Gpdh1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IDA PMID:31399469 Lactate dehydrogenase and glycerol-3-phosphate dehydrogenase...	MODIFY	Summary: Gpdh1 is a soluble cytoplasmic enzyme; the cytoplasm term is correct but less specific than the localizations established for the gene. Reason: Cytoplasm is correct but general. The gene already carries cytosol (IBA from PTN000198006 and IDA) for the soluble enzyme pool. The flight-muscle isoform is additionally localized to Z disc and M band of the sarcomere (IDA), which are also cytoplasmic. Per refinement practice all supported specific descendants are listed as replacements. Proposed replacements: cytosol Z disc M band Supporting Evidence: PMID:35536221 GPDH1 promotes cytosolic redox balance, ATP production, and TAG accumulation. PMID:9307964 We find that glycerol-3-phosphate dehydrogenase (GPDH) is localized at Z-discs and M-lines.
GO:0005737 cytoplasm	IEA GO_REF:0000044	MODIFY	Summary: UniProt subcellular location mapping (Cytoplasm); correct but general. Reason: Same claim as the IDA cytoplasm row; refined to cytosol for the soluble pool and to Z disc and M band for the sarcomere-targeted flight-muscle isoform, all of which the gene already carries. Proposed replacements: cytosol Z disc M band Supporting Evidence: file:DROME/Gpdh1/Gpdh1-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm. PMID:9307964 We find that glycerol-3-phosphate dehydrogenase (GPDH) is localized at Z-discs and M-lines.
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: Cytosolic localization inherited from PAINT node PTN000198006, for which Gpdh1 is one of the experimental donors. Reason: The NAD-dependent G3P dehydrogenase of flies is the cytosolic (GPD1-type) enzyme; the G3P shuttle requires its cytosolic action on NADH and DHAP. Gpdh1 appearing in the donor list reflects its own experimental cytosol annotation and is expected, not circular. Supporting Evidence: PMID:35536221 GPDH1 promotes cytosolic redox balance, ATP production, and TAG accumulation.
GO:0005829 cytosol	IDA PMID:109448 Biochemical analyses of natural and induced null variants of...	ACCEPT	Summary: Gpdh1 was purified as a soluble enzyme from fly extracts alongside other cytosolic dehydrogenases. Reason: The cached record is abstract-only; the abstract reports co-purification of GPDH with cytoplasmic enzymes (alcohol dehydrogenase, cytoplasmic malate dehydrogenase). The cytosolic location is consistent with all other evidence, so the curator's annotation is accepted. Supporting Evidence: PMID:109448 several Drosophila enzymes including alcohol dehydrogenase, cytoplasmic malate dehydrogenase, alpha-glycerol phosphate dehydrogenase, and phosphoglucose isomerase were co-purified to homogeneity
GO:0005975 carbohydrate metabolic process	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: Generic InterPro2GO process; Gpdh1 acts on triose phosphate/alditol phosphate at the junction of glycolysis and glycerolipid metabolism. Reason: Gpdh1's substrates, DHAP and G3P, are carbohydrate derivatives; in GO, glycerol-3-phosphate metabolic process sits under carbohydrate derivative metabolic process, not carbohydrate metabolic process. The enzyme branches off glycolysis rather than catalysing a carbohydrate-metabolic step, and the accepted G3P metabolic and biosynthetic process terms describe its role precisely. Supporting Evidence: PMID:35536221 GPDH1 relies on the cofactor NAD+/NADH to interconvert the glycolytic intermediate DHAP to G3P.
GO:0006067 ethanol metabolic process	IMP PMID:19033156 Direct evidence that genetic variation in glycerol-3-phospha...	UNDECIDED	Summary: Gpdh activity genotypes affect adult ethanol tolerance; whether Gpdh1 participates in ethanol metabolism itself is not shown in the available abstract. Reason: The cached record is abstract-only (PMC full text not retrievable). The abstract reports that higher GPDH activity, including duplications, increases tolerance to ethanol exposure. This is a tolerance phenotype. GPDH might contribute by reoxidizing NADH made during ethanol oxidation, or by channelling carbon into lipid, but the abstract does not show that Gpdh1 performs a step of ethanol metabolism. Without the full text the curator's IMP can neither be confirmed nor rejected. Supporting Evidence: PMID:19033156 Duplications show an increase of 50% in activity and an increase of adult tolerance to ethanol exposure.
GO:0006072 glycerol-3-phosphate metabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Core process of the NAD-dependent G3P dehydrogenase family, inherited from PTN000198006 with Gpdh1 as an experimental donor. Reason: Gpdh1 directly catalyses the interconversion of DHAP and G3P; null alleles lower larval G3P. The IBA node placement is sound and Gpdh1 is in the inheriting clade. Supporting Evidence: PMID:35536221 G3P levels were significantly decreased in relative to the control strain
GO:0006072 glycerol-3-phosphate metabolic process	IDA PMID:4204332 Alpha-glycerophosphate dehydrogenase in Drosophila melanogas...	ACCEPT	Summary: Kinetic characterization of the larval and adult GPDH isozymes. Reason: The cached record has no abstract text, but the paper is a kinetic study of the larval and adult alpha-glycerophosphate dehydrogenase isozymes, i.e. direct biochemical evidence for the enzyme acting on G3P. Consistent with all other evidence; curator deferred to. Supporting Evidence: PMID:4204332 Alpha-glycerophosphate dehydrogenase in Drosophila melanogaster: kinetic differences and developmental differentiation of the larval and adult isozymes.
GO:0006072 glycerol-3-phosphate metabolic process	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO mapping from the NAD-dependent G3P dehydrogenase signatures; correct. Reason: Same claim as the IBA and IDA rows; Gpdh1 is a bona fide member of the family with the catalytic lysine (K206) and GxGxxG NAD loop intact. Supporting Evidence: file:DROME/Gpdh1/Gpdh1-uniprot.txt DR InterPro; IPR017751; G3P_DH_NAD-dep_euk.
GO:0006096 glycolysis	IGI PMID:31399469 Lactate dehydrogenase and glycerol-3-phosphate dehydrogenase...	MARK AS OVER ANNOTATED	Summary: Ldh; Gpdh1 double mutants have decreased glycolytic flux, showing that Gpdh1 and LDH redundantly regenerate NAD+ needed to sustain glycolysis. Reason: Gpdh1 reduces DHAP, which is diverted from the glycolytic pathway, and in doing so regenerates the cytosolic NAD+ that glyceraldehyde-3-phosphate dehydrogenase consumes. The genetic interaction shows Gpdh1 is needed to sustain glycolytic flux when LDH is absent. It does not catalyse a step that converts glucose to pyruvate. This is necessity rather than participation. The supported functions are G3P biosynthesis and cytosolic NADH reoxidation (redox balance), both captured elsewhere in this review. The record is abstract-only, so the row is not removed. Supporting Evidence: PMID:31399469 larvae lacking both LDH and G3P dehydrogenase (GPDH1) exhibit growth defects, synthetic lethality and decreased glycolytic flux PMID:35536221 the GPDH1-dependent conversion of DHAP to G3P functions in parallel with LDH to maintain redox balance
GO:0006127 glycerol-3-phosphate shuttle	IMP PMID:405967 Origin of alpha-glycerophosphate dehydrogenase isozymes in D...	ACCEPT	Summary: Gpdh1 is the cytosolic NADH-consuming enzyme of the alpha-glycerophosphate cycle that fuels flight muscle respiration. Reason: The GO term definition names cytosolic G3P dehydrogenase converting DHAP to G3P with NADH as the cytosolic step of the shuttle. Bewley and Lucchesi analysed the alpha-glycerophosphate cycle with Gpdh null alleles, and later work describes Gpdh1 acting with mitochondrial GPO1. Gpdh1 catalyses a defining step of this process; core function. Supporting Evidence: PMID:405967 observations are reported which bear on the functional divergence of the alpha-glycerophosphate cycle in the adult and larval stage of development PMID:35536221 G3P is used as a precursor for TAG synthesis and functions in the G3P electron shuttle to transfer reducing equivalents to the mitochondria.
GO:0006641 triglyceride metabolic process	IMP PMID:16204217 Triglyceride pools, flight and activity variation at the Gpd...	KEEP AS NON CORE	Summary: Reduced GPDH activity lowers the adult triglyceride pool; Gpdh1 supplies the G3P backbone for triglyceride synthesis. Reason: Gpdh1 makes the glycerol-3-phosphate precursor for glycerolipid synthesis. It contributes the first committed precursor of the glycerol backbone, but the acylation steps of triglyceride synthesis are done by other enzymes. This annotation reflects a real metabolic contribution made through its core G3P-synthesizing activity, so it is kept as non-core. Supporting Evidence: PMID:16204217 We observe small but statistically significant reductions in triglyceride content for adult Gpdh genotypes possessing 33-80% reductions from normal activity. PMID:35536221 The larval fat body displays high levels of GPDH1 activity and relies on this enzyme to generate glycerol-3-phosphate (G3P; Fig. 1), which is used in triglyceride (TAG) synthesis
GO:0006650 glycerophospholipid metabolic process	IEA GO_REF:0000041	KEEP AS NON CORE	Summary: UniPathway mapping (alpha-glycerophosphate cycle under phospholipid metabolism). Reason: G3P is the precursor of the glycerophospholipid backbone, so Gpdh1 contributes a precursor to this broad process in the same way as to triglyceride metabolism. The mapping is plausible but peripheral; the experimental evidence in flies concerns triglyceride and the shuttle. Supporting Evidence: file:DROME/Gpdh1/Gpdh1-uniprot.txt CC -!- PATHWAY: Phospholipid metabolism; alpha-glycerophosphate cycle.
GO:0007629 flight behavior	IMP PMID:16204217 Triglyceride pools, flight and activity variation at the Gpd...	MARK AS OVER ANNOTATED	Summary: Reduced GPDH activity lowers wing-beat frequency in tethered flight, an organismal consequence of reduced G3P-shuttle energy supply. Reason: Gpdh1 supports flight by supplying reducing equivalents to flight-muscle mitochondria through the G3P shuttle, which is annotated and accepted separately. Flight behavior is a downstream organismal phenotype of that metabolic role; the enzyme does not take part in the behavior itself. Supporting Evidence: PMID:16204217 activity reductions from 60 to 10% showed statistically significant reductions of approximately 7% in WBF
GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	IEA GO_REF:0000002	MODIFY	Summary: Correct but general parent of the specific G3P dehydrogenase activity. Reason: The specific NAD+-dependent glycerol-3-phosphate dehydrogenase activity is experimentally established for Gpdh1 and already carried by the gene. Proposed replacements: glycerol-3-phosphate dehydrogenase (NAD+) activity Supporting Evidence: file:DROME/Gpdh1/Gpdh1-uniprot.txt Reaction=sn-glycerol 3-phosphate + NAD(+) = dihydroxyacetone phosphate
GO:0030018 Z disc	IDA PMID:12756285 Analysis of glycolytic enzyme co-localization in Drosophila ...	ACCEPT	Summary: GPDH and other glycolytic enzymes co-localize at Z-discs in flight muscle. Reason: Immunolocalization in flight muscle (PMID:9307964, PMID:12756285) places GPDH at Z-discs and M-lines. Only the isoform with the C-terminal QNL tripeptide (GPDH-1, UniProt isoform C) localizes there, and localization is required for flight. Isoform-specific but well-established. Supporting Evidence: PMID:12756285 In Drosophila flight muscles, glycolytic enzymes are co-localized along sarcomeres at M-lines and Z-discs PMID:9307964 transgenic flies that synthesize only GPDH-3, lacking the C-terminal tripeptide, do not show the periodic banding pattern of localization at Z-discs and M-lines for GPDH
GO:0031430 M band	IDA PMID:12756285 Analysis of glycolytic enzyme co-localization in Drosophila ...	ACCEPT	Summary: GPDH accumulates at M-lines of flight muscle sarcomeres, more strongly than at Z-discs. Reason: As for Z disc; the flight-muscle isoform localizes to M-lines, which is required for co-localization of other glycolytic enzymes and normal flight. Supporting Evidence: PMID:12756285 In optimally fixed preparations of myofibrils, accumulation of the enzymes at M-lines is much greater than at Z-discs.
GO:0042803 protein homodimerization activity	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Eukaryotic NAD-dependent G3P dehydrogenases are homodimers; UniProt records Gpdh1 as a homodimer. Reason: Dimerization is a structural property of the family (InterPro IPR017751, eukaryotic GPD1-type) rather than the enzyme's functional role; kept as non-core. Supporting Evidence: file:DROME/Gpdh1/Gpdh1-uniprot.txt DR InterPro; IPR017751; G3P_DH_NAD-dep_euk.
GO:0046167 glycerol-3-phosphate biosynthetic process	IMP PMID:31399469 Lactate dehydrogenase and glycerol-3-phosphate dehydrogenase...	ACCEPT	Summary: Larval G3P production depends on Gpdh1; Ldh mutants compensate by making excess G3P. Reason: Gpdh1 catalyses the NADH-dependent reduction of DHAP to G3P, the net in vivo direction in larval fat body. Metabolomics of Gpdh1 mutants shows reduced G3P (PMID:35536221), and Ldh mutants produce excess G3P (PMID:31399469). Core process. Supporting Evidence: PMID:31399469 Ldh mutants compensate for the inability to produce lactate by generating excess glycerol-3-phosphate (G3P)
GO:0046167 glycerol-3-phosphate biosynthetic process	IMP PMID:35536221 The Drosophila melanogaster enzyme glycerol-3-phosphate dehy...	ACCEPT	Summary: Gpdh1 null larvae have significantly decreased G3P. Reason: Direct metabolomic evidence that Gpdh1 is the main source of larval G3P, consistent with its DHAP reductase activity. Supporting Evidence: PMID:35536221 G3P levels were significantly decreased in relative to the control strain
GO:0046168 glycerol-3-phosphate catabolic process	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro2GO mapping assigning the oxidative (G3P to DHAP) direction. Reason: The reaction is reversible, but in flies the evidence places Gpdh1 in net G3P synthesis (fat body) and in the reductive, cytosolic half of the G3P shuttle. In flight muscle, G3P is oxidized by mitochondrial glycerophosphate oxidase (GPO1), not by Gpdh1. No experimental evidence shows Gpdh1-mediated G3P breakdown in vivo. Supporting Evidence: PMID:35536221 In adult flight muscle, GPDH1 function in conjunction with GPO1 and the TCA cycle
GO:0047952 glycerol-3-phosphate dehydrogenase [NAD(P)+] activity	IBA GO_REF:0000033	MODIFY	Summary: Family-level NAD(P)+ G3P dehydrogenase activity inherited from PTN000919759, for which Gpdh1 is an experimental donor. Reason: The IBA is correct and the node placement sound. PAINT chose the NAD(P) parent term because cofactor specificity varies across the family. For Gpdh1 itself, purified-enzyme and kinetic studies establish the NAD+-specific child term GO:0141152, which GO places as an is_a child of GO:0047952 and which the gene already carries by IDA/IMP. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000919759 SUPPORTS TRANSFER Deep NAD(P)+ G3P dehydrogenase IBD node; Gpdh1 (FBgn0001128) is itself an experimental donor. Transfer is sound; only the cofactor-level granularity is refined for this gene. Proposed replacements: glycerol-3-phosphate dehydrogenase (NAD+) activity Supporting Evidence: PMID:35536221 GPDH1 relies on the cofactor NAD+/NADH to interconvert the glycolytic intermediate DHAP to G3P.
GO:0051287 NAD binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: NAD binding via the N-terminal Rossmann domain (GxGxxG loop at residues 11-16). Reason: Correct; the NAD-binding loop and other cofactor-binding residues are conserved. Cofactor binding is part of the catalytic activity rather than a separate function, so it is non-core. Supporting Evidence: file:DROME/Gpdh1/Gpdh1-uniprot.txt DR Pfam; PF01210; NAD_Gly3P_dh_N; 1.
GO:0055093 response to hyperoxia	IMP PMID:20668515 Experimental selection for Drosophila survival in extremely ...	MARK AS OVER ANNOTATED	Summary: A P-element line with reduced Gpdh expression showed improved survival in extreme high O2; Gpdh was one of several genes down-regulated in hyperoxia-selected flies. Reason: The evidence is the eclosion rate in hyperoxia of a single P-element insertion line (EY01534) with reduced Gpdh mRNA, from a screen of genes found down-regulated by experimental selection. The authors speculate that lower oxidative phosphorylation and ROS production explain the effect. This is an indirect organismal phenotype of reduced energy metabolism, not evidence that Gpdh1 takes part in a response to oxygen. Supporting Evidence: PMID:20668515 These P-element lines have insertions within or around genes including Tropomyosin 1 (Tm1), CG33129, UGP, and Glycerol 3 phosphate dehydrogenase (Gpdh) respectively.
GO:0141152 glycerol-3-phosphate dehydrogenase (NAD+) activity	IDA PMID:109448 Biochemical analyses of natural and induced null variants of...	ACCEPT	Summary: GPDH purified to homogeneity from Drosophila. Reason: Core molecular function. The enzyme was purified and characterized from flies, and it is the classic NAD-dependent alpha-glycerophosphate dehydrogenase. Supporting Evidence: PMID:109448 several Drosophila enzymes including alcohol dehydrogenase, cytoplasmic malate dehydrogenase, alpha-glycerol phosphate dehydrogenase, and phosphoglucose isomerase were co-purified to homogeneity
GO:0141152 glycerol-3-phosphate dehydrogenase (NAD+) activity	IDA PMID:405967 Origin of alpha-glycerophosphate dehydrogenase isozymes in D...	ACCEPT	Summary: All GPDH isozyme activity in flies derives from the single Gpdh structural gene. Reason: Null mutations at Gpdh abolish all alpha-GPDH isozymes at every stage, establishing that the enzyme activity is the product of this gene. Core function. Supporting Evidence: PMID:405967 mutations at the Gpdh locus obliterate all isozymatic species of alpha-GPDH in all developmental stages
GO:0141152 glycerol-3-phosphate dehydrogenase (NAD+) activity	IDA PMID:4204332 Alpha-glycerophosphate dehydrogenase in Drosophila melanogas...	ACCEPT	Summary: Kinetic comparison of larval and adult GPDH isozymes. Reason: Direct enzymological study of the Drosophila enzyme; abstract not available in cache but the title establishes it as a kinetic analysis of the isozymes. Core function, consistent with all other evidence. Supporting Evidence: PMID:4204332 Alpha-glycerophosphate dehydrogenase in Drosophila melanogaster: kinetic differences and developmental differentiation of the larval and adult isozymes.
GO:0141152 glycerol-3-phosphate dehydrogenase (NAD+) activity	IEA GO_REF:0000120	ACCEPT	Summary: Combined IEA from EC 1.1.1.8 / RHEA:11092; matches the experimentally established activity. Reason: Consistent with the IDA rows; the curated UniProt catalytic activity is EC 1.1.1.8. Supporting Evidence: file:DROME/Gpdh1/Gpdh1-uniprot.txt Reaction=sn-glycerol 3-phosphate + NAD(+) = dihydroxyacetone phosphate
GO:0141152 glycerol-3-phosphate dehydrogenase (NAD+) activity	IMP PMID:35536221 The Drosophila melanogaster enzyme glycerol-3-phosphate dehy...	ACCEPT	Summary: A CRISPR frameshift null allele disrupting the NAD-binding and catalytic domains lowers larval G3P. Reason: Consistent with the biochemical evidence; core function. Supporting Evidence: PMID:35536221 The mutation is a putative null allele that disrupts both the NAD(P)-binding domain and the C-terminal catalytic domain.

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FlyBase gene description for Gpdh1 (DROME)

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