Literature summary extracted from

Pendini, N.R.; Bailey, L.M.; Booker, G.W.; Wilce, M.C.; Wallace, J.C.; Polyak, S.W.
Microbial biotin protein ligases aid in understanding holocarboxylase synthetase deficiency (2008), Biochim. Biophys. Acta, 1784, 973-982.

Cloned(Commentary)

EC Number	Cloned (Comment)	Organism
6.3.4.15	construction and expression of the C-terminal 87 amino acids of biotin carboxyl carrier protein, i.e. BCCP-87. cross-species activity of BPLs permitts functional cloning of the cDNA for yeast BPL through genetic complementation with a conditional lethal birA- strain of Escherichia coli	Escherichia coli
6.3.4.15	cross-species activity of BPLs permitts functional cloning of the cDNA for human BPL through genetic complementation with a conditional lethal birA? strain of Escherichia coli	Homo sapiens
6.3.4.15	cross-species activity of BPLs permitts functional cloning of the cDNA for yeast BPL through genetic complementation with a conditional lethal birA? strain of Escherichia coli	Saccharomyces cerevisiae

Crystallization (Commentary)

EC Number	Crystallization (Comment)	Organism
6.3.4.15	EcBPL domains determination through X-ray crystallography at 2.3 A resolution, and determination of the crystal structure of EcBPL in complex with biotin	Escherichia coli
6.3.4.15	PhBPL in complex with biotin, ATP and biotinyl-5'-AMP, X-ray diffraction and structure analysis at 1.6 A, 1.6 A, 1.45 A resolution, respectively. Structure-function relationship, modelling, overview	Pyrococcus horikoshii

Protein Variants

EC Number	Protein Variants	Comment	Organism
6.3.4.15	D571N	naturally occuring mutation, important in positioning K579 in the AMP binding site	Homo sapiens
6.3.4.15	D615Y	naturally occuring mutation in the loop between alpha3 and beta6 that cover AMP, may coordinate oxygens of the AMP phosphate	Homo sapiens
6.3.4.15	D634Y	naturally occuring mutation of a solvent exposed residue, distal to active site on alpha4 and alpha5, respectively	Homo sapiens
6.3.4.15	D715G	naturally occuring mutation on beta9, may be involved in capping and stabilising the catalytic domain structure	Homo sapiens
6.3.4.15	G518E	naturally occuring mutation close to the active site and part of the ligand-binding loop, the mutation may not allow as much flexibility of this loop. As part of the hydrophobic pocket, making this polar residue would perturb biotin binding	Homo sapiens
6.3.4.15	G581S	naturally occuring mutation of a residue involved in hydrophobic interactions with biotin in the binding pocket	Homo sapiens
6.3.4.15	G582R	naturally occuring mutation of a residue involved in hydrophobic interactions with biotin in the binding pocket	Homo sapiens
6.3.4.15	L237P	the mutant shows reduced catalytic activity compared to the wild-type enzyme	Escherichia coli
6.3.4.15	L470S	naturally occuring mutation in an unstructured loop distal to the ligand-binding site	Homo sapiens
6.3.4.15	additional information	HCS mutants with deletions up to Ala235 or Thr266 still show catalytic activity and can complement an enzyme-deficient Escherichia coli birA- strain. Enzyme deficiency can cause symptoms like ketoacidosis, feeding difficulties, hypotonia, seizures, developmental delay and dermal abnormalities such as rashes, dryness of the skin and alopecia, multiple carboxylase deficiency is caused by a lack of activity of the biotin-dependent enzymes, phenotypes, overview. Molecular modelling of mutations causing HCS deficiency, detailed overview	Homo sapiens
6.3.4.15	additional information	mutational analysis, overview. The C-terminal 87 amino acids of biotin carboxyl carrier protein, i.e. BCCP-87, are recognised and biotinylated by BPL as well as full-length BCCP due to the fact that this peptide adopts the tertiary structure that is required for the interaction with BPL	Escherichia coli
6.3.4.15	R118G	mutation of Arg118 to glycine in EcBPL causes altered affinity of BPL for biotin, increased dissociation rates for biotin and biotinyl-5'-AMP, and consequently, promiscuous biotinylation of inappropriate proteins	Escherichia coli
6.3.4.15	R508W/N511K	naturally occuring mutation of a residue critical in loop covering the ligand-binding site. R508 co-ordinates to the backbone carbonyl N712 to form a salt bridge, removing this would result in a more flexible loop, analogous to EcBPL R118 and R121 that co-ordinate oxygens within the AMP phosphate group	Homo sapiens
6.3.4.15	T462I	naturally occuring mutation in an unstructured loop distal to the ligand-binding site	Homo sapiens
6.3.4.15	V547G	naturally occuring mutation of a buried hydrophobic residue in alpha2 that reside near the AMP-binding beta5 strand	Homo sapiens
6.3.4.15	V550M	naturally occuring mutation of a buried hydrophobic residue in alpha2 that reside near the AMP-binding beta5 strand	Homo sapiens
6.3.4.15	Y456C	naturally occuring mutation in an unstructured loop distal to the ligand-binding site	Homo sapiens

Localization

EC Number	Localization	Comment	Organism	GeneOntology No.	Textmining
6.3.4.15	cytoplasm	-	Homo sapiens	5737	-
6.3.4.15	mitochondrial membrane	-	Homo sapiens	31966	-

Metals/Ions

EC Number	Metals/Ions	Comment	Organism	Structure
6.3.4.15	Mg2+	-	Homo sapiens
6.3.4.15	Mg2+	-	Saccharomyces cerevisiae
6.3.4.15	Mg2+	-	Pyrococcus horikoshii
6.3.4.15	Mg2+	-	Escherichia coli

Molecular Weight [Da]

EC Number	Molecular Weight [Da]	Molecular Weight Maximum [Da]	Comment	Organism
6.3.4.15	265000	-	acetyl-CoA carboxylase-1	Homo sapiens

Natural Substrates/ Products (Substrates)

EC Number	Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
6.3.4.15	ATP + biotin + apo-[acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	Pyrococcus horikoshii	-	AMP + diphosphate + [acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	-	?
6.3.4.15	ATP + biotin + apo-[acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	Homo sapiens	activation by biotinylation, HCS is the enzyme responsible for specifically attaching biotin onto the mammalian biotin domains. Biotinylation is catalysed through a two-step reaction where biotin is first activated to biotinyl-5'-AMP in an ATP-dependent manner, the biotin is then transferred onto the epsilon-amino group of a specific target lysine residue. All biotin-dependent enzymes utilise the enzyme-bound biotin group for the transfer of CO2 between metabolites	AMP + diphosphate + [acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	-	?
6.3.4.15	ATP + biotin + apo-[acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	Saccharomyces cerevisiae	all biotin-dependent enzymes utilise the enzyme-bound biotin group for the transfer of CO2 between metabolites	AMP + diphosphate + [acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	-	?
6.3.4.15	ATP + biotin + apo-[acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	Escherichia coli	the holo-enzyme is a multienzyme complex, in which biotin is bound to the biotin carboxyl carrier protein, binding structure, overview. All biotin-dependent enzymes utilise the enzyme-bound biotin group for the transfer of CO2 between metabolites	AMP + diphosphate + [acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	-	?
6.3.4.15	ATP + biotin + apo-[acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	Pyrococcus horikoshii OT-3	-	AMP + diphosphate + [acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	-	?
6.3.4.15	additional information	Homo sapiens	acetyl-CoA carboxylase-1 and -2 perform the essential role of converting acetyl CoA to malonyl CoA, the first committed step in fatty acid synthesis, required for membrane biogenesis. The enzyme exists either as catalytic homodimers or associated with more highly active filamentous fibres. Development of an assay method using apo-pyruvate carboxylase partially purified from the livers of biotin-deficient rats for detection of biotin in fibroblast samples from healthy persons and patients with multiple carboxylase deficiency	?	-	?

Organism

EC Number	Organism	UniProt	Comment	Textmining
6.3.4.15	Escherichia coli	P06709	-	-
6.3.4.15	Homo sapiens	-	-	-
6.3.4.15	Pyrococcus horikoshii	-	strain OT3	-
6.3.4.15	Pyrococcus horikoshii OT-3	-	strain OT3	-
6.3.4.15	Saccharomyces cerevisiae	-	-	-

Source Tissue

EC Number	Source Tissue	Comment	Organism	Textmining
6.3.4.15	fibroblast	-	Homo sapiens	-

Substrates and Products (Substrate)

EC Number	Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
6.3.4.15	ATP + biotin + apo-[acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	-	Saccharomyces cerevisiae	AMP + diphosphate + [acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	-	?
6.3.4.15	ATP + biotin + apo-[acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	-	Pyrococcus horikoshii	AMP + diphosphate + [acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	-	?
6.3.4.15	ATP + biotin + apo-[acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	activation by biotinylation, HCS is the enzyme responsible for specifically attaching biotin onto the mammalian biotin domains. Biotinylation is catalysed through a two-step reaction where biotin is first activated to biotinyl-5'-AMP in an ATP-dependent manner, the biotin is then transferred onto the epsilon-amino group of a specific target lysine residue. All biotin-dependent enzymes utilise the enzyme-bound biotin group for the transfer of CO2 between metabolites	Homo sapiens	AMP + diphosphate + [acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	-	?
6.3.4.15	ATP + biotin + apo-[acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	all biotin-dependent enzymes utilise the enzyme-bound biotin group for the transfer of CO2 between metabolites	Saccharomyces cerevisiae	AMP + diphosphate + [acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	-	?
6.3.4.15	ATP + biotin + apo-[acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	the holo-enzyme is a multienzyme complex, in which biotin is bound to the biotin carboxyl carrier protein, binding structure, overview. All biotin-dependent enzymes utilise the enzyme-bound biotin group for the transfer of CO2 between metabolites	Escherichia coli	AMP + diphosphate + [acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	-	?
6.3.4.15	ATP + biotin + apo-[acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	activation by biotinylation. The biotinylated lysine itself is located in a hairpin turn between beta-strands 4 and 5 in the centre of the polypeptide, present in a Met-Lys-Met motif that is essentially invariant in all biotin domains. HCS may well contain proofreading activity to select appropriate substrates	Homo sapiens	AMP + diphosphate + [acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	-	?
6.3.4.15	ATP + biotin + apo-[acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	conformational changes occur upon biotin binding. Structure-function relationship, modelling, overview	Escherichia coli	AMP + diphosphate + [acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	-	?
6.3.4.15	ATP + biotin + apo-[acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	structure-function relationship, modelling, overview	Pyrococcus horikoshii	AMP + diphosphate + [acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	-	?
6.3.4.15	ATP + biotin + apo-[acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	-	Pyrococcus horikoshii OT-3	AMP + diphosphate + [acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	-	?
6.3.4.15	ATP + biotin + apo-[acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	structure-function relationship, modelling, overview	Pyrococcus horikoshii OT-3	AMP + diphosphate + [acetyl-CoA:carbon-dioxide ligase (ADP-forming)]	-	?
6.3.4.15	additional information	acetyl-CoA carboxylase-1 and -2 perform the essential role of converting acetyl CoA to malonyl CoA, the first committed step in fatty acid synthesis, required for membrane biogenesis. The enzyme exists either as catalytic homodimers or associated with more highly active filamentous fibres. Development of an assay method using apo-pyruvate carboxylase partially purified from the livers of biotin-deficient rats for detection of biotin in fibroblast samples from healthy persons and patients with multiple carboxylase deficiency	Homo sapiens	?	-	?
6.3.4.15	additional information	protein-protein interaction between BPL and biotin-dependent enzymes is highly conserved. substrate recognition by BPLs occurs through conserved structural cues that govern the specificity of biotinylation, molecular modelling, overview. The region between Leu166 and Arg290 of BPL is required for catalysis. Development of an assay method using apo-pyruvate carboxylase partially purified from the livers of biotin-deficient rats for detection of biotin in samples from healthy persons and patients with multiple carboxylase deficiency	Homo sapiens	?	-	?

Subunits

EC Number	Subunits	Comment	Organism
6.3.4.15	dimer	dimerization upon biotin binding	Escherichia coli
6.3.4.15	dimer	the protein is a constitutive dimer, i.e. dimerises independently of biotin binding	Pyrococcus horikoshii
6.3.4.15	More	EcBPL contains three distinct domains determined through X-ray crystallography. Monomeric and dimeric forms of the enzyme are involved in enzyme regulation, overview. Structure-function relationship, overview. EcBPL contains a DNA binding motif	Escherichia coli
6.3.4.15	More	PhBPL does not contain a DNA binding motif	Pyrococcus horikoshii
6.3.4.15	More	structure-activity molecular modelling. Acetyl-CoA carboxylase-1 exists either as catalytic homodimers or associated with more highly active filamentous fibres. The region between Leu166 and Arg290 is required for catalysis	Homo sapiens

Synonyms

EC Number	Synonyms	Comment	Organism
6.3.4.15	biotin protein ligase	-	Homo sapiens
6.3.4.15	biotin protein ligase	-	Saccharomyces cerevisiae
6.3.4.15	biotin protein ligase	-	Pyrococcus horikoshii
6.3.4.15	biotin protein ligase	-	Escherichia coli
6.3.4.15	BPL	-	Homo sapiens
6.3.4.15	BPL	-	Saccharomyces cerevisiae
6.3.4.15	BPL	-	Pyrococcus horikoshii
6.3.4.15	BPL	-	Escherichia coli
6.3.4.15	HCS	-	Homo sapiens
6.3.4.15	HCS	-	Saccharomyces cerevisiae
6.3.4.15	HCS	-	Escherichia coli
6.3.4.15	Holocarboxylase synthetase	-	Homo sapiens
6.3.4.15	Holocarboxylase synthetase	-	Saccharomyces cerevisiae
6.3.4.15	Holocarboxylase synthetase	-	Escherichia coli

Cofactor

EC Number	Cofactor	Comment	Organism	Structure
6.3.4.15	ATP	-	Homo sapiens
6.3.4.15	ATP	-	Saccharomyces cerevisiae
6.3.4.15	ATP	-	Pyrococcus horikoshii
6.3.4.15	ATP	-	Escherichia coli
6.3.4.15	biotin	-	Pyrococcus horikoshii
6.3.4.15	biotin	bound to the biotin domain, structure, overview	Homo sapiens
6.3.4.15	biotin	bound to the biotin domain, structure, overview	Saccharomyces cerevisiae
6.3.4.15	biotin	bound to the biotin domain, structure, overview	Escherichia coli

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Release 2023.1 (January 2023)