GPD1 encodes the cytosolic NAD-dependent glycerol-3-phosphate dehydrogenase (alpha-glycerophosphate dehydrogenase; GPD-C/GPDH-C; EC 1.1.1.8), a homodimeric enzyme that reversibly interconverts dihydroxyacetone phosphate (DHAP) and sn-glycerol 3-phosphate (G3P) coupled to the NAD+/NADH redox pair. In its physiological (reductive) direction it converts DHAP plus NADH to G3P plus NAD+, regenerating cytosolic NAD+ and providing the glycerol-3-phosphate backbone for glycerolipid, glycerophospholipid and triacylglycerol biosynthesis. It is the cytosolic component of the glycerol-3-phosphate (glycerophosphate) shuttle: acting with the mitochondrial FAD-dependent glycerol-3-phosphate dehydrogenase (GPD2), it transfers reducing equivalents from cytosolic NADH into the mitochondrial ubiquinone pool. The enzyme is strongly NAD+-preferring (its affinity for NADP is negligible) and adopts an N-terminal NAD-binding Rossmann fold together with a C-terminal substrate/catalytic domain, with the catalytic proton acceptor in the C-terminal domain. GPD1 is a soluble cytoplasmic protein, expressed prominently in liver, adipose tissue and skeletal muscle. Biallelic loss-of-function variants cause transient infantile hypertriglyceridemia with hepatomegaly, fatty liver and hepatic fibrosis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006072 glycerol-3-phosphate metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to the core biological process of GPD1: metabolism of glycerol-3-phosphate. GPD1 interconverts DHAP and sn-glycerol 3-phosphate, so this is the central process the enzyme participates in. Reason: This is a well-supported, correctly-scoped core BP for a cytosolic glycerol-3-phosphate dehydrogenase. Corroborated by the enzyme's catalytic activity and by InterPro and Reactome evidence. Supporting Evidence: file:human/GPD1/GPD1-uniprot.txt Reaction=sn-glycerol 3-phosphate + NAD(+) = dihydroxyacetone phosphate |
| GO:0047952 glycerol-3-phosphate dehydrogenase [NAD(P)+] activity | IBA GO_REF:0000033 | MODIFY | Summary: Phylogenetic (IBA) annotation to the dual-cofactor [NAD(P)+] dehydrogenase activity. The human enzyme is essentially NAD+-specific: KM for NAD is 140 uM whereas KM for NADP is 1070 mM (roughly 10,000-fold weaker), so the NADP arm of the [NAD(P)+] term is not physiologically relevant. Reason: The [NAD(P)+] term overstates cofactor breadth. The precise, current catalytic term GO:0141152 (glycerol-3-phosphate dehydrogenase (NAD+) activity) matches the UniProt/Rhea reaction (RHEA:11092) and EC 1.1.1.8 and is the term GOA already applies from other sources. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: glycerol-3-phosphate dehydrogenase (NAD+) activity Supporting Evidence: file:human/GPD1/GPD1-uniprot.txt KM=140 uM for NAD file:human/GPD1/GPD1-uniprot.txt KM=1070 mM for NADP |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation placing the active enzyme in the cytosol. GPD1 is a soluble cytoplasmic protein and the cytosolic half of the glycerol-3-phosphate shuttle; cytosol is the correct, specific compartment. Reason: Consistent with the experimentally-supported cytoplasmic localization and with the enzyme's role as the cytosolic partner of the mitochondrial GPD2. Cytosol is the appropriate specific CC term. Supporting Evidence: file:human/GPD1/GPD1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic annotation from the UniProt Subcellular Location keyword mapping (SL-0086, Cytoplasm). Correct but less specific than the cytosol term also annotated to this gene. Reason: Not wrong, but 'cytoplasm' is a broad parent of the more informative 'cytosol' annotation. Retained as non-core to avoid loss of the SubCell-derived location while cytosol carries the core CC. Supporting Evidence: file:human/GPD1/GPD1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005975 carbohydrate metabolic process | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO electronic annotation mapping the G3P-dehydrogenase domain to the very general 'carbohydrate metabolic process'. GPD1 acts on the phosphorylated three-carbon metabolites DHAP/G3P at the interface of glycolysis and lipid metabolism; the specific process is glycerol-3-phosphate metabolism, which is also annotated. Reason: Too general and not the most informative description of GPD1's role. The specific glycerol-3-phosphate metabolic/biosynthetic processes better capture the biology; this broad carbohydrate-metabolism term adds little. Supporting Evidence: file:human/GPD1/GPD1-uniprot.txt Reaction=sn-glycerol 3-phosphate + NAD(+) = dihydroxyacetone phosphate |
| GO:0006072 glycerol-3-phosphate metabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic annotation to glycerol-3-phosphate metabolic process, duplicating the IBA annotation to the same term. This is the correct core BP for GPD1. Reason: Correctly-scoped core biological process, independently supported by the phylogenetic annotation and by the catalytic activity. Supporting Evidence: file:human/GPD1/GPD1-uniprot.txt Reaction=sn-glycerol 3-phosphate + NAD(+) = dihydroxyacetone phosphate |
| GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO electronic annotation to the parent oxidoreductase class (CH-OH donor, NAD/NADP acceptor). This is a true but non-specific ancestor of the precise catalytic term GO:0141152. Reason: Correct as a grouping class but less informative than the specific glycerol-3-phosphate dehydrogenase (NAD+) activity term that is also annotated. The specific MF should carry the core annotation. Supporting Evidence: file:human/GPD1/GPD1-uniprot.txt Reaction=sn-glycerol 3-phosphate + NAD(+) = dihydroxyacetone phosphate |
| GO:0042803 protein homodimerization activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO electronic annotation to protein homodimerization. GPD1 is indeed a homodimer, confirmed by X-ray crystallography and stated in the UniProt SUBUNIT line, so the annotation reflects real structural biology. Reason: Homodimerization is a genuine, structurally-verified property of the active enzyme but describes its quaternary structure rather than its catalytic function. Kept as non-core supporting information. Supporting Evidence: file:human/GPD1/GPD1-uniprot.txt SUBUNIT: Homodimer Reactome:R-HSA-75889 The active forms of both enzymes are homodimers. |
| GO:0046168 glycerol-3-phosphate catabolic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO annotation to glycerol-3-phosphate catabolic process, i.e. the oxidative direction G3P + NAD+ -> DHAP + NADH. This is in fact the direction that UniProt's PhysiologicalDirection=left-to-right annotates (the reaction is written G3P + NAD+ = DHAP + NADH), but the dominant cellular role of cytosolic GPD1 is the reductive (biosynthetic/shuttle) DHAP -> G3P direction. Reason: Captures a chemically valid direction of the reversible reaction; however the predominant physiological role of cytosolic GPD1 is reductive (glycerolipid biosynthesis and the glycerol-phosphate shuttle, per Reactome R-HSA-75889). Kept as non-core rather than core. Supporting Evidence: file:human/GPD1/GPD1-uniprot.txt PhysiologicalDirection=left-to-right |
| GO:0051287 NAD binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO annotation to NAD binding. GPD1 has a defined NAD-binding Rossmann fold with multiple crystallographically-mapped NAD(+) contact residues, so this molecular-function detail is well supported. Reason: Directly supported by the UniProt NAD(+) BINDING features and the NAD-complex crystal structures. An accurate cofactor-binding MF that underlies the catalytic activity. Supporting Evidence: file:human/GPD1/GPD1-uniprot.txt /ligand="NAD(+)" |
| GO:0141152 glycerol-3-phosphate dehydrogenase (NAD+) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (Rhea/EC-based) annotation to the precise NAD+-specific catalytic activity. This matches the UniProt CATALYTIC ACTIVITY (RHEA:11092) and EC 1.1.1.8 and is the core molecular function of GPD1. Reason: This is the correct, current, precise catalytic term for GPD1 and represents its defining molecular function. Also independently supported by experimental TAS annotation (PMID:7772607). Supporting Evidence: file:human/GPD1/GPD1-uniprot.txt EC=1.1.1.8 file:human/GPD1/GPD1-uniprot.txt Reaction=sn-glycerol 3-phosphate + NAD(+) = dihydroxyacetone phosphate |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Bare 'protein binding' IPI from the human binary protein interactome (HuRI) yeast two-hybrid screen, recording a GPD1-FAM25A interaction (UniProt INTERACTION line lists FAM25A, B3EWG3). FAM25A is a small uncharacterised protein and the interaction has no established functional consequence for GPD1. Reason: 'Protein binding' is uninformative about molecular function, and this high-throughput binary interaction has not been shown to be functionally meaningful for GPD1. No more informative MF can be substituted, so the bare protein-binding term is removed; removal does not mean the interaction is false. Supporting Evidence: file:human/GPD1/GPD1-uniprot.txt P21695; B3EWG3: FAM25A |
| GO:0005829 cytosol | TAS Reactome:R-HSA-75889 | ACCEPT | Summary: Reactome TAS annotation placing GPD1 in the cytosol, where it catalyses the DHAP -> G3P reaction. Consistent with the enzyme's soluble cytoplasmic localization and its role as the cytosolic arm of the glycerol-3-phosphate shuttle. Reason: Author-traceable statement corroborating the core cytosolic localization. Supporting Evidence: Reactome:R-HSA-75889 DHAP is converted to G3P by GPD1/GPD1L |
| GO:0005737 cytoplasm | EXP PMID:7772607 Molecular cloning, sequencing and expression of a cDNA encod... | KEEP AS NON CORE | Summary: Experimental (EXP) annotation of cytoplasmic localization from the original human liver GPD1 cloning/expression study, the basis for the UniProt SUBCELLULAR LOCATION 'Cytoplasm' statement. Correct but less specific than the cytosol term. Reason: Experimentally supported and not removed, but 'cytoplasm' is a broad parent of the more informative 'cytosol' annotation that carries the core localization. Supporting Evidence: file:human/GPD1/GPD1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:7772607} |
| GO:0141152 glycerol-3-phosphate dehydrogenase (NAD+) activity | TAS PMID:7772607 Molecular cloning, sequencing and expression of a cDNA encod... | ACCEPT | Summary: TAS annotation to the NAD+-specific glycerol-3-phosphate dehydrogenase activity from the paper that cloned and expressed human liver GPD1 and defined it as an NAD-dependent alpha-glycerol-3-phosphate dehydrogenase (EC 1.1.1.8). Core molecular function. Reason: Precise, current catalytic term backed by the primary characterization of the human enzyme; this is the defining molecular function of GPD1. Supporting Evidence: file:human/GPD1/GPD1-uniprot.txt EC=1.1.1.8 {ECO:0000269|PubMed:7772607} |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Detected in an extracellular-vesicle proteome. The protein is plausible EV content, but this is not where it functions. Reason: Cytoplasmic enzyme. Cytosolic protein (UniProt); cytosolic proteins, including abundant enzymes and cytoskeletal proteins, are expected and often promiscuous EV contents (MISEV2018 (PMID:30637094) category 2b). True, but not its core location. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: MARK_AS_OVER_ANNOTATED.) Supporting Evidence: PMID:19056867 we used LC-MS/MS to profile the proteome of human urinary exosomes |
| GO:0046167 glycerol-3-phosphate biosynthetic process | IEA file:human/GPD1/GPD1-uniprot.txt | NEW | Summary: Proposed core BP not currently in GOA. The physiological direction of the GPD1 reaction is reductive (DHAP + NADH -> G3P + NAD+), i.e. biosynthesis of glycerol-3-phosphate, which supplies the glycerol backbone for glycerolipid synthesis. Reason: The predominant physiological role of cytosolic GPD1 is reductive (DHAP + NADH -> G3P + NAD+), supplying the glycerol-3-phosphate backbone for glycerolipid biosynthesis; this direction is directly modelled by Reactome R-HSA-75889. (UniProt's PhysiologicalDirection=left-to-right annotates the oxidative direction, as its reaction is written G3P + NAD+ = DHAP + NADH, so it is not cited here as support for biosynthesis.) The biosynthetic term is more specific than the general metabolic-process term. Supporting Evidence: Reactome:R-HSA-75889 GPD1/GPD1L reduces dihydroxyacetone phosphate with NADH donating electrons to this reduction Reactome:R-HSA-75889 DHAP is converted to G3P by GPD1/GPD1L |
| GO:0006127 glycerol-3-phosphate shuttle | IEA file:human/GPD1/GPD1-uniprot.txt | NEW | Summary: Proposed core BP not currently in GOA. GPD1 is the cytosolic half of the glycerol-3-phosphate (glycerophosphate) shuttle: it reduces DHAP to G3P using cytosolic NADH, and the mitochondrial FAD-dependent GPD2 re-oxidises G3P, so the pair transfers reducing equivalents from cytosol to the mitochondrial ubiquinone pool. Reason: The glycerol-3-phosphate shuttle is a well-established role of cytosolic NAD-dependent glycerol-3-phosphate dehydrogenase acting with mitochondrial GPD2; this specific process is missing from the current GOA set. Supporting Evidence: file:human/GPD1/GPD1-uniprot.txt Reaction=sn-glycerol 3-phosphate + NAD(+) = dihydroxyacetone phosphate |
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