GPT2 encodes the mitochondrial alanine aminotransferase ALT2, a pyridoxal 5'-phosphate-dependent enzyme that reversibly transfers an amino group between L-alanine and 2-oxoglutarate to form pyruvate and L-glutamate. Its reaction links alanine turnover, nitrogen transfer and mitochondrial carbon metabolism. Depending on substrate supply and cellular context, it can generate alanine and 2-oxoglutarate or consume alanine to make pyruvate. Human disease variants reduce catalytic activity and cause a neurodevelopmental disorder; mouse models link loss of GPT2 to altered alanine metabolism, anaplerosis and postnatal brain growth. Recombinant canonical ALT2 is active, whereas one tested alternative splice form lacks detectable activity. The cytosolic paralog is GPT/ALT1.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004021 L-alanine:2-oxoglutarate transaminase activity | IDA PMID:11863375 cDNA cloning, genomic structure, chromosomal mapping, and fu... | ACCEPT | Summary: Alanine:2-oxoglutarate transamination is the defining native enzyme activity. Reason: PMID:11863375 expresses functional human ALT2 in bacteria; PMID:25758935 compares recombinant wild-type and inactive disease variant. These establish the canonical reaction independently of electronic propagation. The inactive alternative splice form reported in PMID:19360321 does not negate activity of canonical GPT2. Supporting Evidence: PMID:11863375 Alanine aminotransferase (ALT) catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate PMID:19360321 ALT1 and 2 possess similar enzymatic activity for alanine and pyruvate but with different Km and kcat values |
| GO:0004021 L-alanine:2-oxoglutarate transaminase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Alanine:2-oxoglutarate transamination is the defining native enzyme activity. Reason: PMID:11863375 expresses functional human ALT2 in bacteria; PMID:25758935 compares recombinant wild-type and inactive disease variant. These establish the canonical reaction independently of electronic propagation. The inactive alternative splice form reported in PMID:19360321 does not negate activity of canonical GPT2. Supporting Evidence: PMID:11863375 Alanine aminotransferase (ALT) catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate PMID:19360321 ALT1 and 2 possess similar enzymatic activity for alanine and pyruvate but with different Km and kcat values |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: Retain the supported mitochondrial localization alongside the existing matrix annotation. Reason: PMID:34800366 provides the original human mitochondrial proteome assignment. Independent ALT2 fractionation (PMID:19360321) and curated Reactome localization agree with a mitochondrial pool. The fractionation study also reports an ER fraction, so it is not treated as proof of exclusive mitochondrial localization or as a matrix-resolved assay. The pre-existing matrix rows retain their distinct curated Reactome/ortholog basis. Retain the informative mitochondrion assertion under the root-organelle policy; existing mitochondrial matrix annotations are separate and are not substituted for this row. Supporting Evidence: PMID:19360321 showed localisation of ALT2 to the mitochondrial fraction and endoplasmatic reticulum (ER), but not to the cytosol. Reactome:R-HSA-507749 GPT2 is localized to mitochondria |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000120 | ACCEPT | Summary: Retain the curated matrix assignment for mitochondrial ALT2. Reason: The source Reactome assertions and ortholog transfer place the soluble enzyme in the matrix. Independent human organelle fractionation establishes mitochondria but also reports an ER fraction; it does not directly resolve the matrix or prove localization is exclusive. Retain the curated finer compartment without inventing a submitochondrial experiment or rejecting it solely because the cached source is less detailed. Supporting Evidence: PMID:19360321 showed localisation of ALT2 to the mitochondrial fraction and endoplasmatic reticulum (ER), but not to the cytosol. Reactome:R-HSA-507749 GPT2 is localized to mitochondria |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-507749 | ACCEPT | Summary: Retain the curated matrix assignment for mitochondrial ALT2. Reason: The source Reactome assertions and ortholog transfer place the soluble enzyme in the matrix. Independent human organelle fractionation establishes mitochondria but also reports an ER fraction; it does not directly resolve the matrix or prove localization is exclusive. Retain the curated finer compartment without inventing a submitochondrial experiment or rejecting it solely because the cached source is less detailed. Supporting Evidence: PMID:19360321 showed localisation of ALT2 to the mitochondrial fraction and endoplasmatic reticulum (ER), but not to the cytosol. Reactome:R-HSA-507749 GPT2 is localized to mitochondria |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-507775 | ACCEPT | Summary: Retain the curated matrix assignment for mitochondrial ALT2. Reason: The source Reactome assertions and ortholog transfer place the soluble enzyme in the matrix. Independent human organelle fractionation establishes mitochondria but also reports an ER fraction; it does not directly resolve the matrix or prove localization is exclusive. Retain the curated finer compartment without inventing a submitochondrial experiment or rejecting it solely because the cached source is less detailed. Supporting Evidence: PMID:19360321 showed localisation of ALT2 to the mitochondrial fraction and endoplasmatic reticulum (ER), but not to the cytosol. Reactome:R-HSA-507749 GPT2 is localized to mitochondria |
| GO:0006103 2-oxoglutarate metabolic process | IDA PMID:11863375 cDNA cloning, genomic structure, chromosomal mapping, and fu... | ACCEPT | Summary: GPT2 directly interconverts 2-oxoglutarate and glutamate during alanine transamination. Reason: This process follows the directly measured substrate/product chemistry rather than an indirect metabolomic association. The direction and contribution to anaplerosis depend on the metabolic state. Supporting Evidence: PMID:11863375 Alanine aminotransferase (ALT) catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate |
| GO:0008483 transaminase activity | IEA GO_REF:0000002 | MODIFY | Summary: Refine general transaminase activity to alanine aminotransferase. Reason: Both canonical human enzymes have directly measured alanine/pyruvate transamination. The existing GO:0004021 term is the supported precise descendant; the general chemistry is true. Proposed replacements: L-alanine:2-oxoglutarate transaminase activity Supporting Evidence: PMID:19360321 ALT1 and 2 possess similar enzymatic activity for alanine and pyruvate but with different Km and kcat values |
| GO:0030170 pyridoxal phosphate binding | IEA GO_REF:0000002 | ACCEPT | Summary: PLP is the catalytic cofactor of this alanine aminotransferase. Reason: The class-I aminotransferase family and curated cofactor assignment support PLP dependence. Human GPT2 structure PDB 3IHJ, described by Reactome, contains PLP; human GPT sequence/biochemistry supports the homologous cofactor mechanism. This is enzyme cofactor chemistry, not a second independent physiological function. Supporting Evidence: file:human/GPT2/GPT2-uniprot.txt Name=pyridoxal 5'-phosphate Reactome:R-HSA-507749 one molecule of pyridoxal phosphate associated with each monomer |
| GO:0042852 L-alanine biosynthetic process | IEA GO_REF:0000107 | ACCEPT | Summary: GPT2 can synthesize alanine by transferring nitrogen from glutamate to pyruvate. Reason: The direct reversible human reaction supports alanine biosynthesis; mouse loss-of-function and isotope-tracing work in PMID:27601654 gives physiological context for alanine production and anaplerosis. That context does not imply the enzyme always runs in the biosynthetic direction. Supporting Evidence: PMID:11863375 Alanine aminotransferase (ALT) catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate PMID:27601654 low alanine levels |
| GO:0042853 L-alanine catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Alanine transamination directly executes alanine catabolism. Reason: The alanine-to-pyruvate direction is measured in native human enzyme assays and represented by the curated reaction. Reversibility and alanine synthesis in other conditions do not invalidate this direct catabolic role. Supporting Evidence: PMID:19360321 ALT1 and 2 possess similar enzymatic activity for alanine and pyruvate but with different Km and kcat values PMID:11863375 Alanine aminotransferase (ALT) catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate |
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