PCCB encodes the beta (carboxyltransferase) subunit of mitochondrial propionyl-CoA carboxylase (PCC; EC 6.4.1.3), a biotin-dependent carboxylase of the mitochondrial matrix. The functional holoenzyme is an alpha6-beta6 dodecamer (~750 kDa) built around a central beta6 hexamer core decorated by six PCCA (alpha) subunits. Within PCC, the alpha subunit carboxylates biotin on its biotin-carboxyl-carrier (BCCP) domain in an ATP-dependent step, and the beta subunit then transfers the carboxyl group from carboxybiotin to propionyl-CoA, converting propanoyl-CoA + hydrogencarbonate + ATP to (S)-methylmalonyl-CoA + ADP + phosphate. This is the committed step of propionyl-CoA (propionate) catabolism: propionyl-CoA arises from degradation of the amino acids isoleucine, valine, methionine and threonine, of odd-chain fatty acids, and of the cholesterol side chain, and the methylmalonyl-CoA product is isomerized and converted to succinyl-CoA, an anaplerotic entry point into the tricarboxylic acid cycle. The enzyme is promiscuous, also carboxylating butyryl-CoA and acetyl-CoA at much lower rates. Biallelic loss-of-function variants in PCCB (or PCCA) cause propionic acidemia, an autosomal recessive organic acidemia characterized by metabolic acidosis, ketosis, hyperammonemia, and multi-organ complications; many PCCB missense variants act by impairing holoenzyme assembly and stability rather than by directly abolishing catalysis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred mitochondrial localization of the PCC beta subunit. PCC is a well-established mitochondrial matrix enzyme, so mitochondrion is correct but less specific than the matrix annotations. Reason: PCC is a mitochondrial biotin-dependent enzyme; the beta subunit is imported into the mitochondrial matrix. Mitochondrion is correct at a broader granularity than mitochondrial matrix (GO:0005759), which is the precise compartment. Supporting Evidence: PMID:8188292 Propionyl-CoA carboxylase (PCC) is a mitochondrial, biotin-dependent enzyme, composed of an equal number of alpha and beta subunits |
| GO:0004658 propionyl-CoA carboxylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred propionyl-CoA carboxylase activity. This is the defining molecular function of the PCC beta (carboxyltransferase) subunit and is directly supported by biochemical characterization of the human enzyme. Reason: Core molecular function. The beta subunit supplies the carboxyltransferase activity that transfers the carboxyl group from carboxybiotin to propionyl-CoA; the holoenzyme carboxylates propionyl-CoA to (S)/D-methylmalonyl-CoA. Consistent with the IDA/EXP annotations from the purified human enzyme. Supporting Evidence: PMID:20725044 the alpha-subunit contains the biotin carboxylase (BC) and biotin carboxyl carrier protein (BCCP) domains, whereas the beta-subunit supplies the carboxyltransferase (CT) activity |
| GO:0004658 propionyl-CoA carboxylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of propionyl-CoA carboxylase activity mapped from RHEA:23720 / EC 6.4.1.3. Concordant with the experimental molecular function and the UniProt catalytic activity statement. Reason: Correct core molecular function; the RHEA/EC mapping matches the experimentally characterized reaction (propanoyl-CoA + hydrogencarbonate + ATP = (S)-methylmalonyl-CoA + ADP + phosphate). Supporting Evidence: PMID:15890657 Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation to mitochondrial matrix from the UniProt subcellular location vocabulary mapping (SL-0170). Matches the experimental IDA/NAS/TAS matrix annotations. Reason: Correct core localization. The mature beta subunit resides in the mitochondrial matrix, where the PCC holoenzyme functions. Supporting Evidence: PMID:29033250 It is often described as a matrix enzyme because it can dissociate with sonication |
| GO:0009062 fatty acid catabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic annotation to fatty acid catabolic process. Odd-chain fatty acid beta-oxidation is one of the sources of the propionyl-CoA substrate, so PCC contributes to fatty acid catabolism, but this is a broad framing rather than PCC's direct committed reaction (propionate catabolism). Reason: Not wrong: propionyl-CoA is the end product of beta-oxidation of odd-numbered fatty acids, and PCC clears it. However this is a downstream/broad biological-process framing; the precise, direct role is propionate catabolic process (proposed as a core BP). Keep as non-core contextual annotation. 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:0016874 ligase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO electronic annotation to the generic parent term ligase activity, from the CoA carboxyltransferase C-terminal domain signature (IPR011763). The specific activity (propionyl-CoA carboxylase) is experimentally established. Reason: Ligase activity is far too general for a protein whose specific molecular function is known. Propionyl-CoA carboxylase is formally an ATP-dependent ligase (EC 6.4.1.3), and the precise term GO:0004658 propionyl-CoA carboxylase activity is available and experimentally supported. Replace with the specific term. Proposed replacements: propionyl-CoA carboxylase activity 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:0005515 protein binding | IPI PMID:20725044 Crystal structure of the alpha(6)beta(6) holoenzyme of propi... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation with PCCA (P05165), the obligate alpha partner subunit, from the PCC holoenzyme crystal-structure study. The interaction is biologically real (PCCB and PCCA form the alpha6-beta6 dodecamer) but the bare "protein binding" term is uninformative. Reason: Per curation guidelines, bare protein binding (GO:0005515) conveys no specific molecular function. The meaningful biology (PCCB-PCCA holoenzyme assembly) is captured by the catalytic-complex annotation (GO:1902494) and the carboxylase MF, so this IPI is redundant/over-annotated as an MF. Not removed, per policy on IPI protein-binding annotations. 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: IPI protein-binding annotation from the HuRI binary interactome (yeast two-hybrid) with ACTN3 (Q08043), a cytoskeletal alpha-actinin. There is no biological corroboration for a physical role of the mitochondrial matrix enzyme PCCB with a sarcomeric protein. Reason: Bare protein binding (GO:0005515) is uninformative, and this high-throughput binary interactome hit (with a cytoskeletal protein not co-localized with the matrix enzyme) is most consistent with a screen artifact. Marked as over-annotated rather than removed, per policy on IPI protein-binding annotations. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation from the BioPlex (AP-MS) interactome with PCCA (P05165), the obligate alpha partner subunit. Recapitulates the known PCCB-PCCA physical association but via the uninformative "protein binding" term. Reason: Bare protein binding (GO:0005515) is uninformative. The captured PCCB-PCCA association is already represented by the holoenzyme/complex (GO:1902494) and MF annotations. Marked as over-annotated rather than removed, per policy on IPI protein-binding annotations. Supporting Evidence: PMID:29033250 PCCB requires PCCA for stability |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation from a multimodal cell-map / AP-MS study with PCCA (P05165), the obligate alpha partner subunit. Again reflects the known PCCB-PCCA association through the uninformative "protein binding" term. Reason: Bare protein binding (GO:0005515) is uninformative and redundant with the complex and MF annotations that already capture PCCB-PCCA holoenzyme assembly. Marked as over-annotated rather than removed, per policy on IPI protein-binding annotations. Supporting Evidence: PMID:29033250 PCC is 750 kDa heterododecamer composed of 6 propionyl-CoA carboxylase, alpha (PCCA, OMIM 232000) and 6 propionyl-CoA carboxylase, beta subunits |
| GO:0005759 mitochondrial matrix | NAS PMID:29033250 Propionyl-CoA carboxylase - A review. | ACCEPT | Summary: ComplexPortal NAS annotation to mitochondrial matrix, consistent with the established localization of the PCC holoenzyme. Reason: Correct core localization. Multiple independent lines (IDA, IEA, TAS) place PCC in the mitochondrial matrix. 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 annotation to the broad term fatty acid metabolic process. PCC participates in odd-chain fatty acid catabolism (a source of its propionyl-CoA substrate), but this is a high-level parent term, not the committed reaction. Reason: Broad and contextual. Odd-chain fatty acid metabolism generates the propionyl-CoA that PCC carboxylates, so involvement in fatty acid metabolism is defensible, but the direct role is propionate catabolic process. Retain as non-core. Supporting Evidence: PMID:29033250 Propionyl-CoA is produced by catabolism of cholesterol, valine, odd chain fatty acids, methionine, isoleucine and threonine |
| GO:0009081 branched-chain amino acid metabolic process | NAS PMID:29033250 Propionyl-CoA carboxylase - A review. | KEEP AS NON CORE | Summary: ComplexPortal NAS annotation reflecting that degradation of the branched-chain amino acids isoleucine and valine (and of methionine and threonine) feeds propionyl-CoA into the PCC reaction. This is an upstream metabolic-context role rather than PCC's direct catalytic step. Reason: Correct in that Ile/Val (BCAA) catabolism produces propionyl-CoA, the PCC substrate; PCC clears this intermediate. But PCC's own reaction is propionate catabolism, not BCAA metabolism per se, so retain as a non-core contextual annotation. 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 annotation (CPX-6169, mitochondrial propionyl-CoA carboxylase complex) that PCCB is part of a catalytic complex. PCCB is a constitutive subunit of the alpha6-beta6 PCC holoenzyme. Reason: Correct and informative: PCCB is an obligate subunit of the PCC catalytic holoenzyme (the mitochondrial propionyl-CoA carboxylase complex). Captures the PCCB-PCCA assembly better than a bare protein-binding term. Supporting Evidence: PMID:20725044 The holoenzyme of PCC is an alpha(6)beta(6) dodecamer, with a molecular mass of 750 kDa |
| GO:0004658 propionyl-CoA carboxylase activity | EXP PMID:15890657 Characterization of four variant forms of human propionyl-Co... | ACCEPT | Summary: Experimental annotation of propionyl-CoA carboxylase activity from recombinant human PCC (wild-type and PCCB variants) purified and assayed. Directly supports the defining molecular function of the beta subunit. Reason: Core molecular function, experimentally established. The study purified recombinant human PCC containing the beta subunit and measured propionyl-CoA carboxylase kinetics (kcat/Km), confirming the carboxylase activity. Supporting Evidence: PMID:15890657 Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput proteomics annotation placing PCCB in the mitochondrion, from a quantitative high-confidence human mitochondrial proteome study. Concordant with the established matrix localization. Reason: Correct localization at the organelle level (less specific than mitochondrial matrix). Consistent with all other localization evidence. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context |
| GO:0005759 mitochondrial matrix | IDA PMID:16023992 Mitochondrial targeting signals and mature peptides of 3-met... | ACCEPT | Summary: IDA annotation to mitochondrial matrix based on direct determination of the PCC N-terminal targeting presequence and mature peptide, showing matrix import by the classical presequence pathway. Reason: Core localization, directly supported. The study identified the cleavage sites and mature amino-termini and demonstrated matrix import of PCC (studied alongside its paralog MCC) via cleavable presequences. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving cleavable amino-terminal targeting presequences |
| GO:0019626 short-chain fatty acid catabolic process | IC PMID:6765947 Isolation and characterization of propionyl-CoA carboxylase ... | KEEP AS NON CORE | Summary: Curator-inferred (IC, from GO:0004658) annotation to short-chain fatty acid catabolic process. Propionyl-CoA (a short-chain acyl-CoA) is catabolized via the PCC reaction, so this is defensible, but the precise process term is propionate catabolic process. Reason: Reasonable framing (propionyl-CoA/propionate is a short-chain fatty acid derivative and PCC initiates its catabolism), but the direct, specific biological process is propionate catabolic process (GO:0019543), proposed as the core BP. Retain this broader term as non-core rather than removing it. Supporting Evidence: PMID:6765947 The enzyme also catalyzes the carboxylation of acetyl-CoA and butyryl-CoA to a limited degree, but not that of crotonyl-CoA |
| GO:0004658 propionyl-CoA carboxylase activity | IDA PMID:6765947 Isolation and characterization of propionyl-CoA carboxylase ... | ACCEPT | Summary: IDA annotation of propionyl-CoA carboxylase activity from the enzyme purified to homogeneity from normal human liver, with measured kinetics for propionyl-CoA, ATP and bicarbonate. This is the strongest experimental support for the core molecular function. Reason: Core molecular function, directly demonstrated on the human enzyme. The purified PCC (alpha/beta) carboxylates propionyl-CoA with defined Km values. 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 | TAS Reactome:R-HSA-3065959 | ACCEPT | Summary: Reactome TAS annotation to mitochondrial matrix (in the context of PCC degradation). Consistent with the established matrix localization of PCCB. Reason: Correct core localization, concordant with experimental evidence. 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 annotation to mitochondrial matrix (from the "Cytosolic carboxylases translocate to mitochondrial matrix" reaction). Represents the functional matrix compartment of PCC. Reason: Correct core localization. This reaction models the endpoint of import into the matrix, where PCC functions. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving cleavable amino-terminal targeting presequences |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-71031 | ACCEPT | Summary: Reactome TAS annotation to mitochondrial matrix from the PCC catalytic reaction (propionyl-CoA + CO2 + ATP <=> D-methylmalonyl-CoA + ADP + orthophosphate). Places the enzymatic activity in the matrix. Reason: Correct core localization; the PCC-catalyzed reaction occurs in the mitochondrial matrix. Supporting Evidence: PMID:29033250 catalyzes the carboxylation of propionyl-CoA with bicarbonate producing methylmalonyl-CoA which is then converted to succinyl-CoA |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838081 | ACCEPT | Summary: Reactome TAS annotation to mitochondrial matrix (LONP1-mediated matrix protein degradation context). Consistent with PCCB being a matrix protein. Reason: Correct core localization, concordant with all other evidence for matrix residence. 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-9838093 | ACCEPT | Summary: Reactome TAS annotation to mitochondrial matrix (LONP1 binds mitochondrial matrix proteins context). Consistent with the established matrix localization. Reason: Correct core localization, concordant with experimental evidence. Supporting Evidence: PMID:29033250 It is often described as a matrix enzyme because it can dissociate with sonication |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2993447 | KEEP AS NON CORE | Summary: Reactome TAS annotation to cytosol from the "HLCS biotinylates 6x(PCCA:PCCB)" reaction, which Reactome models in the cytosol prior to mitochondrial import. This reflects a transient biogenesis stage, not the mature functional compartment. Reason: The functional PCC holoenzyme acts in the mitochondrial matrix. Reactome places biotinylation/assembly steps in the cytosol before import, so this cytosol annotation captures a transient itinerary compartment. Retain as non-core rather than treating it as a functional localization. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving cleavable amino-terminal targeting presequences |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3323111 | KEEP AS NON CORE | Summary: Reactome TAS annotation to cytosol from the "Cytosolic carboxylases translocate to mitochondrial matrix" reaction, representing the pre-import cytosolic stage of the carboxylase precursor. Reason: Transient localization of the newly synthesized precursor before matrix import; not the functional compartment. Retain as non-core. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving cleavable amino-terminal targeting presequences |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9035990 | KEEP AS NON CORE | Summary: Reactome TAS annotation to cytosol from the "Defective HLCS does not biotinylate 6x(PCCA:PCCB)" reaction, again a cytosolic biogenesis step preceding matrix import. Reason: Reflects the pre-import cytosolic assembly/biotinylation stage, not the mature functional site. Retain as non-core. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving cleavable amino-terminal targeting presequences |
| GO:0005739 mitochondrion | TAS PMID:8188292 Correction of the metabolic defect in propionic acidemia fib... | ACCEPT | Summary: TAS annotation to mitochondrion. The microinjection/complementation study confirmed that beta subunits are transported into mitochondria and assemble with alpha subunits to form functional PCC. Reason: Correct localization at the organelle level (less specific than matrix). Directly supported by the demonstration that beta subunits are imported into mitochondria and form functional holoenzyme. Supporting Evidence: PMID:8188292 the capacity for beta subunits derived from the microinjected cDNA or RNA to be transported into mitochondria and assembled with endogenously derived alpha subunits to form functional PCC |
| GO:0019543 propionate catabolic process | IC PMID:29033250 Propionyl-CoA carboxylase - A review. | NEW | Summary: Proposed core biological-process annotation. PCC catalyzes the committed step of propionyl-CoA (propionate) catabolism, converting propionyl-CoA to methylmalonyl-CoA en route to succinyl-CoA; loss of PCC activity in propionic acidemia directly reflects a defect in propionate catabolism. Reason: GOA currently annotates PCCB only to broader/adjacent process terms (fatty acid catabolic/metabolic process, short-chain fatty acid catabolic process, branched-chain amino acid metabolic process). The precise, direct biological process is propionate catabolic process, which is the process decreased in propionic acidemia (per the disorder knowledge base). Inferred (IC) from the established propionyl-CoA carboxylase activity (GO:0004658). Supporting Evidence: PMID:29033250 catalyzes the carboxylation of propionyl-CoA with bicarbonate producing methylmalonyl-CoA which is then converted to succinyl-CoA, an intermediate in the tricarboxylic acid cycle |
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Download this section (compressed HTML)Q: Are any of the reported minor substrate activities of PCC (butyryl-CoA, acetyl-CoA) physiologically relevant in humans, or purely in vitro promiscuity?
Q: Do the proposed non-catalytic/moonlighting roles of the PCCB precursor in the cytosol (e.g., reported interactions with glucokinase or the mineralocorticoid receptor) have any physiological significance, or are they artifacts?
Experiment: Structure-guided kinetic characterization of additional PCCB carboxyltransferase active-site residues to distinguish variants that impair catalysis from those that impair holoenzyme assembly.
Hypothesis: Some PCCB pathogenic variants abolish carboxyltransferase catalysis directly, whereas others reduce activity indirectly by destabilizing the alpha6-beta6 holoenzyme.
Experiment: Quantitative mitochondrial import and holoenzyme-assembly assays comparing PCCB isoform 1 and isoform 2 to determine whether the alternative splice product forms functional PCC.
Hypothesis: PCCB isoform 2 (VSP_042568) differs in its capacity to assemble into a catalytically competent holoenzyme.
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