Affinage

GPD2

Glycerol-3-phosphate dehydrogenase, mitochondrial · UniProt P43304

Length
727 aa
Mass
80.9 kDa
Annotated
2026-06-10
23 papers in source corpus 16 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPD2 encodes a glycerol-3-phosphate dehydrogenase that catalyzes the unidirectional, FAD-coupled oxidation of glycerol-3-phosphate (G3P) to dihydroxyacetone phosphate (DHAP), serving as the mitochondrial arm of the glycerol phosphate shuttle that reoxidizes cytosolic reducing equivalents (PMID:19011903). In its yeast origins, the GPD2 isoform was defined genetically as an anaerobically induced, NAD+-dependent enzyme acting as a redox sink for excess cytosolic NADH, distinct in regulation from its paralog GPD1 (PMID:9171333, PMID:7476212). Across mammalian systems, this single catalytic activity is repurposed for divergent physiological outputs: it boosts glucose oxidation to generate acetyl-CoA for histone acetylation at inflammatory loci in LPS-activated macrophages (PMID:31384058, PMID:31551573), supplies DHAP for ether lipid biosynthesis that sustains Akt/mTORC1 signaling and tumor growth in cancer cells (PMID:36632231), and supports G3P-driven ATP synthesis that is cardioprotective during ischemia downstream of LPL/AQP7-mediated glycerol supply (PMID:34807469). GPD2 enzymatic activity is set by its expression and by direct protein partners — the mitochondrial regulator GCN5L1 binds GPD2 to control the shuttle and hepatic gluconeogenesis (PMID:35802941), SPARC binds GPD2 to tune respiration and HCC cell migration (PMID:38334876) — and by IMMP2L-mediated cleavage of its mitochondrial transit peptide, which affects respiration and its homodimeric assembly in the inner membrane (PMID:38256063). Human GPD2 haploinsufficiency and a loss-of-function p.Pro205Leu mutation reduce or abolish mGPDH enzyme activity in patient cells (PMID:19011903, PMID:23554088).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1995 High

    Establishing that GPD2 encodes a functional NAD+-dependent glycerol-3-phosphate dehydrogenase defined the gene's core catalytic identity and showed its expression is carbon-source dependent but not stress-induced.

    Evidence Gene cloning, disruption, overexpression with enzyme activity assay and promoter-reporter analysis in S. cerevisiae

    PMID:7476212

    Open questions at the time
    • Did not resolve the physiological condition selecting for GPD2 over GPD1
    • No mammalian context
  2. 1997 High

    Genetic dissection answered why a second isoenzyme exists, showing GPD2 is specifically required under anaerobic conditions as a redox sink for excess cytosolic NADH, regulated independently of the osmotic HOG pathway.

    Evidence Deletion mutants, anaerobic growth assays, NADH measurements and acetaldehyde rescue in yeast

    PMID:9171333

    Open questions at the time
    • Yeast NAD+-dependent activity differs from mammalian FAD-coupled mitochondrial enzyme
    • Membrane topology not addressed
  3. 2008 Medium

    Characterizing the human enzyme established GPD2 as mitochondrial glycerophosphate dehydrogenase on the inner membrane catalyzing unidirectional G3P-to-DHAP conversion, and linked gene dosage to enzyme activity in patients.

    Evidence FISH breakpoint mapping, transcript quantification and enzyme activity assay in patient lymphoblastoid lines

    PMID:19011903

    Open questions at the time
    • No structural validation
    • Single lab
    • Disease causality from haploinsufficiency alone not firmly established
  4. 2013 Medium

    A genotype-activity correlation identified residue Pro205 as critical, showing combined hemizygous missense plus deletion abolishes activity while heterozygotes retain ~50%.

    Evidence aCGH, Sanger sequencing and enzyme activity assays in patient-derived cells

    PMID:23554088

    Open questions at the time
    • No structural mechanism for how Pro205Leu impairs catalysis
    • Single family
  5. 2019 High

    Connecting GPD2 flux to chromatin showed the shuttle drives glucose oxidation and acetyl-CoA-dependent histone acetylation to set inflammatory gene expression in macrophages and to enforce LPS tolerance.

    Evidence Macrophage loss-of-function, metabolic flux, histone acetylation and gene expression analyses

    PMID:31384058 PMID:31551573

    Open questions at the time
    • Direct enzymatic coupling to specific histone marks not biochemically reconstituted
    • Mechanism of tolerance-phase shutdown unresolved
  6. 2020 Medium

    Cancer studies tied GPD2-driven G3P-ATP synthesis to malignant phenotype and placed GPD2 expression downstream of CD133/p38 signaling.

    Evidence GPD2 knockdown, G3P-ATP synthesis assay, p38 inhibition and anchorage-independent growth in CD133+ hepatocarcinoma cells

    PMID:31887237

    Open questions at the time
    • Pathway placement relies on inhibitor only
    • Single lab
  7. 2021 Medium

    An in vivo KO defined a cardioprotective role, showing GPD2 enables ATP synthesis from glycerol during ischemia downstream of LPL/AQP7 glycerol supply.

    Evidence GPD2-deficient mouse, myocardial infarction model, cardiac function and metabolic assays with LPL/AQP7 KO

    PMID:34807469

    Open questions at the time
    • Single lab
    • Mechanism of GPD2 activation under ischemia not detailed
  8. 2022 Medium

    Identifying GCN5L1 as a direct binding partner revealed protein-level regulation of GPD2 activity that controls cytosolic redox and hepatic gluconeogenesis.

    Evidence Co-IP, GCN5L1 deletion cells/mice, gluconeogenesis and cytosolic redox assays

    PMID:35802941

    Open questions at the time
    • No reciprocal validation or binding interface mapped
    • Single lab
  9. 2023 High

    Multi-omics with rescue redefined GPD2's oncogenic role as biosynthetic rather than purely bioenergetic, establishing a GPD2-DHAP-ether lipid-Akt/mTORC1 axis.

    Evidence GPD2 KO cells, in vivo tumor growth, metabolomics/lipidomics, DHAP precursor and ether lipid rescue

    PMID:36632231

    Open questions at the time
    • Direct enzyme-to-ether-lipid flux not measured in real time
    • Single lab
  10. 2024 Medium

    Several findings established additional layers of GPD2 regulation: IMMP2L cleaves its transit peptide affecting respiration and dimer structure, SPARC binds and tunes GPD2-dependent respiration in HCC, and lactate-induced H3K18 lactylation drives GPD2 to promote M2 macrophage polarization.

    Evidence Immp2l KO mice with substrate respiration and AlphaFold2 modeling; SPARC-GPD2 co-IP with Seahorse assays; H3K18la ChIP-seq with GPD2 knockdown

    PMID:38256063 PMID:38334876 PMID:39504115

    Open questions at the time
    • Structural effect of IMMP2L cleavage is computational
    • SPARC and GCN5L1 binding interfaces unmapped
    • Lactylation-to-transcription mechanism incomplete
  11. 2025 Medium

    Newer studies extended GPD2 to platelet function via promoter methylation suppressing energy metabolism/NF-kB/P2Y12, and to anti-ferroptosis protection in sepsis-induced lung injury via the GPX4 pathway.

    Evidence CRISPR-dCas9 epigenome editing with clotting assays; AAV knockdown in CLP sepsis with GPX4 activator rescue

    PMID:40682019 PMID:41313944

    Open questions at the time
    • GPX4-GPD2 link rests on pharmacological rescue only
    • Mechanism connecting enzymatic activity to ferroptosis unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single G3P-DHAP catalytic activity is mechanistically routed to such divergent outputs (chromatin acetylation, ether lipid synthesis, redox, ferroptosis) and how its partner interactions structurally regulate catalysis remain unresolved.
  • No experimental atomic structure of human GPD2
  • Binding interfaces for GCN5L1/SPARC undefined
  • Determinants selecting bioenergetic vs biosynthetic flux unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0016740 transferase activity 2
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 2
Partners
GCN5L1GPIIMMP2LSPARC

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 In S. cerevisiae, GPD2 encodes one of two isoenzymes of NAD+-dependent glycerol 3-phosphate dehydrogenase; GPD2 (unlike GPD1) is specifically induced by anaerobic/anoxic conditions and is required for anaerobic growth, functioning as a redox sink for excess cytosolic NADH. Its anaerobic induction is independent of the HOG pathway that controls osmotic induction of GPD1. Gene deletion (gpd1Δ, gpd2Δ, double mutant), anaerobic growth assays, NADH accumulation measurements, acetaldehyde rescue experiment, CAT reporter gene transcriptional analysis The EMBO journal High 9171333
1995 GPD2 encodes an sn-glycerol 3-phosphate dehydrogenase (NAD+) in S. cerevisiae sharing 69% identity with GPD1; GPD2 overexpression increases GPDH enzyme activity, and its promoter activity is decreased on non-fermentable carbon sources and is not induced by osmotic stress or heat shock. Gene cloning, disruption, overexpression, CAT reporter gene fusion transcriptional analysis, enzyme activity assay Molecular microbiology High 7476212
2019 In LPS-activated macrophages, GPD2 (mitochondrial glycerol 3-phosphate dehydrogenase, a component of the glycerol phosphate shuttle) boosts glucose oxidation to fuel acetyl-CoA production, driving histone acetylation at inflammatory gene loci. During prolonged LPS exposure (tolerance), GPD2 coordinates a shutdown of oxidative metabolism, limiting acetyl-CoA availability for histone acetylation and suppressing inflammatory gene expression. GPD2 loss-of-function in macrophages, metabolic flux analysis, histone acetylation assays, gene expression analysis in LPS-stimulated and LPS-tolerant macrophages Nature immunology High 31384058 31551573
2008 GPD2 encodes mitochondrial glycerophosphate dehydrogenase (mGPDH), located on the outer surface of the inner mitochondrial membrane, catalyzing the unidirectional conversion of glycerol-3-phosphate (G3P) to dihydroxyacetone phosphate with concomitant reduction of enzyme-bound FAD. Haploinsufficiency of GPD2 leads to ~50% reduction in mGPDH transcript and activity in patient lymphoblastoid cell lines. FISH mapping of chromosomal breakpoint, molecular transcript quantification, functional enzyme activity assay in patient-derived lymphoblastoid cell lines Human genetics Medium 19011903
2013 A hemizygous GPD2 missense mutation (p.Pro205Leu) combined with chromosomal deletion results in completely absent GPD2 enzymatic activity, while heterozygous carriers (mother, sister) have ~50% activity, establishing this residue as critical for enzymatic function. aCGH deletion mapping, Sanger sequencing, functional enzyme activity assay in patient-derived cells American journal of medical genetics. Part A Medium 23554088
2021 Under ischemic conditions in cardiomyocytes, GPD2 is activated and converts glycerol-3-phosphate to dihydroxyacetone phosphate to facilitate ATP synthesis from glycerol. GPD2 deficiency exacerbates cardiac dysfunction after acute myocardial infarction, placing GPD2 downstream of LPL/AQP7-mediated glycerol supply in a cardioprotective pathway. GPD2-deficient mouse model, myocardial infarction (coronary ligation) model, cardiac function measurements, metabolic activity assays, cardiomyocyte-specific LPL and AQP7 deficiency models FASEB journal Medium 34807469
2023 GPD2 KO in cancer cells suppresses tumor growth not through its conventional bioenergetic role but by reducing dihydroxyacetone phosphate (DHAP) supply for ether lipid biosynthesis. Reduced ether lipid levels downregulate the Akt/mTORC1 pathway, and cell growth is rescued by supplementation with a DHAP precursor or ether lipids, defining a GPD2-ether lipid-Akt signaling axis. GPD2 knockout cells, in vivo tumor growth assay, multi-omics (metabolomics, transcriptomics, lipidomics), DHAP precursor and ether lipid supplementation rescue experiments Theranostics High 36632231
2022 Mitochondrial GCN5L1 directly binds GPD2 and modulates its enzymatic activity, regulating the glycerol phosphate shuttle and thereby controlling cytosolic redox state and hepatic gluconeogenesis from glycerol and lactate. GCN5L1 deletion cells/mice, gluconeogenesis assays, cytosolic redox measurement, co-immunoprecipitation of GCN5L1 and GPD2 Biochemical and biophysical research communications Medium 35802941
2024 IMMP2L mitochondrial peptidase cleaves the mitochondrial transit peptide of GPD2; loss of IMMP2L reduces GPD2-mediated glycerol-3-phosphate-driven mitochondrial respiration (~20% decrease in females, ~7% in males) and alters the homodimeric structure of GPD2 within the inner mitochondrial membrane. Immp2l knockout mouse, substrate-specific mitochondrial respiration assays (G3P as substrate), AlphaFold2-Multimer structural prediction, EchoMRI, primary MEF cell lines International journal of molecular sciences Medium 38256063
2020 In CD133-positive HuH-7 hepatocarcinoma cells, GPD2 knockdown strongly reduces glycerol-3-phosphate-driven ATP synthesis (G3P-ATPase activity) and decreases anchorage-independent cell proliferation. p38 signaling downstream of CD133 regulates GPD2 expression and G3P-ATPase activity. GPD2 knockdown, G3P-driven ATP synthesis assay, p38 inhibitor treatment, anchorage-independent growth assay, CD133-positive cell sorting Genes to cells Medium 31887237
2024 Mitochondrial SPARC interacts with GPD2 (identified by co-immunoprecipitation), modulates GPD2 expression levels, and thereby regulates GPD2-mediated mitochondrial respiration to control migration and invasion of hepatocellular carcinoma cells. Cellular fractionation, immunofluorescence, Proteinase K protection assay for SPARC mitochondrial localization, co-immunoprecipitation (SPARC-GPD2), Seahorse XF Mito Stress Test, shRNA knockdown Biochemical genetics Medium 38334876
2025 GPD2 methylation at CpG site cg03230175 in its promoter region reduces GPD2 expression, suppresses mitochondrial energy metabolism, decreases ROS production, attenuates NF-κB activation, and reduces P2Y12 expression, ultimately inhibiting coagulation/platelet function. GPD2 enzyme inhibition prolongs clotting time in mice. 850k methylation array, EWAS, CRISPR-dCas9-DNMT3A/Tet1CD epigenome editing, transcriptomic sequencing, cellular ROS/NF-κB/P2Y12 measurements, animal clotting assay Cellular & molecular biology letters Medium 40682019
2024 Lactate secreted by cervical cancer cells upregulates H3K18 lactylation at the GPD2 locus in macrophages, driving GPD2 expression; GPD2 knockdown in macrophages reverses lactate-induced M2 polarization, establishing a lactate→histone lactylation→GPD2→M2 macrophage polarization axis. ChIP-seq for H3K18la, GPD2 knockdown in macrophages, conditioned medium experiments, M1/M2 marker measurement DNA and cell biology Medium 39504115
2020 GPD2 binds directly to GPI (glucose-6-phosphate isomerase) as detected by microscale thermophoresis and protein interaction assays; esculetin binds GPD2 (and PGK2, GPI) and inhibits glycolytic flux as measured by lactate production and glucose consumption in HepG2 cells. Microscale thermophoresis (MST) binding assay, transcriptome/proteomics/reverse docking target identification, cellular glycolysis assay (lactate, glucose), animal xenograft Frontiers in pharmacology Low 32292350
2025 GPD2 knockdown in septic mice (CLP model) exacerbates lung injury by promoting ferroptosis; GPX4 activator (SeMet) reverses this, suggesting GPD2 suppresses ferroptosis through activation of the GPX4 pathway in the lung. AAV-mediated GPD2 knockdown, CLP sepsis mouse model, ferroptosis markers, GPX4 activator (SeMet) rescue, lung injury phenotype quantification Biochemical and biophysical research communications Medium 41313944

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 The two isoenzymes for yeast NAD+-dependent glycerol 3-phosphate dehydrogenase encoded by GPD1 and GPD2 have distinct roles in osmoadaptation and redox regulation. The EMBO journal 390 9171333
2019 Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses. Nature immunology 167 31384058
1995 Cloning and characterization of GPD2, a second gene encoding sn-glycerol 3-phosphate dehydrogenase (NAD+) in Saccharomyces cerevisiae, and its comparison with GPD1. Molecular microbiology 120 7476212
2011 Gpd1 and Gpd2 fine-tuning for sustainable reduction of glycerol formation in Saccharomyces cerevisiae. Applied and environmental microbiology 61 21724879
2020 Esculetin Inhibits Cancer Cell Glycolysis by Binding Tumor PGK2, GPD2, and GPI. Frontiers in pharmacology 39 32292350
2024 Histone Lactylation-Driven GPD2 Mediates M2 Macrophage Polarization to Promote Malignant Transformation of Cervical Cancer Progression. DNA and cell biology 29 39504115
2008 Haploinsufficiency of the GPD2 gene in a patient with nonsyndromic mental retardation. Human genetics 23 19011903
2022 Ethanol yield improvement in Saccharomyces cerevisiae GPD2 Delta FPS1 Delta ADH2 Delta DLD3 Delta mutant and molecular mechanism exploration based on the metabolic flux and transcriptomics approaches. Microbial cell factories 21 35964044
2021 LPL/AQP7/GPD2 promotes glycerol metabolism under hypoxia and prevents cardiac dysfunction during ischemia. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 21 34807469
2023 Non-bioenergetic roles of mitochondrial GPD2 promote tumor progression. Theranostics 20 36632231
2022 CRISPR-Cas9 Approach Constructed Engineered Saccharomyces cerevisiae with the Deletion of GPD2, FPS1, and ADH2 to Enhance the Production of Ethanol. Journal of fungi (Basel, Switzerland) 20 35887459
2020 Contribution of GPD2/mGPDH to an alternative respiratory chain of the mitochondrial energy metabolism and the stemness in CD133-positive HuH-7 cells. Genes to cells : devoted to molecular & cellular mechanisms 16 31887237
2013 Intellectual disability and hemizygous GPD2 mutation. American journal of medical genetics. Part A 16 23554088
2019 Author Correction: Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses. Nature immunology 15 31551573
2021 Taraxasterol suppresses cell proliferation and boosts cell apoptosis via inhibiting GPD2-mediated glycolysis in gastric cancer. Cytotechnology 13 34776631
2022 Mitochondrial GCN5L1 regulates cytosolic redox state and hepatic gluconeogenesis via glycerol phosphate shuttle GPD2. Biochemical and biophysical research communications 8 35802941
2022 GPD2: The relationship with cancer and neural stemness. Cells & development 5 36592694
1996 Construction and characterization of a deletion mutant of gpd2 that encodes an isozyme of NADH-dependent glycerol-3-phosphate dehydrogenase in fission yeast. Bioscience, biotechnology, and biochemistry 5 8704325
2024 Immp2l Enhances the Structure and Function of Mitochondrial Gpd2 Dehydrogenase. International journal of molecular sciences 2 38256063
2025 GPD2 inhibition impairs coagulation function via ROS/NF-κB/P2Y12 pathway. Cellular & molecular biology letters 1 40682019
2025 The role of GPD2 on ferroptosis in sepsis-induced acute lung injury. Biochemical and biophysical research communications 0 41313944
2024 SPARC Controls Migration and Invasion of Hepatocellular Carcinoma Cells Via Regulating GPD2-Mediated Mitochondrial Respiration. Biochemical genetics 0 38334876
2006 Identification of the genes GPD1 and GPD2 of Pichia jadinii. DNA sequence : the journal of DNA sequencing and mapping 0 17381046

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