BCAT2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (PAN-GO) inference that BCAT2 is active in the mitochondrion. Consistent with the cleaved N-terminal mitochondrial transit peptide (residues 1-27) and with all experimental localization evidence. Reason: BCAT2 has a 27-residue mitochondrial targeting presequence and is well established as a mitochondrial-matrix enzyme; the IBA is correct. Mitochondrial matrix (GO:0005759) is the more specific location captured elsewhere in the annotation set. Supporting Evidence: PMID:9165094 encode mature proteins of 41.2 and 41.3 kDa with presequences of 27 amino acids
GO:0006550 L-isoleucine catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference that BCAT2 is involved in L-isoleucine catabolism. BCAT2 transaminates isoleucine as the committed first step of its catabolism. Reason: Isoleucine transamination is a core BCAT2 activity (GO:0052656), and the enzyme initiates isoleucine catabolism. Direct process annotation is appropriate and core. Supporting Evidence: PMID:8702755 Activity of branched-chain amino acid aminotransferase was measured in the wild-type and mutants with either leucine, isoleucine, or valine as substrates
GO:0006574 L-valine catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference that BCAT2 is involved in L-valine catabolism, initiating valine breakdown by transamination to 3-methyl-2-oxobutanoate. Reason: Valine transamination (GO:0052655) is a core BCAT2 activity; the enzyme initiates valine catabolism. Valine is the most conspicuously elevated BCAA in BCAT2 deficiency, underscoring its physiological role here. Supporting Evidence: PMID:8702755 Activity of branched-chain amino acid aminotransferase was measured in the wild-type and mutants with either leucine, isoleucine, or valine as substrates
GO:0052654 L-leucine:2-oxoglutarate transaminase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference of L-leucine:2-oxoglutarate transaminase activity, one of the three substrate-specific BCAT activities. Corroborated by IDA (PMID:8702755) and Rhea IEA. Reason: This substrate-specific molecular function is directly demonstrated for BCAT2 and is one of its core enzymatic activities. Supporting Evidence: PMID:8702755 code for cytosolic and mitochondrial branched-chain amino acid aminotransferases
GO:0052655 L-valine:2-oxoglutarate transaminase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference of L-valine:2-oxoglutarate transaminase activity. Corroborated by IDA (PMID:8702755) and Rhea IEA (RHEA:24813). Reason: Core substrate-specific transaminase activity of BCAT2, directly measured with valine as substrate. Supporting Evidence: PMID:8702755 Activity of branched-chain amino acid aminotransferase was measured in the wild-type and mutants with either leucine, isoleucine, or valine as substrates
GO:0052656 L-isoleucine:2-oxoglutarate transaminase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference of L-isoleucine:2-oxoglutarate transaminase activity. Corroborated by IDA (PMID:8702755) and Rhea IEA (RHEA:24801). Reason: Core substrate-specific transaminase activity of BCAT2, directly measured with isoleucine as substrate. Supporting Evidence: PMID:8702755 Activity of branched-chain amino acid aminotransferase was measured in the wild-type and mutants with either leucine, isoleucine, or valine as substrates
GO:0003824 catalytic activity	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro2GO mapping to the root catalytic-activity term. Correct but uninformative: BCAT2 is a specific PLP-dependent transaminase. Reason: GO:0003824 is a very general parent of the specific branched-chain aminotransferase activity (GO:0004084) and substrate-specific transaminase terms already annotated. It conveys no information beyond "is an enzyme" and is subsumed by the more precise MF annotations.
GO:0004084 branched-chain-amino-acid:2-oxoglutarate transaminase activity	IEA GO_REF:0000120	ACCEPT	Summary: Combined multi-method IEA (ARBA + orthology + InterPro + EC:2.6.1.42) assigning the general branched-chain aminotransferase molecular function. This is the correct core EC-level activity. Reason: GO:0004084 is the primary molecular function of BCAT2 (EC 2.6.1.42) and is independently supported by direct experimental evidence (IDA PMID:8702755) and TAS (PMID:9165094). Supporting Evidence: PMID:8702755 code for cytosolic and mitochondrial branched-chain amino acid aminotransferases
GO:0005739 mitochondrion	IEA GO_REF:0000120	ACCEPT	Summary: IEA localization to mitochondrion (orthology to mouse O35855 plus UniProt SubCell SL-0173). Consistent with all other localization evidence. Reason: Mitochondrial localization is firmly established; matrix is the specific compartment. Supporting Evidence: PMID:9165094 encode mature proteins of 41.2 and 41.3 kDa with presequences of 27 amino acids
GO:0009081 branched-chain amino acid metabolic process	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: InterPro2GO mapping to the general BCAA metabolic process. Correct but a broad parent of the specific catabolic-process annotations. Reason: GO:0009081 (BCAA metabolic process) is a correct but general parent of the more specific and physiologically directional BCAA catabolic process (GO:0009083) and the amino-acid-specific catabolic terms already annotated. Keep as non-core; the catabolic terms carry the core signal.
GO:0009082 branched-chain amino acid biosynthetic process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: ARBA machine-learning IEA (and an older TAS) annotating branched-chain amino acid BIOSYNTHETIC process. The BCAT reaction is chemically reversible, but in humans BCAAs are essential and are not synthesized de novo; the physiological direction is catabolic. Reason: The reversible transamination can in principle re-aminate branched-chain keto acids, but net de novo BCAA biosynthesis is a bacterial/plant/fungal role of BCAT-family enzymes (e.g. IlvE), not the human physiological function. The biosynthetic-process annotation is transferred from the family/EC and over-states the in vivo role; the catabolic annotations are correct and core. (Retained as an over-annotation rather than removed, since the underlying reversible chemistry is real.) Supporting Evidence: PMID:8702755 Activity of branched-chain amino acid aminotransferase was measured in the wild-type and mutants with either leucine, isoleucine, or valine as substrates
GO:0009083 branched-chain amino acid catabolic process	IEA GO_REF:0000117	ACCEPT	Summary: ARBA IEA to branched-chain amino acid catabolic process. This is the correct core biological process for BCAT2 and is independently supported by direct experimental evidence (IDA on the same term, PMID:8702755). Reason: BCAT2 catalyzes the committed first step of BCAA catabolism; this is its central physiological role. Supporting Evidence: PMID:8702755 code for cytosolic and mitochondrial branched-chain amino acid aminotransferases file:human/BCAT2/BCAT2-deep-research-falcon.md BCAT2 catalyzes the first step in mitochondrial BCAA catabolism
GO:0052654 L-leucine:2-oxoglutarate transaminase activity	IEA GO_REF:0000116	ACCEPT	Summary: Rhea-based IEA (RHEA:18321) for L-leucine:2-oxoglutarate transaminase activity. Matches the UniProt CATALYTIC ACTIVITY reaction for leucine. Reason: Directly corresponds to a UniProt-documented catalytic reaction of BCAT2 and duplicates the experimentally supported (IDA/IBA) substrate-specific MF; correct and core. Supporting Evidence: PMID:8702755 code for cytosolic and mitochondrial branched-chain amino acid aminotransferases
GO:0052655 L-valine:2-oxoglutarate transaminase activity	IEA GO_REF:0000116	ACCEPT	Summary: Rhea-based IEA (RHEA:24813) for L-valine:2-oxoglutarate transaminase activity, matching the UniProt CATALYTIC ACTIVITY reaction for valine. Reason: Directly corresponds to a UniProt-documented catalytic reaction of BCAT2; core substrate-specific activity. Supporting Evidence: PMID:8702755 Activity of branched-chain amino acid aminotransferase was measured in the wild-type and mutants with either leucine, isoleucine, or valine as substrates
GO:0052656 L-isoleucine:2-oxoglutarate transaminase activity	IEA GO_REF:0000116	ACCEPT	Summary: Rhea-based IEA (RHEA:24801) for L-isoleucine:2-oxoglutarate transaminase activity, matching the UniProt CATALYTIC ACTIVITY reaction for isoleucine. Reason: Directly corresponds to a UniProt-documented catalytic reaction of BCAT2; core substrate-specific activity. Supporting Evidence: PMID:8702755 Activity of branched-chain amino acid aminotransferase was measured in the wild-type and mutants with either leucine, isoleucine, or valine as substrates
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Interaction detected in the BioPlex 2.0 high-throughput AP-MS interactome screen (interactors include HSPD1/P10809 and YBEY/P58557). "Protein binding" is uninformative about BCAT2's molecular function. Reason: GO:0005515 "protein binding" from a proteome-scale AP-MS screen conveys no specific functional information and is discouraged for core-function purposes. Per curation policy the experimental IPI is retained rather than removed, but it is marked as an over-annotation. (The BCAT2-HSPD1/HSP60 co-purification plausibly reflects mitochondrial chaperone association rather than a discrete functional partnership.) Supporting Evidence: PMID:28514442 robust affinity purification-mass spectrometry methodology to elucidate protein interaction networks and co-complexes
GO:0005515 protein binding	IPI PMID:29568061 An AP-MS- and BioID-compatible MAC-tag enables comprehensive...	MARK AS OVER ANNOTATED	Summary: Interaction (with HSPD1/P10809) detected using the MAC-tag AP-MS/BioID proximity-labeling platform. Bare "protein binding" from a high-throughput mapping method. Reason: High-throughput proximity/AP-MS "protein binding" is uninformative for BCAT2 core function. Retained as an experimental IPI per policy but marked as over-annotation; the HSPD1/HSP60 association is consistent with the mitochondrial matrix chaperone environment rather than a specific functional interaction. Supporting Evidence: PMID:29568061 comprehensive mapping of protein interactions and subcellular localizations
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Interactions (HSPD1/P10809, YBEY/P58557) from the BioPlex 3.0 dual proteome-scale AP-MS interactome. Bare "protein binding" from a high-throughput screen. Reason: Proteome-scale AP-MS "protein binding" is uninformative about BCAT2's molecular function. Retained as an experimental IPI per policy, marked as over-annotation. Supporting Evidence: PMID:33961781 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: Interactions (HSPD1/P10809, YBEY/P58557) from a multimodal cell-map interactome dataset. Bare "protein binding" from a high-throughput mapping study. Reason: High-throughput interactome "protein binding" is uninformative for BCAT2 core function. Retained as an experimental IPI per policy, marked as over-annotation. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics
GO:0005759 mitochondrial matrix	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl-Compara orthology IEA (from mouse) placing BCAT2 activity in the mitochondrial matrix, the specific compartment where BCAA transamination occurs. Reason: Mitochondrial matrix is the correct, specific subcellular location for this soluble matrix enzyme, consistent with its cleaved transit peptide and TAS/Reactome annotations. Supporting Evidence: PMID:9165094 encode mature proteins of 41.2 and 41.3 kDa with presequences of 27 amino acids
GO:0006552 L-leucine catabolic process	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl-Compara orthology IEA (from mouse) for L-leucine catabolic process. BCAT2 initiates leucine catabolism by transamination to 4-methyl-2-oxopentanoate (KIC). Reason: Leucine transamination (GO:0052654) is a core BCAT2 activity and the enzyme initiates leucine catabolism; the process annotation is appropriate and core. Supporting Evidence: PMID:8702755 Activity of branched-chain amino acid aminotransferase was measured in the wild-type and mutants with either leucine, isoleucine, or valine as substrates
GO:0006574 L-valine catabolic process	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl-Compara orthology IEA (from mouse) for L-valine catabolic process. Duplicates the IBA valine-catabolism annotation; correct and core. Reason: BCAT2 initiates valine catabolism; core biological process. Supporting Evidence: PMID:8702755 Activity of branched-chain amino acid aminotransferase was measured in the wild-type and mutants with either leucine, isoleucine, or valine as substrates
GO:0097009 energy homeostasis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara orthology IEA (from mouse) for energy homeostasis. BCAA catabolism feeds acetyl-CoA/succinyl-CoA into the TCA cycle and BCAT2 loss alters energy expenditure in mice, but this is a broad downstream physiological consequence rather than the enzyme's molecular role. Reason: Energy homeostasis is a general, pleiotropic downstream process to which BCAA catabolism contributes indirectly (e.g. BCAT2-knockout mice show increased energy expenditure). It is not the core enzymatic function; keep as non-core.
GO:0005739 mitochondrion	IDA GO_REF:0000052	ACCEPT	Summary: Direct immunofluorescence localization (Human Protein Atlas) placing BCAT2 in the mitochondrion. Reason: Experimental (IDA) immunofluorescence confirms mitochondrial localization, in agreement with all other evidence; matrix is the specific compartment.
GO:0005739 mitochondrion	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity localization to mitochondrion, transferred from rat ortholog (O35854). Consistent with the transit peptide and experimental data. Reason: Mitochondrial localization is firmly established across evidence types. Supporting Evidence: PMID:9165094 encode mature proteins of 41.2 and 41.3 kDa with presequences of 27 amino acids
GO:0009083 branched-chain amino acid catabolic process	IDA PMID:8702755 Two yeast homologs of ECA39, a target for c-Myc regulation, ...	ACCEPT	Summary: Direct experimental evidence that BCAT2 participates in BCAA catabolism: BCAT activity toward leucine, isoleucine and valine was measured, and the human/yeast homologs encode the branched-chain aminotransferases initiating BCAA breakdown. Reason: This is the core biological process of BCAT2, supported by direct enzymatic assays with all three BCAA substrates. Supporting Evidence: PMID:8702755 Activity of branched-chain amino acid aminotransferase was measured in the wild-type and mutants with either leucine, isoleucine, or valine as substrates
GO:0050873 brown fat cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sequence-similarity annotation transferred from mouse (O35855): BCAA catabolism supplies lipogenic acetyl-CoA that EP300/p300 uses to acetylate and inhibit PRDM16, preventing adipose browning. A real but indirect metabolic-signalling role, downstream of the catabolic function. Reason: This links BCAT2 to a specific downstream developmental/metabolic output (brown fat differentiation) via acetyl-CoA supply and PRDM16 regulation. It is genuine (documented in mouse orthologs) but is a peripheral, indirect role rather than BCAT2's core enzymatic function; keep as non-core. Supporting Evidence: UniProtKB:O35855 acetyl-CoA derived from branched chain amino acid catabolism is used by EP300/p300 to acetylate and inhibit PRDM16, thereby preventing adipose tissue browning
GO:0004084 branched-chain-amino-acid:2-oxoglutarate transaminase activity	IDA PMID:8702755 Two yeast homologs of ECA39, a target for c-Myc regulation, ...	ACCEPT	Summary: Direct experimental demonstration of branched-chain aminotransferase activity for the cloned mitochondrial enzyme, assayed with leucine, isoleucine and valine as substrates. Reason: This is the core molecular function of BCAT2 (EC 2.6.1.42), established by direct enzymatic assay. Supporting Evidence: PMID:8702755 Activity of branched-chain amino acid aminotransferase was measured in the wild-type and mutants with either leucine, isoleucine, or valine as substrates
GO:1903444 negative regulation of brown fat cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sequence-similarity annotation transferred from mouse (MGI:1276534) for negative regulation of brown fat cell differentiation, via BCAA-catabolism-derived acetyl-CoA and EP300/PRDM16 signalling. Reason: Same indirect brown-fat/PRDM16 axis as GO:0050873; a genuine downstream metabolic-signalling role documented in mouse but peripheral to BCAT2's core transaminase function. Keep as non-core. Supporting Evidence: UniProtKB:O35855 acetyl-CoA derived from branched chain amino acid catabolism is used by EP300/p300 to acetylate and inhibit PRDM16, thereby preventing adipose tissue browning
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput proteomic assignment of BCAT2 to the high-confidence human mitochondrial proteome (MitoCoP). Reason: Corroborates mitochondrial localization by an orthogonal high-throughput proteomics method, consistent with all other evidence. Supporting Evidence: PMID:34800366 defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP)
GO:0052654 L-leucine:2-oxoglutarate transaminase activity	IDA PMID:8702755 Two yeast homologs of ECA39, a target for c-Myc regulation, ...	ACCEPT	Summary: Direct experimental demonstration of L-leucine transaminase activity for the mitochondrial branched-chain aminotransferase. Reason: Core substrate-specific molecular function, directly measured with leucine as substrate. Supporting Evidence: PMID:8702755 Activity of branched-chain amino acid aminotransferase was measured in the wild-type and mutants with either leucine, isoleucine, or valine as substrates
GO:0052655 L-valine:2-oxoglutarate transaminase activity	IDA PMID:8702755 Two yeast homologs of ECA39, a target for c-Myc regulation, ...	ACCEPT	Summary: Direct experimental demonstration of L-valine transaminase activity for the mitochondrial branched-chain aminotransferase. Reason: Core substrate-specific molecular function, directly measured with valine as substrate. Supporting Evidence: PMID:8702755 Activity of branched-chain amino acid aminotransferase was measured in the wild-type and mutants with either leucine, isoleucine, or valine as substrates
GO:0052656 L-isoleucine:2-oxoglutarate transaminase activity	IDA PMID:8702755 Two yeast homologs of ECA39, a target for c-Myc regulation, ...	ACCEPT	Summary: Direct experimental demonstration of L-isoleucine transaminase activity for the mitochondrial branched-chain aminotransferase. Reason: Core substrate-specific molecular function, directly measured with isoleucine as substrate. Supporting Evidence: PMID:8702755 Activity of branched-chain amino acid aminotransferase was measured in the wild-type and mutants with either leucine, isoleucine, or valine as substrates
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-508179	ACCEPT	Summary: Reactome traceable-author-statement placing the BCAT2 reaction in the mitochondrial matrix (reverse direction: keto acids + glutamate to BCAAs + alpha-ketoglutarate). Reason: Mitochondrial matrix is the correct specific location for this enzyme; Reactome annotation is consistent with all other evidence.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-70724	ACCEPT	Summary: Reactome traceable-author-statement placing the BCAT2 reaction in the mitochondrial matrix (forward catabolic direction: BCAAs + alpha-ketoglutarate to keto acids + glutamate). Reason: Mitochondrial matrix is the correct specific location for this enzyme; consistent with all other evidence.
GO:0004084 branched-chain-amino-acid:2-oxoglutarate transaminase activity	TAS PMID:9165094 Cloning of the rat and human mitochondrial branched chain am...	ACCEPT	Summary: Traceable author statement (cloning of rat and human BCATm) supporting the branched-chain aminotransferase molecular function. This paper established the BCAT1/BCAT2 nomenclature and showed the cloned enzyme has BCAT activity. Reason: Corroborates the core EC-level molecular function of BCAT2 with TAS from the defining cloning paper. Supporting Evidence: PMID:9165094 the protein exhibits BCAT activity and correct processing of the mitochondrial targeting sequence
GO:0005739 mitochondrion	TAS PMID:9165094 Cloning of the rat and human mitochondrial branched chain am...	ACCEPT	Summary: Traceable author statement for mitochondrial localization from the BCATm cloning paper, which demonstrated correct processing of the mitochondrial targeting presequence. Reason: Mitochondrial localization is established; the cloning paper showed proper mitochondrial targeting-sequence processing. Supporting Evidence: PMID:9165094 the protein exhibits BCAT activity and correct processing of the mitochondrial targeting sequence
GO:0009082 branched-chain amino acid biosynthetic process	TAS PMID:8702755 Two yeast homologs of ECA39, a target for c-Myc regulation, ...	MARK AS OVER ANNOTATED	Summary: Older TAS annotating branched-chain amino acid BIOSYNTHETIC process, presumably reflecting the chemically reversible transamination. In humans BCAAs are essential and not synthesized de novo, so the physiological direction is catabolic. Reason: The reversible reaction can re-aminate branched-chain keto acids, but net BCAA biosynthesis is a microbial/plant role of BCAT-family enzymes, not the human function; humans require dietary BCAAs. The biosynthetic-process annotation over-states the in vivo role. Retained as an over-annotation (the reversible chemistry is real) rather than removed. Supporting Evidence: PMID:8702755 code for cytosolic and mitochondrial branched-chain amino acid aminotransferases
GO:0030170 pyridoxal phosphate binding	IDA PMID:8702755 Two yeast homologs of ECA39, a target for c-Myc regulation, ...	NEW	Summary: Proposed annotation (not in current GOA): BCAT2 binds pyridoxal 5'-phosphate (PLP) as its essential catalytic cofactor. UniProt records PLP as the cofactor (COFACTOR, from crystallographic studies) and a Schiff-base MOD_RES at Lys-229; PLP binding is required for the demonstrated aminotransferase activity. Reason: PLP-binding is a well-established, structurally and biochemically documented molecular function of this class-IV PLP-dependent aminotransferase (many BCATm crystal structures resolve the PLP cofactor; the Schiff-base lysine is annotated in UniProt) and directly underlies its catalytic activity. It is currently missing from GOA and is added here as a core function. Supporting Evidence: file:human/BCAT2/BCAT2-uniprot.txt Name=pyridoxal 5'-phosphate; Xref=ChEBI:CHEBI:597326;
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	KEEP AS NON CORE	Summary: The reported physical interaction is retained as non-core; generic protein binding does not specify the catalytic mechanism. Reason: Physical interaction and catalytic function are distinct claims. The observed interaction does not independently establish a new enzyme activity.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: The reported physical interaction is retained as non-core; generic protein binding does not specify the catalytic mechanism. Reason: Physical interaction and catalytic function are distinct claims. The observed interaction does not independently establish a new enzyme activity.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	KEEP AS NON CORE	Summary: The reported physical interaction is retained as non-core; generic protein binding does not specify the catalytic mechanism. Reason: Physical interaction and catalytic function are distinct claims. The observed interaction does not independently establish a new enzyme activity.

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