GPD2 (mGPDH) is the mitochondrial FAD-dependent glycerol-3-phosphate dehydrogenase, a flavoenzyme of the mitochondrial inner membrane that faces the intermembrane-space side. It oxidises sn-glycerol-3-phosphate to dihydroxyacetone phosphate (DHAP) and passes the electrons through its bound FAD cofactor to ubiquinone in the respiratory chain (EC 1.1.5.3). Together with the cytosolic NAD-linked isozyme GPD1, it forms the glycerol-phosphate shuttle, which delivers cytosolic reducing equivalents to the mitochondrial ubiquinone pool and thereby bypasses Complex I. The enzyme carries two C-terminal EF-hand motifs and binds calcium, which enhances its activity; this calcium responsiveness makes GPD2 an important component of the pancreatic beta-cell glucose-sensing apparatus. The protein is synthesised as a precursor with an N-terminal mitochondrial transit peptide and exists as two alternatively spliced isoforms.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: GPD2 is a mitochondrial enzyme; this phylogenetic annotation is correct but non-specific. UniProt gives the location as Mitochondrion, and the protein is more precisely an inner-membrane enzyme (GO:0005743), which is the location captured in the core functions. Supporting Evidence: file:human/GPD2/GPD2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion. |
| GO:0006127 glycerol-3-phosphate shuttle | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process. With cytosolic GPD1, GPD2 constitutes the glycerol-phosphate shuttle that transfers reducing equivalents from the cytosol into the mitochondrial respiratory chain via glycerol-3-phosphate. Well supported phylogenetically and by Reactome. Supporting Evidence: Reactome:R-HSA-188467 FAD-linked mitochondrial glycerol 3-phosphate dehydrogenase (GPD2, alias: mGPDH) and its NAD-linked cytosolic isoform (GPD1, alias:cGPDH) constitute glycerol phosphate shuttle. |
| GO:0004368 glycerol-3-phosphate dehydrogenase (quinone) activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. This is the catalytic activity of GPD2 (EC 1.1.5.3): oxidation of sn-glycerol 3-phosphate to DHAP with electron transfer to a quinone. Phylogenetic call is consistent with the experimental IDA (PMID:9070847) and the UniProt catalytic activity. Supporting Evidence: file:human/GPD2/GPD2-uniprot.txt Reaction=a quinone + sn-glycerol 3-phosphate = dihydroxyacetone |
| GO:0006072 glycerol-3-phosphate metabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Correct but general parent process. GPD2 does participate in glycerol-3-phosphate metabolism, but the specific biological roles are better captured by the glycerol-3-phosphate shuttle (GO:0006127) and glycerol catabolic pathway; retain as non-core. |
| GO:0004368 glycerol-3-phosphate dehydrogenase (quinone) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic prediction (ARBA/InterPro/RHEA/EC 1.1.5.3) of the same core catalytic activity that is experimentally supported by PMID:9070847 and by the UniProt catalytic-activity annotation. Correct; duplicate of the IDA and IBA calls for this term. Supporting Evidence: file:human/GPD2/GPD2-uniprot.txt Reaction=a quinone + sn-glycerol 3-phosphate = dihydroxyacetone |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: GPD2 has two C-terminal EF-hand domains and binds calcium; this InterPro EF-hand prediction is biologically correct. Calcium binding is regulatory (it enhances catalytic activity) rather than the core catalytic function, so retain as non-core. Supporting Evidence: file:human/GPD2/GPD2-uniprot.txt Calcium-binding enhance the activity of the |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Correct but non-specific location derived from the UniProt subcellular location vocabulary. The more informative location is mitochondrial inner membrane (GO:0005743); retain as non-core. Supporting Evidence: file:human/GPD2/GPD2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion. |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000117 | ACCEPT | Summary: Correct and specific location. GPD2 is an integral inner-membrane flavoenzyme facing the intermembrane space, where it feeds electrons to the ubiquinone pool. This ARBA electronic call agrees with the Reactome TAS annotation to the same term and is the core location. |
| GO:0006072 glycerol-3-phosphate metabolic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro electronic annotation to the general glycerol-3-phosphate metabolic process; same term as the IBA call above. Correct but general; retain as non-core in favour of the specific shuttle/catabolic terms. |
| GO:0006127 glycerol-3-phosphate shuttle | TAS Reactome:R-HSA-188467 | ACCEPT | Summary: Reactome traceable-author annotation to the glycerol-phosphate shuttle, the core biological process of GPD2. Agrees with the IBA call for this term. Supporting Evidence: Reactome:R-HSA-188467 FAD-linked mitochondrial glycerol 3-phosphate dehydrogenase (GPD2, alias: mGPDH) and its NAD-linked cytosolic isoform (GPD1, alias:cGPDH) constitute glycerol phosphate shuttle. |
| GO:0019563 glycerol catabolic process | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: UniPathway-derived pathway annotation. GPD2 catalyses the final step of glycerol degradation via the glycerol kinase pathway (glycerol -> glycerol-3-phosphate -> DHAP), so participation in glycerol catabolism is pathway-appropriate. However, GPD2 acts on glycerol-3-phosphate rather than free glycerol, and this is a broad pathway-level process; retain as non-core. Supporting Evidence: file:human/GPD2/GPD2-uniprot.txt Polyol metabolism; glycerol degradation via glycerol kinase |
| GO:0004368 glycerol-3-phosphate dehydrogenase (quinone) activity | TAS Reactome:R-HSA-188467 | ACCEPT | Summary: Reactome traceable-author annotation of the core catalytic activity, consistent with the experimental IDA and the UniProt catalytic activity. Supporting Evidence: Reactome:R-HSA-188467 GPD2 catalyzes the unidirectional conversion of glycerol-3-phosphate (G-3-P) to dihydroxyacetone phosphate (DHAP) with concomitant reduction of the enzyme-bound FAD. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Human Protein Atlas immunofluorescence localisation to mitochondrion. Correct but non-specific relative to the inner-membrane location; retain as non-core supporting evidence. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput mitochondrial-proteome evidence: GPD2/P43304 is a member of the high-confidence human mitochondrial proteome (MitoCoP). Corroborates mitochondrial localisation; non-specific relative to the inner membrane, so retain as non-core. Supporting Evidence: PMID:34800366 high-confidence mitochondrial proteome MitoCoP |
| GO:0004368 glycerol-3-phosphate dehydrogenase (quinone) activity | IDA PMID:9070847 Mutation in the calcium-binding domain of the mitochondrial ... | ACCEPT | Summary: Experimental (IDA) support for the core catalytic activity. Novials et al. assayed FAD-linked (m-GDH) glycerophosphate dehydrogenase activity and its calcium-dependent regulation in cells from diabetic subjects; this is the experimental basis for the EC 1.1.5.3 catalytic-activity annotation in UniProt. Accept as the core molecular function. Supporting Evidence: PMID:9070847 The Ca(2+)-sensitive and mitochondrial enzyme FAD-linked glycerophosphate |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-188467 | ACCEPT | Summary: Reactome traceable-author annotation to the mitochondrial inner membrane, the specific and correct location for this inner-membrane flavoenzyme. Core location. |
| GO:0050660 flavin adenine dinucleotide binding | IEA GO_REF:0000002 | NEW | Summary: GPD2 binds FAD as its redox cofactor (InterPro FAD-binding domain; UniProt COFACTOR Name=FAD), which accepts the electrons abstracted from glycerol-3-phosphate and passes them to ubiquinone. This core cofactor molecular function is absent from the current GOA snapshot. Reason: FAD binding is an essential, well-supported cofactor MF for this FAD-dependent glycerol-3-phosphate dehydrogenase but is missing from GOA; added as NEW to make the proposed annotation explicit (mirrors its use in core_functions). Supporting Evidence: file:human/GPD2/GPD2-uniprot.txt Name=FAD |
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