MCCC1 is the biotin-containing alpha subunit of mitochondrial 3-methylcrotonyl-CoA carboxylase (MCC), a biotin-dependent carboxylase (EC 6.4.1.4). MCC catalyses the ATP-dependent carboxylation of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA, the committed carboxylation step of the leucine (and isovalerate) catabolic pathway, downstream of isovaleryl-CoA dehydrogenase. The holoenzyme is an alpha6-beta6 dodecamer assembled from six MCCC1 subunits and six MCCC2 subunits: MCCC1 carries the biotin carboxylase and biotinyl (biotin-carboxyl-carrier) domains, holds the covalently attached biotin cofactor (on a conserved lysine) and binds ATP, while MCCC2 provides the carboxyltransferase activity. The protein is synthesized with an N-terminal mitochondrial transit peptide and functions in the mitochondrial matrix. Loss of MCC activity due to biallelic variants in MCCC1 (or its partner MCCC2) causes 3-methylcrotonyl-CoA carboxylase deficiency, an autosomal recessive organic aciduria that is one of the most common findings on newborn tandem mass spectrometry screening and is frequently benign or asymptomatic.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004485 methylcrotonoyl-CoA carboxylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred core molecular function of the MCC alpha subunit. The contributes_to qualifier correctly reflects that the full carboxylase activity is a property of the assembled alpha6-beta6 holoenzyme to which MCCC1 contributes. Reason: This is the core molecular function of MCCC1. The IBA is consistent with the biochemically characterized activity of the human enzyme. Supporting Evidence: PMID:17360195 a heteromultimeric complex that is composed of alpha and beta subunits which are encoded by distinct genes |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of mitochondrial localization. Correct but less specific than the mitochondrial matrix localization supported by direct evidence. Reason: MCCC1 is a mitochondrial matrix protein; the mitochondrion annotation is correct though the matrix term is more informative. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving cleavable amino-terminal targeting presequences |
| GO:0004485 methylcrotonoyl-CoA carboxylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic inference (RHEA:13589 / EC 6.4.1.4) of the core carboxylase activity, consistent with the curated catalytic activity in UniProt. Reason: Correctly maps the EC 6.4.1.4 / RHEA:13589 reaction to the core MCC activity. Supporting Evidence: PMID:17360195 a heteromultimeric complex that is composed of alpha and beta subunits which are encoded by distinct genes |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based inference of ATP binding, consistent with the ATP-grasp domain of the biotin carboxylase module that binds ATP during the carboxylation reaction. Reason: MCCC1 contains an ATP-grasp domain and binds ATP as part of the biotin carboxylation half-reaction (curated ATP-binding residues in UniProt). Supporting Evidence: PMID:11401427 biotin carboxylase, and biotin-carrier domains |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic inference of mitochondrial matrix localization (UniProt-SubCell SL-0170), matching direct experimental evidence. Reason: MCCC1 is imported into and functions in the mitochondrial matrix. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving cleavable amino-terminal targeting presequences |
| GO:0046872 metal ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro (ATP-grasp) inference of metal ion binding. ATP-grasp carboxylase domains use a divalent metal (Mg2+) for ATP-dependent catalysis, so a generic metal-ion-binding inference is biologically plausible but uninformative. Reason: Divalent metal (Mg2+) coordination is expected for the ATP-grasp biotin carboxylase reaction; the generic term is a reasonable, if low-information, InterPro inference and is not contradicted by evidence. Supporting Evidence: PMID:22869039 biotin carboxylase (BC), carboxyltransferase (CT), and biotin-carboxyl carrier protein components |
| GO:0005515 protein binding | IPI PMID:17360195 Expression, purification, characterization of human 3-methyl... | MARK AS OVER ANNOTATED | Summary: IntAct protein-binding annotation capturing the MCCC1-MCCC2 (Q9HCC0) interaction, i.e. assembly of the MCC holoenzyme. The bare protein binding term is uninformative; the biologically meaningful interaction is captured by the methylcrotonoyl-CoA carboxylase complex annotation. Reason: Bare GO:0005515 provides no functional information beyond the fact of an interaction. The relevant partner here is the obligate holoenzyme subunit MCCC2, already captured by GO:1905202 (methylcrotonoyl-CoA carboxylase complex). Retained (not removed) per curation policy on protein-binding IPIs. Supporting Evidence: PMID:17360195 stoichiometry of alpha and beta subunits are at a one:one ratio |
| GO:0005515 protein binding | IPI PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat... | MARK AS OVER ANNOTATED | Summary: IntAct protein-binding annotation from a high-throughput mitochondrial interaction mapping study (partner MCCC2/Q9HCC0). Uninformative bare-binding term. Reason: Bare GO:0005515 from a high-throughput screen; the meaningful holoenzyme partnership with MCCC2 is captured by GO:1905202. Retained per policy on protein-binding IPIs. Supporting Evidence: PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: IntAct protein-binding annotation from the BioPlex human interactome (partner OXCT2/Q9BYC2). Bare-binding term with no functional content. Reason: Bare GO:0005515 from high-throughput AP-MS. The OXCT2 co-purification is a mitochondrial-matrix proximity/co-complex observation without established functional meaning for MCCC1. Retained per policy on protein-binding IPIs. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: IntAct protein-binding annotation from BioPlex 3.0 (partner OXCT2/Q9BYC2). Bare-binding term. Reason: Bare GO:0005515 from high-throughput interactome data; no specific molecular function conveyed. Retained per policy on protein-binding IPIs. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Second IntAct protein-binding annotation from BioPlex 3.0 for the same paper, capturing the MCCC1-MCCC2 (Q9HCC0) holoenzyme interaction. Bare-binding term. Reason: Bare GO:0005515 from a high-throughput screen; the MCCC2 partnership is already represented by GO:1905202. Retained per policy on protein-binding IPIs. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: IntAct protein-binding annotation from a multimodal cell-mapping resource (partner MCCC2/Q9HCC0). Bare-binding term. Reason: Bare GO:0005515 from a high-throughput mapping study; the MCCC2 holoenzyme partnership is captured by GO:1905202. Retained per policy on protein-binding IPIs. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics |
| GO:0006552 L-leucine catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic inference (UniPathway UPA00363, L-leucine degradation) of the core biological process in which MCC acts. Reason: MCC catalyses the committed carboxylation step of leucine catabolism; this is the core biological process. Supporting Evidence: PMID:11401427 plays an essential role in the catabolism of leucine and isovalerate |
| GO:0005759 mitochondrial matrix | IDA PMID:17360195 Expression, purification, characterization of human 3-methyl... | ACCEPT | Summary: Direct assignment (ComplexPortal) of mitochondrial matrix localization for the MCC complex, consistent with import studies. Reason: MCCC1 is a mitochondrial matrix protein; this is the core cellular location. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving cleavable amino-terminal targeting presequences |
| GO:0009083 branched-chain amino acid catabolic process | NAS PMID:17360195 Expression, purification, characterization of human 3-methyl... | KEEP AS NON CORE | Summary: Leucine is a branched-chain amino acid, so MCC participation in leucine catabolism is subsumed by branched-chain amino acid catabolism. This parent term is correct but less specific than L-leucine catabolic process. Reason: Biologically correct but a generalization of the more precise leucine-catabolism annotation; MCC specifically acts on the leucine branch, not other BCAAs (valine/isoleucine). Supporting Evidence: PMID:11401427 plays an essential role in the catabolism of leucine and isovalerate |
| GO:1905202 methylcrotonoyl-CoA carboxylase complex | IPI PMID:17360195 Expression, purification, characterization of human 3-methyl... | ACCEPT | Summary: MCCC1 is a subunit of the alpha6-beta6 methylcrotonoyl-CoA carboxylase holoenzyme, directly demonstrated by expression, purification and characterization of the assembled human complex. Reason: Core cellular-component annotation; MCCC1 is an integral subunit of the MCC complex. Supporting Evidence: PMID:17360195 a heteromultimeric complex that is composed of alpha and beta subunits which are encoded by distinct genes |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence-based (HPA) mitochondrial localization. Correct but less specific than the mitochondrial matrix. Reason: Consistent with the established mitochondrial matrix localization; the matrix term is more informative. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving cleavable amino-terminal targeting presequences |
| GO:0004485 methylcrotonoyl-CoA carboxylase activity | EXP PMID:32561715 Leucine regulates autophagy via acetylation of the mTORC1 co... | ACCEPT | Summary: Experimental-code annotation of the core carboxylase activity. UniProt attaches the catalytic-activity claim to this paper, which studies MCCC1 as the leucine-metabolizing enzyme via knockdown; the enzymatic function itself is most directly supported by the biochemical characterization in PMID:17360195. Reason: The core molecular function of MCCC1. The annotated activity is well established biochemically for the assembled MCC enzyme. Supporting Evidence: PMID:32561715 the Leu-metabolizing enzyme MCCC1 PMID:17360195 a heteromultimeric complex that is composed of alpha and beta subunits which are encoded by distinct genes |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput mitochondrial proteomics detection. Correct but less specific than the mitochondrial matrix. Reason: Consistent with the established mitochondrial localization of MCCC1. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9909466 | ACCEPT | Summary: Reactome traceable-author-statement placing MCCC1 in the mitochondrial matrix, consistent with all other localization evidence. Reason: Core cellular location, consistent with direct import/localization studies. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving cleavable amino-terminal targeting presequences |
| GO:1905202 methylcrotonoyl-CoA carboxylase complex | IDA PMID:17360195 Expression, purification, characterization of human 3-methyl... | ACCEPT | Summary: Direct-assignment (UniProt) membership in the MCC holoenzyme complex, duplicate of the ComplexPortal IPI annotation. Reason: Core cellular-component annotation; MCCC1 is an integral subunit of the MCC complex. Supporting Evidence: PMID:17360195 a heteromultimeric complex that is composed of alpha and beta subunits which are encoded by distinct genes |
| GO:0004485 methylcrotonoyl-CoA carboxylase activity | IDA PMID:17360195 Expression, purification, characterization of human 3-methyl... | ACCEPT | Summary: Direct assay of the recombinant human MCC holoenzyme with measurable carboxylase kinetics; MCCC1 contributes the biotin carboxylase and biotinyl components of the activity. Reason: This is the primary experimental evidence for the core molecular function of MCC and is the best-supported carboxylase-activity annotation. Supporting Evidence: PMID:17360195 possesses K(m) values (ATP: 45+/-11microM; 3-methylcrotonyl-CoA: 74+/-7microM) similar to those reported for the native enzyme |
| GO:0004075 biotin carboxylase activity | NAS PMID:22869039 Structure and function of biotin-dependent carboxylases. | MARK AS OVER ANNOTATED | Summary: Biotin carboxylase (BC) is a component activity of the biotin carboxylase domain that MCCC1 contributes to the holoenzyme; it is a partial reaction, not the committed cellular molecular function of MCC (methylcrotonoyl-CoA carboxylase activity). Reason: The BC half-reaction is a mechanistic sub-step shared by all biotin-dependent carboxylases and is captured within GO:0004485; asserting a standalone biotin carboxylase activity for MCCC1 over-annotates a domain-level partial reaction. Sourced from a family-level review (NAS). Supporting Evidence: PMID:22869039 biotin carboxylase (BC), carboxyltransferase (CT), and biotin-carboxyl carrier protein components |
| GO:0004485 methylcrotonoyl-CoA carboxylase activity | NAS PMID:11170888 The molecular basis of 3-methylcrotonylglycinuria, a disorde... | ACCEPT | Summary: Non-traceable assertion of the core carboxylase activity from the primary MCCA characterization paper. Reason: Core molecular function; consistent with all experimental and inferred evidence. Supporting Evidence: PMID:11170888 MCC, an heteromeric enzyme consisting of alpha (biotin-containing) and beta subunits |
| GO:0004485 methylcrotonoyl-CoA carboxylase activity | NAS PMID:11181649 The molecular basis of human 3-methylcrotonyl-CoA carboxylas... | ACCEPT | Summary: Non-traceable assertion of the core carboxylase activity from an independent primary characterization of MCC deficiency. Reason: Core molecular function; consistent with all other evidence. Supporting Evidence: PMID:11181649 MCC is a heteromeric mitochondrial enzyme composed of biotin-containing alpha subunits and smaller beta subunits |
| GO:0004485 methylcrotonoyl-CoA carboxylase activity | NAS PMID:11401427 Human biotin-containing subunit of 3-methylcrotonyl-CoA carb... | ACCEPT | Summary: Non-traceable assertion of the core carboxylase activity from the MCCA cDNA/genomic characterization paper. Reason: Core molecular function; consistent with all other evidence. Supporting Evidence: PMID:11401427 plays an essential role in the catabolism of leucine and isovalerate |
| GO:0006768 biotin metabolic process | NAS PMID:22869039 Structure and function of biotin-dependent carboxylases. | MARK AS OVER ANNOTATED | Summary: MCCC1 uses biotin as a covalently attached cofactor but does not participate in biotin biosynthesis or turnover. Annotating a biotin metabolic process conflates the requirement for the biotin cofactor with actual biotin metabolism. Reason: MCCC1's biological process is leucine catabolism; its dependence on the biotin cofactor does not make it a participant in biotin metabolism. Sourced from a family-level review (NAS). Supporting Evidence: PMID:22869039 Biotin-dependent carboxylases include acetyl-CoA carboxylase (ACC), |
| GO:1905202 methylcrotonoyl-CoA carboxylase complex | NAS PMID:11170888 The molecular basis of 3-methylcrotonylglycinuria, a disorde... | ACCEPT | Summary: Non-traceable assertion of MCC complex membership from the primary MCCA characterization. Reason: Core cellular-component annotation; MCCC1 is an integral subunit of the MCC holoenzyme. Supporting Evidence: PMID:11170888 MCC, an heteromeric enzyme consisting of alpha (biotin-containing) and beta subunits |
| GO:1905202 methylcrotonoyl-CoA carboxylase complex | NAS PMID:11181649 The molecular basis of human 3-methylcrotonyl-CoA carboxylas... | ACCEPT | Summary: Non-traceable assertion of MCC complex membership from an independent primary study. Reason: Core cellular-component annotation; MCCC1 is an integral subunit of the MCC holoenzyme. Supporting Evidence: PMID:11181649 MCC is a heteromeric mitochondrial enzyme composed of biotin-containing alpha subunits and smaller beta subunits |
| GO:1905202 methylcrotonoyl-CoA carboxylase complex | NAS PMID:11401427 Human biotin-containing subunit of 3-methylcrotonyl-CoA carb... | ACCEPT | Summary: Non-traceable assertion of MCC complex membership from the MCCA cDNA characterization paper. Reason: Core cellular-component annotation; MCCC1 is an integral subunit of the MCC holoenzyme. Supporting Evidence: PMID:11401427 MCCase consists of two subunits, |
| GO:1905202 methylcrotonoyl-CoA carboxylase complex | TAS PMID:22869039 Structure and function of biotin-dependent carboxylases. | ACCEPT | Summary: Traceable-author-statement membership in the MCC complex, from the biotin-dependent carboxylase structure/function review. Reason: Core cellular-component annotation; MCC assembles into a defined holoenzyme. Supporting Evidence: PMID:22869039 biotin carboxylase (BC), carboxyltransferase (CT), and biotin-carboxyl carrier protein components |
| GO:0005759 mitochondrial matrix | IDA PMID:16023992 Mitochondrial targeting signals and mature peptides of 3-met... | ACCEPT | Summary: Direct experimental evidence (protein import and presequence-cleavage analysis) that MCCC1 localizes to the mitochondrial matrix. Reason: Primary experimental support for the core mitochondrial matrix location. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving cleavable amino-terminal targeting presequences |
| GO:0006552 L-leucine catabolic process | ISS PMID:11170888 The molecular basis of 3-methylcrotonylglycinuria, a disorde... | ACCEPT | Summary: Sequence-similarity-based assignment of the core leucine catabolic process, supported in the same work by an mccA-null fungal model demonstrating the in vivo role of MCC in leucine catabolism. Reason: Core biological process; MCC catalyses the committed carboxylation step of leucine degradation. Supporting Evidence: PMID:11170888 to demonstrate, in vivo, the involvement of MCC in leucine catabolism |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-3065959 | ACCEPT | Summary: Reactome traceable-author-statement placing MCCC1 in the mitochondrial matrix (protein degradation reaction context). Reason: Core cellular location, consistent with all other evidence. 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-3323111 | ACCEPT | Summary: Reactome traceable-author-statement placing MCCC1 in the mitochondrial matrix. Reason: Core cellular location, consistent with all other evidence. 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-508308 | ACCEPT | Summary: Reactome traceable-author-statement placing MCCC1 in the mitochondrial matrix (carboxylation reaction context). Reason: Core cellular location, consistent with all other evidence. 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-70773 | ACCEPT | Summary: Reactome traceable-author-statement placing MCCC1 in the mitochondrial matrix (carboxylation reaction context). Reason: Core cellular location, consistent with all other evidence. 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-2993799 | MARK AS OVER ANNOTATED | Summary: Reactome models newly translated carboxylase subunits transiently in the cytosol before mitochondrial import (HLCS biotinylation / translocation reactions). MCCC1 is not a steady-state cytosolic protein; its mature functional location is the mitochondrial matrix. Reason: The cytosolic annotation reflects a transient pre-import biosynthetic intermediate in the Reactome pathway, not a functional cytosolic localization. MCCC1 carries a cleavable mitochondrial transit peptide and functions in the matrix. 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 | MARK AS OVER ANNOTATED | Summary: Reactome cytosolic annotation reflecting the pre-import translocation step (cytosolic carboxylases translocate to mitochondrial matrix), not a functional steady-state cytosolic location. Reason: Transient pre-import intermediate; MCCC1's mature functional compartment is the mitochondrial matrix. 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-9035987 | MARK AS OVER ANNOTATED | Summary: Reactome cytosolic annotation from the defective-HLCS biotinylation reaction, representing the transient pre-import state rather than a functional cytosolic localization. Reason: Transient pre-import intermediate; MCCC1's mature functional compartment is the mitochondrial matrix. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving cleavable amino-terminal targeting presequences |
| GO:0005759 mitochondrial matrix | NAS PMID:11170888 The molecular basis of 3-methylcrotonylglycinuria, a disorde... | ACCEPT | Summary: Non-traceable assertion of mitochondrial matrix localization from the primary MCCA characterization. Reason: Core cellular location, consistent with direct experimental import studies. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving cleavable amino-terminal targeting presequences |
| GO:0006552 L-leucine catabolic process | NAS PMID:11170888 The molecular basis of 3-methylcrotonylglycinuria, a disorde... | ACCEPT | Summary: Non-traceable assertion of the core leucine catabolic process, supported by the mccA-null fungal complementation model in the same paper. Reason: Core biological process; MCC catalyses the committed carboxylation step of leucine degradation. Supporting Evidence: PMID:11170888 to demonstrate, in vivo, the involvement of MCC in leucine catabolism |
| GO:0006768 biotin metabolic process | NAS PMID:11401427 Human biotin-containing subunit of 3-methylcrotonyl-CoA carb... | MARK AS OVER ANNOTATED | Summary: MCCC1 requires biotin as a covalently attached cofactor but does not participate in biotin biosynthesis or turnover; the biotin metabolic process annotation conflates cofactor usage with biotin metabolism. Reason: MCCC1's biological process is leucine (and isovalerate) catabolism; being a biotin-dependent enzyme does not make it a participant in biotin metabolism. Supporting Evidence: PMID:11401427 plays an essential role in the catabolism of leucine and isovalerate |
| GO:0009374 biotin binding | NAS PMID:11401427 Human biotin-containing subunit of 3-methylcrotonyl-CoA carb... | ACCEPT | Summary: MCCC1 carries a biotinyl (biotin-carrier) domain and holds the covalently attached biotin cofactor on a conserved lysine (Lys681), consistent with a biotin-binding molecular function. Reason: MCCC1 is the biotin-containing subunit; biotin binding/carriage is a genuine, structurally supported molecular function of the biotinyl-binding domain. Supporting Evidence: PMID:11401427 biotin carboxylase, and biotin-carrier domains |
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