity, and optimal growth
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additional information
the N- and C-terminal halves of enzyme HAS consist of four-helix bundles and they align in a pseudo twofold symmetry manner. Each bundle contains a pair of histidine residues and forms a heme-binding domain. The C-half domain binds a cofactor-heme molecule, while the N-half domain is vacant. A completely conserved glutamate, Glu57 in Bacillus subtilis, is the catalytic residue for the formylation reaction. Substrate-heme binding structure and mechanism, overview. Structure comparisons
additional information
structure-function analysis of HAS, comparison to heme o synthase, HOS, overview
additional information
the elongated extracellular loops of eukaryotic HAS may play a role in forming protein-protein interactions. Homology modeling of Saccharomyces cerevisiae cytochrome c oxidase based on the bovine crystal structure. Structure-function analysis of HAS, comparison to heme o synthase, HOS, overview
additional information
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the N- and C-terminal halves of enzyme HAS consist of four-helix bundles and they align in a pseudo twofold symmetry manner. Each bundle contains a pair of histidine residues and forms a heme-binding domain. The C-half domain binds a cofactor-heme molecule, while the N-half domain is vacant. A completely conserved glutamate, Glu57 in Bacillus subtilis, is the catalytic residue for the formylation reaction. Substrate-heme binding structure and mechanism, overview. Structure comparisons
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additional information
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structure-function analysis of HAS, comparison to heme o synthase, HOS, overview
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Show AA Sequence and Transmembrane Helices (3335 entries)
Please use the AA Sequence and Transmembrane Helices Search for a specific query.
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
heterotrimer
homodimer
homooligomer
multimer
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Cox15 exhibits homotypic interactions, forming highly stable complexes dependent upon hydrophobic interactions. This multimerization is evolutionarily conserved and independent of heme levels and heme a synthase catalytic activity. Cox15 multimerization is important for heme a biosynthesis and/or transfer to maturing cytochrome c oxidase
trimer
3 * 34960, about, SDS-PAGE, spectroetric assays, and sequence calculation
additional information
heterotrimer
the 11-subunit Saccharomyces cerevisiae cytochrome c oxidase (a mitochondrial-type aa3 oxidase) contains subunit I, which binds low-spin heme a, high-spin heme a3, and CuB, subunit II, which includes the binuclear CuA site, and subunit III
additional information
the initiator methionine is cleaved from the mature AaHAS. The AaHAS trimer is mainly formed by hydrophobic interactions
additional information
the N- and C-terminal halves of enzyme HAS consist of four-helix bundles and they align in a pseudo twofold symmetry manner. Each bundle contains a pair of histidine residues and forms a heme-binding domain. The C-half domain binds a cofactor-heme molecule, while the N-half domain is vacant. BsHAS has eight transmembrane helices (TM1-TM8) and two long extracellular loop regions (ECL1 and ECL3). The N-half (TM1-TM4) and C-half (TM5-TM8) domains are connected by an intracellular loop (ICL2). Each domain is formed from four-helix bundles and is organized in counterclockwise order as viewed from the extracellular side. Each four-helix bundle contains a pair of conserved histidine residues and forms a heme-binding site. The C-half domain has one heme B molecule, while a cavity exists in the N-half domain. The C-half domain is the cofactor-heme binding domain and the N-half domain is the substrate-heme binding domain
additional information
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the N- and C-terminal halves of enzyme HAS consist of four-helix bundles and they align in a pseudo twofold symmetry manner. Each bundle contains a pair of histidine residues and forms a heme-binding domain. The C-half domain binds a cofactor-heme molecule, while the N-half domain is vacant. BsHAS has eight transmembrane helices (TM1-TM8) and two long extracellular loop regions (ECL1 and ECL3). The N-half (TM1-TM4) and C-half (TM5-TM8) domains are connected by an intracellular loop (ICL2). Each domain is formed from four-helix bundles and is organized in counterclockwise order as viewed from the extracellular side. Each four-helix bundle contains a pair of conserved histidine residues and forms a heme-binding site. The C-half domain has one heme B molecule, while a cavity exists in the N-half domain. The C-half domain is the cofactor-heme binding domain and the N-half domain is the substrate-heme binding domain
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified recombinant, detagged, ultrafiltrated, and substrate-free enzyme, mixing of 500 nl of 20 mg/ml protein solution with 0.015 ml of precipitant solution containing 30% v/v PEG 600, 100 mM NaCl, 100 mM Li2SO4, and 100 mM Na-HEPES, pH 7.0, and equilibration against 0.3 ml of precipitant solution, 1 month, X-ray diffraction structure determination and analysis at 2.2 A resolution, modeling
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C191A/C197A
C35A/C42A
DELTA211-217
Bacillus subtilis LMT20R is deleted for the ctaA gene and, therefore, completely blocked in heme A synthesis. Plasmid pH216MS is obtained from plasmid pH216M (encoding the mutant CtaA-H216M) and carries a 21 bp deletion in ctaA. The CtaADELTA211-217 variant encoded by pH216MS is active in heme A synthesis and supports assembly of normal levels of cytochrome caa3
E57A
heme content of the mutant enzyme is 62% compared to wild-type enzyme
E57A/H216A
heme content of the mutant enzyme is 28% compared to wild-type enzyme
E57A/H278A
heme content of the mutant enzyme is 42% compared to wild-type enzyme
E57Q
heme content of the mutant enzyme is 65% compared to wild-type enzyme
H123A
heme content of the mutant enzyme is 74% compared to wild-type enzyme
H123L
H123M
H123Q
heme content of the mutant enzyme is 64% compared to wild-type enzyme
H216A
heme content of the mutant enzyme is 22% compared to wild-type enzyme
H216A-H278A
heme content of the mutant enzyme is 5% compared to wild-type enzyme
H216M
H216M/DELTA211-217
Bacillus subtilis LMT20R is deleted for the ctaA gene and, therefore, completely blocked in heme A synthesis. Plasmid pH216MS is obtained from plasmid pH216M (encoding the mutant CtaA-H216M) and carries a 21 bp deletion in ctaA. The CtaADELTA211-217 variant encoded by pH216MS is active in heme A synthesis and supports assembly of normal levels of cytochrome caa3
H216Q
heme content of the mutant enzyme is 33% compared to wild-type enzyme
H216Q-H278Q
heme content of the mutant enzyme is 6% compared to wild-type enzyme
H278A
heme content of the mutant enzyme is 56% compared to wild-type enzyme
H278C
heme content of the mutant enzyme is 14% compared to wild-type enzyme
H278M
H278Q
heme content of the mutant enzyme is 15% compared to wild-type enzyme
H60A
heme content of the mutant enzyme is 74% compared to wild-type enzyme
H60A/H123A
heme content of the mutant enzyme is 88% compared to wild-type enzyme
H60M
H60Q
heme content of the mutant enzyme is 65% compared to wild-type enzyme
H60Q-H123Q
heme content of the mutant enzyme is 83% compared to wild-type enzyme
Q103A
heme content of the mutant enzyme is 82% compared to wild-type enzyme
Q257A
heme content of the mutant enzyme is 78% compared to wild-type enzyme
R217A
heme content of the mutant enzyme is 84% compared to wild-type enzyme
R217Q
heme content of the mutant enzyme is 89% compared to wild-type enzyme
R61A
heme content of the mutant enzyme is 77% compared to wild-type enzyme
R61Q
heme content of the mutant enzyme is 79% compared to wild-type enzyme
W39A
heme content of the mutant enzyme is 84% compared to wild-type enzyme
DELTA211-217
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Bacillus subtilis LMT20R is deleted for the ctaA gene and, therefore, completely blocked in heme A synthesis. Plasmid pH216MS is obtained from plasmid pH216M (encoding the mutant CtaA-H216M) and carries a 21 bp deletion in ctaA. The CtaADELTA211-217 variant encoded by pH216MS is active in heme A synthesis and supports assembly of normal levels of cytochrome caa3
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E57A
-
heme content of the mutant enzyme is 62% compared to wild-type enzyme
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E57Q
-
heme content of the mutant enzyme is 65% compared to wild-type enzyme
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H123L
H123M
H216M
H216M/DELTA211-217
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Bacillus subtilis LMT20R is deleted for the ctaA gene and, therefore, completely blocked in heme A synthesis. Plasmid pH216MS is obtained from plasmid pH216M (encoding the mutant CtaA-H216M) and carries a 21 bp deletion in ctaA. The CtaADELTA211-217 variant encoded by pH216MS is active in heme A synthesis and supports assembly of normal levels of cytochrome caa3
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H60A
-
heme content of the mutant enzyme is 74% compared to wild-type enzyme
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H60M
H60Q
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heme content of the mutant enzyme is 65% compared to wild-type enzyme
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W39A
-
heme content of the mutant enzyme is 84% compared to wild-type enzyme
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R217W
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mutations of COX15 causing single amino acid conversions associated with fatal infantile hypertrophic cardiomyopathy and the neurological disorder Leigh syndrome results in impaired catalytic function, and the mutation affects oligomeric properties of the enzyme. The mutations affects protein folding and heme binding
S344P
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mutations of COX15 causing single amino acid conversions associated with fatal infantile hypertrophic cardiomyopathy and the neurological disorder Leigh syndrome results in impaired stability. The mutations affect protein folding and heme binding
H129A
overexpression of the non-functional TcCox15 mutants causes a negative effect over heme A synthesis, affecting the function of the CcO complex and proliferation of epimastigotes
H206A
overexpression of the non-functional TcCox15 mutants causes a negative effect over heme A synthesis, affecting the function of the CcO complex and proliferation of epimastigotes
H307A
overexpression of the non-functional TcCox15 mutants causes a negative effect over heme A synthesis, affecting the function of the CcO complex and proliferation of epimastigotes
H129A
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overexpression of the non-functional TcCox15 mutants causes a negative effect over heme A synthesis, affecting the function of the CcO complex and proliferation of epimastigotes
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H206A
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overexpression of the non-functional TcCox15 mutants causes a negative effect over heme A synthesis, affecting the function of the CcO complex and proliferation of epimastigotes
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H307A
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overexpression of the non-functional TcCox15 mutants causes a negative effect over heme A synthesis, affecting the function of the CcO complex and proliferation of epimastigotes
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additional information
C191A/C197A
the heme content is reduced to a half of the wild-type level
C35A/C42A
heme content of the mutant enzyme is 77% compared to wild-type enzyme
H216M
the H216M variant binds the enzyme substrate heme O, probably with methionine as an axial ligand, but is defective in heme A synthesis and accumulates a mono-hydroxylated reaction intermediate, heme I
H216M
the variant has a decreased heme A synthase activity. It contains heme B, heme O, and heme I, as well as trace amounts of heme A
H216M
heme content of the mutant enzyme is 37% compared to wild-type enzyme
H278M
heme content of the mutant enzyme is 40% compared to wild-type enzyme
H60M
the mutant enzyme contains heme B and heme A at levels comparable to that of wild-type enzyme
H216M
-
the H216M variant binds the enzyme substrate heme O, probably with methionine as an axial ligand, but is defective in heme A synthesis and accumulates a mono-hydroxylated reaction intermediate, heme I
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H216M
-
the variant has a decreased heme A synthase activity. It contains heme B, heme O, and heme I, as well as trace amounts of heme A
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H60M
-
the mutant enzyme contains heme B and heme A at levels comparable to that of wild-type enzyme
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additional information
cellular proteome remodeling in DELTActaA mutant compared to its parental wild-type strain AH187 at early exponential (EE), late exponential (LE), and stationary (S) growth phases, overview. Comparison of effects of different stresses on wild-type and mutant strains. Upregulation of sporulation-associated proteins during exponential growth of the DELTActaA mutant suggests that a signal that normally makes sporulation a post-exponential growth-phase response in wild-type strains can be detected earlier in DELTActaA. This signal could be redox stress, which DctaA cells are exposed to from the beginning of growth
additional information
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cellular proteome remodeling in DELTActaA mutant compared to its parental wild-type strain AH187 at early exponential (EE), late exponential (LE), and stationary (S) growth phases, overview. Comparison of effects of different stresses on wild-type and mutant strains. Upregulation of sporulation-associated proteins during exponential growth of the DELTActaA mutant suggests that a signal that normally makes sporulation a post-exponential growth-phase response in wild-type strains can be detected earlier in DELTActaA. This signal could be redox stress, which DctaA cells are exposed to from the beginning of growth
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additional information
-
mutations in COX15 repress heme O synthesis and have a dominant effect when combined with other mutations
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
62.4 - 75.3
purified AaHAS trimer, nano-differential scanning fluorimetry, two melting temperatures, probably due to the presence of two distinct thermally induced transitions
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
intracellular copper levels do not affect the stability of the enzyme
intracellular copper levels do not affect the stability of the enzyme
intracellular copper levels do not affect the stability of the enzyme
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OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
the stability of Cox15 is not decreased in the absence of cytochrome c oxidase
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727866
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged enzyme by membrane isolation, nickel affinity chromatography, tag cleavage by thrombin, and gel filtration
recombinant Strep II-tagged enzyme from Escherichia coli by affinity chromatography (elution with desthiobiotin), and gel filtration. Both heme O and heme B, but not heme A, are identified in the purified AaHAS, while heme A is absent
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli
expression in Escherichia coli BL21 cells. Heme O synthase and heme A synthase heterologously expressed in Escherichia coli form a complex in vivo
expression in Escherichia coli. Bacillus stearothermophilus CtaA produced in Escherichia coli catalyzes the conversion of heme O to heme A in vitro
gene COA89_14165, DNA and amino acid sequence comparisons and analysis, COX gene clusters of iron-oxidizing bacteria, phylogenetic analysis
gene ENJ61_04570, amino acid sequence determination and analysis, recombinant expression of Strep II-tagged enzyme in Escherichia coli
heterologously expressed in Escherichia coli
expression in Escherichia coli BL21 cells. Heme O synthase and heme A synthase heterologously expressed in Escherichia coli form a complex in vivo
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expression in Escherichia coli BL21 cells. Heme O synthase and heme A synthase heterologously expressed in Escherichia coli form a complex in vivo
gene COA89_14165, DNA and amino acid sequence comparisons and analysis, COX gene clusters of iron-oxidizing bacteria, phylogenetic analysis
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gene COA89_14165, DNA and amino acid sequence comparisons and analysis, COX gene clusters of iron-oxidizing bacteria, phylogenetic analysis
A0A2G2K2S2
gene COA89_14165, DNA and amino acid sequence comparisons and analysis, COX gene clusters of iron-oxidizing bacteria, phylogenetic analysis
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
transcription of COX15 is positively regulated by by Hap1, a transcription factor whose activity is positively controlled by intracellular heme concentration. While COX15 mRNA levels increase with increasing intracellular heme levels in the presence of Hap1, the mRNA levels of COX15 are depressed and independent of intracellular heme levels in the absence of Hap1
transcription of COX15 is positively regulated by by Hap1, a transcription factor whose activity is positively controlled by intracellular heme concentration. While COX15 mRNA levels increase with increasing intracellular heme levels in the presence of Hap1, the mRNA levels of COX15 are depressed and independent of intracellular heme levels in the absence of Hap1
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transcription of COX15 is positively regulated by by Hap1, a transcription factor whose activity is positively controlled by intracellular heme concentration. While COX15 mRNA levels increase with increasing intracellular heme levels in the presence of Hap1, the mRNA levels of COX15 are depressed and independent of intracellular heme levels in the absence of Hap1
Saccharomyces cerevisiae W303a
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Brown, B.M.; Wang, Z.; Brown, K.R.; Cricco, J.A.; Hegg, E.L.
Heme O synthase and heme A synthase from Bacillus subtilis and Rhodobacter sphaeroides interact in Escherichia coli
Biochemistry
43
13541-13548
2004
Bacillus subtilis, Cereibacter sphaeroides (Q3IXW9), Cereibacter sphaeroides, Cereibacter sphaeroides ATCC 17023 (Q3IXW9)
brenda
Wang, Z.; Wang, Y.; Hegg, E.L.
Regulation of the heme A biosynthetic pathway: differential regulation of heme A synthase and heme O synthase in Saccharomyces cerevisiae
J. Biol. Chem.
284
839-847
2009
Saccharomyces cerevisiae, Saccharomyces cerevisiae W303a
brenda
Hegg, E.
Biosynthesis and regulation of the heme a biosynthetic pathway
ACS Symp. Ser.
1012
31-46
2009
Bacillus subtilis, Cereibacter sphaeroides
-
brenda
Merli, M.L.; Cirulli, B.A.; Menendez-Bravo, S.M.; Cricco, J.A.
Heme A synthesis and CcO activity are essential for Trypanosoma cruzi infectivity and replication
Biochem. J.
474
2315-2332
2017
Trypanosoma cruzi (V5BC58), Trypanosoma cruzi, Trypanosoma cruzi Dm28c (V5BC58)
brenda
Brown, K.; Allan, B.; Do, P.; Hegg, E.
Identification of novel hemes generated by heme A synthase Evidence for two successive monooxygenase reactions
Biochemistry
41
10906-10913
2002
Bacillus subtilis (P12946), Bacillus subtilis, Bacillus subtilis 168 (P12946)
brenda
Brown, K.; Brown, B.; Hoagland, E.; Mayne, C.; Hegg, E.
Heme A synthase does not incorporate molecular oxygen into the formyl group of heme A
Biochemistry
43
8616-8624
2004
Bacillus subtilis (P12946), Bacillus subtilis 168 (P12946)
brenda
Morrison, M.; Cricco, J.; Hegg, E.
The biosynthesis of heme O and heme A is not regulated by copper
Biochemistry
44
12554-12563
2005
Bacillus subtilis, Cereibacter sphaeroides (Q3IXW9), Cereibacter sphaeroides, Cereibacter sphaeroides ATCC 17023 (Q3IXW9), Saccharomyces cerevisiae
brenda
Hederstedt, L.
Heme A biosynthesis
Biochim. Biophys. Acta
1817
920-927
2012
Aeropyrum pernix, Bacillus subtilis (P12946), Bacillus subtilis 168 (P12946), Halobacterium salinarum, Saccharomyces cerevisiae, Schizosaccharomyces pombe
brenda
Sakamoto, J.; Hayakawa, A.; Uehara, T.; Noguchi, S.; Sone, N.
Cloning of Bacillus stearothermophilus ctaA and heme a synthesis with the ctaA protein produced in Escherichia coli
Biosci. Biotechnol. Biochem.
63
96-103
1999
Geobacillus stearothermophilus (P94346), Geobacillus stearothermophilus
brenda
Barros, M.H.; Carlson, C.G.; Glerum, D.M.; Tzagoloff, A.
Involvement of mitochondrial ferredoxin and Cox15p in hydroxylation of heme O
FEBS Lett.
492
133-138
2001
Saccharomyces cerevisiae (P40086), Saccharomyces cerevisiae
brenda
Barros, M.; Tzagoloff, A.
Regulation of the heme A biosynthetic pathway in Saccharomyces cerevisiae
FEBS Lett.
516
119-123
2002
Saccharomyces cerevisiae
brenda
Lewin, A.; Hederstedt, L.
Compact archaeal variant of heme A synthase
FEBS Lett.
580
5351-5356
2006
Aeropyrum pernix (Q9YBA3), Aeropyrum pernix, Aeropyrum pernix ATCC 700893 (Q9YBA3)
brenda
Lewin, A.; Hederstedt, L.
Promoted evolution of a shortened variant of heme A synthase in the membrane of Bacillus subtilis
FEBS Lett.
582
1330-1334
2008
Bacillus subtilis (P12946), Bacillus subtilis, Bacillus subtilis 168 (P12946)
brenda
Buchensky, C.; Almirn, P.; Mantilla, B.; Silber, A.; Cricco, J.
The Trypanosoma cruzi proteins TcCox10 and TcCox15 catalyze the formation of heme A in the yeast Saccharomyces cerevisiae
FEMS Microbiol. Lett.
312
133-141
2010
Trypanosoma cruzi (Q4DTN9), Trypanosoma cruzi
brenda
Svensson, B.; Hederstedt, L.
Bacillus subtilis CtaA is a heme-containing membrane protein involved in heme A biosynthesis
J. Bacteriol.
176
6663-6671
1994
Bacillus subtilis
brenda
Clements, M.; Watson, S.; Poole, R.; Foster, S.
CtaA of Staphylococcus aureus is required for starvation survival, recovery, and cytochrome biosynthesis
J. Bacteriol.
181
501-507
1999
Staphylococcus aureus (Q2G2C0), Staphylococcus aureus, Staphylococcus aureus NCTC 8325 (Q2G2C0)
brenda
Hederstedt, L.; Lewin, A.; Throne-Holst, M.
Heme A synthase enzyme functions dissected by mutagenesis of Bacillus subtilis CtaA
J. Bacteriol.
187
8361-8369
2005
Bacillus subtilis (P12946), Bacillus subtilis, Bacillus subtilis 168 (P12946)
brenda
Mogi, T.
Probing structure of heme A synthase from Bacillus subtilis by site-directed mutagenesis
J. Biochem.
145
625-633
2009
Bacillus subtilis (P12946), Bacillus subtilis, Bacillus subtilis 168 (P12946)
brenda
Glerum, D.M.; Muroff, I.; Jin, C.; Tzagoloff, A.
COX15 codes for a mitochondrial protein essential for the assembly of yeast cytochrome oxidase
J. Biol. Chem.
272
19088-19094
1997
Saccharomyces cerevisiae (P40086), Saccharomyces cerevisiae
brenda
Barros, M.; Nobrega, F.; Tzagoloff, A.
Mitochondrial ferredoxin is required for heme a synthesis in Saccharomyces cerevisiae
J. Biol. Chem.
277
9997-10002
2002
Saccharomyces cerevisiae
brenda
Swenson, S.; Cannon, A.; Harris, N.J.; Taylor, N.G.; Fox, J.L.; Khalimonchuk, O.
Analysis of oligomerization properties of heme a synthase provides insights into its function in eukaryotes
J. Biol. Chem.
291
10411-10425
2016
Saccharomyces cerevisiae
brenda
Rivett, D.E.; Heo, L.; Feig, M.; Hegg, E.L.
Biosynthesis and trafficking of heme o and heme a New structural insights and their implications for reaction mechanisms and prenylated heme transfer
Crit. Rev. Biochem. Mol. Biol.
56
640-668
2021
Bacillus subtilis (P12946), Bacillus subtilis 168 (P12946), no activity in Escherichia coli, Saccharomyces cerevisiae (P40086)
brenda
Degli Esposti, M.; Moya-Beltran, A.; Quatrini, R.; Hederstedt, L.
Respiratory heme A-containing oxidases originated in the ancestors of iron-oxidizing bacteria
Front. Microbiol.
12
664216
2021
Acidithiobacillus sp. (A0A2G2K2S2), Rhodobacter capsulatus (A0A4U1JV13), Acidithiobacillus ferrooxidans
brenda
Chateau, A.; Alpha-Bazin, B.; Armengaud, J.; Duport, C.
Heme A synthase deficiency affects the ability of Bacillus cereus to adapt to a nutrient-limited environment
Int. J. Mol. Sci.
23
1033
2022
Bacillus cereus (B7HMD0), Bacillus cereus AH187 (B7HMD0)
brenda
Zeng, H.; Zhu, G.; Zhang, S.; Li, X.; Martin, J.; Morgner, N.; Sun, F.; Peng, G.; Xie, H.; Michel, H.
Isolated heme A synthase from Aquifex aeolicus Is a trimer
mBio
11
1-9
2020
Aquifex aeolicus (A0A7C5L9E1)
brenda
Niwa, S.; Takeda, K.; Kosugi, M.; Tsutsumi, E.; Mogi, T.; Miki, K.
Crystal structure of heme A synthase from Bacillus subtilis
Proc. Natl. Acad. Sci. USA
115
11953-11957
2018
Bacillus subtilis (P12946), Bacillus subtilis 168 (P12946)
brenda
EXTERNAL LINKS (specific for EC-Number 1.17.99.9)
Transporter Classification Database (TCDB): 3.D.4.4.1
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Release 2026.1 (March 2026)
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