PCCA

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004658 propionyl-CoA carboxylase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred propionyl-CoA carboxylase activity. This is the core, defining molecular function of PCCA as the biotin-containing alpha subunit of the PCC holoenzyme, directly supported by biochemistry and disease genetics. Reason: Well-supported core function; the IBA is at the correct level of specificity and concordant with experimental (IDA/IMP) annotations and the EC 6.4.1.3 assignment. Supporting Evidence: PMID:29033250 Propionyl-CoA carboxylase (PCC) is the enzyme which catalyzes the carboxylation of propionyl-CoA to methylmalonyl-CoA and is encoded by the genes PCCA and PCCB to form a hetero-dodecamer.
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred mitochondrial localization/activity. Correct: PCC is a mitochondrial matrix enzyme. Reason: Consistent with experimental matrix localization (below); mitochondrion is a correct, if less specific, compartment for where the enzyme is active. Supporting Evidence: PMID:20725044 Propionyl-coenzyme A carboxylase (PCC), a mitochondrial biotin-dependent enzyme, is essential for the catabolism of the amino acids Thr, Val, Ile and Met, cholesterol and fatty acids with an odd number of carbon atoms.
GO:0004658 propionyl-CoA carboxylase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (RHEA:23720 / EC 6.4.1.3 mapping) assignment of propionyl-CoA carboxylase activity. Redundant with, and confirmed by, the experimental IDA/IMP annotations of the same term. Reason: Correct core molecular function; the EC/RHEA mapping matches the demonstrated catalytic activity. Supporting Evidence: PMID:6765947 We have purified propionyl-CoA carboxylase from normal, postmortem human liver to homogeneity.
GO:0005524 ATP binding	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based ATP binding. The alpha subunit contains an ATP-grasp domain and catalyses the ATP-dependent carboxylation of biotin; ATP is a substrate of the BC reaction (Km ~0.08 mM). Reason: Supported by the catalytic mechanism, the ATP-grasp domain, and multiple ATP binding-site features in UniProt; ATP binding is integral to the alpha-subunit biotin carboxylase step. Supporting Evidence: PMID:6765947 The apparent Km values for ATP, propionyl-CoA, and bicarbonate are 0.08 mM, 0.29 mM, and 3.0 mM, respectively.
GO:0005759 mitochondrial matrix	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (UniProt subcellular location / ARBA) assignment of mitochondrial matrix. Correct and concordant with experimental EXP/IDA matrix annotations. Reason: PCC is a matrix enzyme; the electronic assignment matches the curated UniProt subcellular location and experimental evidence. Supporting Evidence: PMID:29033250 It is often described as a matrix enzyme because it can dissociate with sonication.
GO:0009374 biotin binding	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic assignment of biotin binding. Biotin is the obligate cofactor of PCC and is covalently attached to the C-terminal biotinyl domain of the alpha subunit; each holoenzyme carries biotin almost entirely on the alpha subunit. Reason: Strongly supported: biotin is the defining cofactor of this biotin-dependent carboxylase and is carried by PCCA. Supporting Evidence: PMID:6765947 Each mole of native enzyme contains 4 mol of bound biotin, virtually all of which is found with the larger (alpha) subunit.
GO:0016885 ligase activity, forming carbon-carbon bonds	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic assignment of the parent ligase term. This is the correct broad catalytic class (EC 6.4 ligases forming C-C bonds) for propionyl-CoA carboxylase, but is less informative than the specific GO:0004658 already annotated. Reason: Correct parent activity; not wrong, but subsumed by the more specific propionyl-CoA carboxylase activity. Retained as a valid, if general, IEA. Supporting Evidence: PMID:29033250 Propionyl-CoA carboxylase (PCC) is the enzyme which catalyzes the carboxylation of propionyl-CoA to methylmalonyl-CoA
GO:0046872 metal ion binding	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based metal ion binding. The alpha-subunit biotin carboxylase/ATP-grasp domain binds two divalent metal ions (Mg2+ or Mn2+) per subunit that are required for the ATP-dependent carboxylation step. Reason: Supported by UniProt cofactor annotation (binds 2 Mg2+/Mn2+ per subunit) and metal-binding site features; a general but correct molecular function. Supporting Evidence: PMID:20725044 The active site of the BC domain is conserved with that of E. coli BC, and all the residues that interact with the substrates of this reaction have essentially the same conformation in both structures
GO:0005515 protein binding	IPI PMID:20725044 Crystal structure of the alpha(6)beta(6) holoenzyme of propi...	MARK AS OVER ANNOTATED	Summary: IntAct-curated binary interaction with PCCB (P05166), the beta subunit. This is the genuine, obligate holoenzyme partnership (alpha6-beta6), but the bare "protein binding" term is uninformative about the actual molecular function. Reason: Per curation policy, bare protein binding IPIs are not removed. The interaction itself (with PCCB) is real and biologically central, but "protein binding" adds no functional specificity beyond what is captured by the propionyl-CoA carboxylase complex membership; a more informative term (structural constituent of the PCC holoenzyme) would be preferable. Supporting Evidence: PMID:20725044 The holoenzyme of PCC is an alpha(6)beta(6) dodecamer, with a molecular mass of 750 kDa.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: IntAct/HuRI systematic binary interactome hit, here with MCC (MCCC1, P23508), a paralogous biotin-dependent carboxylase. Bare "protein binding" from a high-throughput all-by-all screen. Reason: Uninformative term from a proteome-scale Y2H screen; not the core function. Retained per policy (not removed) but flagged as over-annotation. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: IntAct-curated interaction with PCCB (P05166) from a proteome-scale interactome study (BioPlex-type). Again the genuine beta-subunit partner, reported via the uninformative "protein binding" term. Reason: Real interaction (PCCB, the holoenzyme partner) but bare protein binding is not the core molecular function; retained per policy and flagged as over-annotation. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: IntAct-curated interaction with PCCB (P05166) from a multimodal cell-map / genomics study. The beta-subunit partner again, via bare "protein binding". Reason: Genuine PCCB partnership but uninformative term; retained per policy and flagged as over-annotation rather than removed. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics.
GO:0005739 mitochondrion	IDA GO_REF:0000052	ACCEPT	Summary: Immunofluorescence (Human Protein Atlas) localization to mitochondrion. Correct, if less specific than the matrix annotations. Reason: Direct localization evidence consistent with PCC being a mitochondrial matrix enzyme. Supporting Evidence: PMID:29033250 It is often described as a matrix enzyme because it can dissociate with sonication.
GO:0005759 mitochondrial matrix	NAS PMID:29033250 Propionyl-CoA carboxylase - A review.	ACCEPT	Summary: ComplexPortal (CPX-6169) NAS assignment of mitochondrial matrix, from the PCC review. Correct compartment for the holoenzyme. Reason: Concordant with experimental EXP/IDA matrix evidence and the curated UniProt subcellular location. Supporting Evidence: PMID:29033250 It is often described as a matrix enzyme because it can dissociate with sonication.
GO:0006631 fatty acid metabolic process	NAS PMID:29033250 Propionyl-CoA carboxylase - A review.	KEEP AS NON CORE	Summary: ComplexPortal NAS: PCC participates in fatty acid metabolism, since propionyl-CoA is the end product of beta-oxidation of odd-chain fatty acids and PCC channels it into the TCA cycle. Broad process term. Reason: Real but non-core physiological context. PCC acts on the propionyl-CoA node of odd-chain fatty acid catabolism; the direct reaction is more precisely propionyl-CoA carboxylation/propionate catabolism than generic fatty acid metabolism. Supporting Evidence: PMID:29033250 Disruption of PCC leads to accumulation of odd-chain fatty acids (FA), as propionyl-CoA is the end product of beta oxidation of odd-numbered FA.
GO:0009081 branched-chain amino acid metabolic process	NAS PMID:29033250 Propionyl-CoA carboxylase - A review.	KEEP AS NON CORE	Summary: ComplexPortal NAS: PCC is downstream in the catabolism of branched-chain and other amino acids (isoleucine, valine, methionine, threonine) that generate propionyl-CoA. Reason: Valid physiological role (Ile and Val catabolism converge on propionyl-CoA), but not the direct reaction PCCA catalyses; kept as a relevant non-core process. Note GO:0009081 covers isoleucine/leucine/valine; PCC also serves Met/Thr, which are not branched-chain, so this term is a partial view of PCC's amino-acid role. Supporting Evidence: PMID:29033250 Propionyl-CoA is produced by catabolism of cholesterol, valine, odd chain fatty acids, methionine, isoleucine and threonine
GO:1902494 catalytic complex	IPI PMID:20725044 Crystal structure of the alpha(6)beta(6) holoenzyme of propi...	ACCEPT	Summary: ComplexPortal IPI: PCCA is part of a catalytic complex, i.e. the alpha6-beta6 PCC holoenzyme (ComplexPortal CPX-6169, Mitochondrial propionyl-CoA carboxylase complex). Reason: Correct: PCCA is an obligate structural subunit of the catalytic PCC holoenzyme. A dedicated "propionyl-CoA carboxylase complex" GO term does not currently exist (only acetyl-CoA and methylcrotonoyl-CoA carboxylase complexes), so the general "catalytic complex" is retained rather than modified to a nonexistent term. Supporting Evidence: PMID:20725044 The holoenzyme of PCC is an alpha(6)beta(6) dodecamer, with a molecular mass of 750 kDa.
GO:0005759 mitochondrial matrix	EXP PMID:10101253 Genetic heterogeneity in propionic acidemia patients with al...	ACCEPT	Summary: Experimental import/localization: in vitro-expressed PCCA precursor is imported into mitochondria and processed to the mature matrix form. Supports mitochondrial matrix localization. Reason: Direct experimental evidence for mitochondrial import and maturation, consistent with the matrix location of the enzyme. Supporting Evidence: PMID:10101253 Both wild-type and mutant proteins were imported into mitochondria and processed into the mature form with similar efficiency
GO:1901290 succinyl-CoA biosynthetic process	IDA PMID:8434582 Cloning of functional alpha propionyl CoA carboxylase and co...	KEEP AS NON CORE	Summary: IDA (propionate-flux complementation) linking PCCA to production of succinyl-CoA. PCC catalyses the first step (propionyl-CoA -> methylmalonyl-CoA); succinyl-CoA is the downstream product of the three-step propanoyl-CoA degradation pathway. Reason: PCC's direct product is (S)-methylmalonyl-CoA, not succinyl-CoA; succinyl-CoA formation requires the downstream MCEE and MUT steps. The annotation reflects PCCA's contribution to the pathway output rather than its direct catalytic product, so it is kept as non-core. Supporting Evidence: PMID:8434582 Both clones reconstitute propionate flux to normal levels in fibroblasts from patients genetically deficient in PCCA (pccA).
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput mitochondrial proteomics assignment to mitochondrion. Concordant with the established mitochondrial matrix localization. Reason: High-confidence mitochondrial proteome evidence consistent with the curated compartment; correct though less specific than matrix. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics
GO:0005759 mitochondrial matrix	IDA PMID:16023992 Mitochondrial targeting signals and mature peptides of 3-met...	ACCEPT	Summary: Direct evidence: the mature PCCA amino-terminus and cleavable N-terminal targeting presequence were defined, showing import into the mitochondrial matrix by the classical presequence pathway. Reason: Experimental determination of the mitochondrial targeting signal and mature matrix peptide directly supports matrix localization. Supporting Evidence: PMID:16023992 the two subunits of the enzyme (MCCalpha; MCCbeta) are imported into the mitochondrial matrix by the classical pathway involving cleavable amino-terminal targeting presequences.
GO:0004658 propionyl-CoA carboxylase activity	IDA PMID:6765947 Isolation and characterization of propionyl-CoA carboxylase ...	ACCEPT	Summary: Direct biochemical demonstration: PCC purified from human liver to homogeneity, shown to be a biotin-containing alpha/beta enzyme carboxylating propionyl-CoA with defined kinetic parameters. Core molecular function. Reason: Definitive experimental evidence for propionyl-CoA carboxylase activity; anchors this as the core function of the enzyme. Supporting Evidence: PMID:6765947 The apparent Km values for ATP, propionyl-CoA, and bicarbonate are 0.08 mM, 0.29 mM, and 3.0 mM, respectively.
GO:0019626 short-chain fatty acid catabolic process	IC PMID:6765947 Isolation and characterization of propionyl-CoA carboxylase ...	MODIFY	Summary: Curator inference (from GO:0004658) that PCC participates in short-chain fatty acid catabolism. Propionate/propionyl-CoA is a short-chain acid, but a more precise process term is available. Reason: The reaction PCC catalyses is specifically the committed step of propionyl-CoA catabolism; "short-chain fatty acid catabolic process" is broader and less accurate than the dedicated term. Propose replacement with propionyl-CoA catabolic process. Proposed replacements: propionyl-CoA catabolic process Supporting Evidence: PMID:29033250 PCC's primary function is to catalyze the carboxylation of propionyl-CoA to produce methylmalonyl-CoA
GO:0019626 short-chain fatty acid catabolic process	IC PMID:8434582 Cloning of functional alpha propionyl CoA carboxylase and co...	MODIFY	Summary: Second curator inference (from GO:0004658) of short-chain fatty acid catabolism, based on the propionate-flux complementation study. Same over-broad term as above. Reason: As above, the direct process is propionyl-CoA / propionate catabolism; replace the broad short-chain fatty acid term with the specific propionyl-CoA catabolic process. Proposed replacements: propionyl-CoA catabolic process Supporting Evidence: PMID:8434582 Both clones reconstitute propionate flux to normal levels in fibroblasts from patients genetically deficient in PCCA (pccA).
GO:0004658 propionyl-CoA carboxylase activity	IMP PMID:8434582 Cloning of functional alpha propionyl CoA carboxylase and co...	ACCEPT	Summary: IMP: recombinant human PCCA rescues (complements) the propionate-flux defect in PCCA-deficient (pccA) patient fibroblasts, demonstrating that PCCA is required for propionyl-CoA carboxylase activity in cells. Core molecular function. Reason: Genetic complementation directly ties PCCA to the propionyl-CoA carboxylase activity and propionate flux; strong support for the core function. Supporting Evidence: PMID:8434582 We describe cDNA clones expressing human PCCA and complementation of the genetic defect in pccA fibroblasts by DNA-mediated gene transfer.
GO:0005829 cytosol	TAS Reactome:R-HSA-2993447	KEEP AS NON CORE	Summary: Reactome TAS placing PCCA in the cytosol, reflecting the pre-import apo-precursor and the Reactome "HLCS biotinylates 6x(PCCA:PCCB)" / cytosolic-to-matrix translocation events. PCC is not catalytically active in the cytosol. Reason: The functional, biotinylated, active holoenzyme resides in the mitochondrial matrix; the cytosolic assignment reflects the transient apo-precursor stage before mitochondrial import (any cytosolic biotinylation is likely non-functional). Kept as a non-core, transient localization rather than removed. Supporting Evidence: PMID:29033250 The PCCA precursor does not contain biotin until imported into the mitochondrion and cleaved
GO:0005829 cytosol	TAS Reactome:R-HSA-3323111	KEEP AS NON CORE	Summary: Reactome TAS (cytosolic carboxylases translocate to mitochondrial matrix) placing the PCCA precursor in the cytosol prior to import. Reason: As above: transient pre-import cytosolic localization of the apo-precursor; the active enzyme is a matrix enzyme. Non-core. Supporting Evidence: PMID:29033250 The PCCA precursor does not contain biotin until imported into the mitochondrion and cleaved
GO:0005829 cytosol	TAS Reactome:R-HSA-9035990	KEEP AS NON CORE	Summary: Reactome TAS (defective HLCS does not biotinylate 6x(PCCA:PCCB)) placing PCCA in the cytosol as part of the biotinylation/multiple-carboxylase-deficiency pathway. Reason: Same transient cytosolic apo-precursor context; not the functional compartment. Kept as non-core. Supporting Evidence: PMID:29033250 The PCCA precursor does not contain biotin until imported into the mitochondrion and cleaved
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-3065959	ACCEPT	Summary: Reactome TAS assignment of mitochondrial matrix (from the carboxylase degradation reaction). Correct functional compartment. Reason: Concordant with experimental matrix evidence; the mature active enzyme is in the matrix. Supporting Evidence: PMID:29033250 It is often described as a matrix enzyme because it can dissociate with sonication.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-3323111	ACCEPT	Summary: Reactome TAS assignment of mitochondrial matrix (post-translocation destination in the cytosol->matrix translocation reaction). Correct functional compartment. Reason: Matches the established matrix localization of the mature enzyme. Supporting Evidence: PMID:29033250 It is often described as a matrix enzyme because it can dissociate with sonication.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-71031	ACCEPT	Summary: Reactome TAS assignment of mitochondrial matrix, associated with the core PCC reaction (propionyl-CoA + CO2 + ATP <=> D-methylmalonyl-CoA + ADP + Pi). This is the compartment where the catalytic reaction occurs. Reason: Correct: the propionyl-CoA carboxylase reaction takes place in the mitochondrial matrix. Supporting Evidence: PMID:29033250 It is often described as a matrix enzyme because it can dissociate with sonication.
GO:0019899 enzyme binding	IPI PMID:19157941 N- and C-terminal domains in human holocarboxylase synthetas...	KEEP AS NON CORE	Summary: IPI interaction with holocarboxylase synthetase (HLCS, P50747), the enzyme that covalently attaches biotin to PCCA. The study used the PCCA-derived C-terminal p67 polypeptide (biotinylation site K669/K694) as the HLCS substrate in Y2H and docking assays, defining the PCCA-HLCS substrate-enzyme interaction. Reason: A real and biologically meaningful interaction (PCCA is the substrate of HLCS- mediated biotinylation, essential for activity), but it describes a post-translational modification relationship rather than PCCA's own core molecular function. "Enzyme binding" is more informative than bare protein binding, so it is retained as non-core. Supporting Evidence: PMID:19157941 The polypeptide p67 comprises the 67 C-terminal amino acids in human PCC (GenBank accession #AAA60035), including the biotin-binding site K669
GO:0009374 biotin binding	TAS PMID:3460076 Isolation of cDNA clones coding for the alpha and beta chain...	ACCEPT	Summary: TAS (ProtInc) biotin binding, from the cDNA-cloning paper that identified the alpha chain via its conserved Ala-Met-Lys-Met biotin-binding-site motif. Biotin is the obligate cofactor carried by PCCA. Reason: Well-established core cofactor relationship; the alpha chain was in fact identified through its biotin-binding-site sequence. Supporting Evidence: PMID:3460076 One class contained the anticipated Ala-Met-Lys-Met sequence, corresponding to the biotin binding site found in several biotin-dependent carboxylases, thus confirming the alpha-chain assignment of these clones.

Gene Description

Existing Annotations Review

Core Functions

Biotin cofactor carrier: the alpha subunit carries the C-terminal biotinyl (BCCP) domain and binds biotin, which is covalently attached (by holocarboxylase synthetase) and is obligately required for catalytic activity of the biotin-dependent carboxylase.

ATP binding: the alpha subunit ATP-grasp/biotin carboxylase domain binds ATP (Km ~0.08 mM) as a substrate of the ATP-dependent biotin carboxylation step.

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