Affinage

GMDS

GDP-mannose 4,6 dehydratase · UniProt O60547

Length
372 aa
Mass
42.0 kDa
Annotated
2026-04-28
26 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GMDS (GDP-mannose 4,6-dehydratase) catalyzes the first and rate-limiting step of the de novo GDP-fucose biosynthesis pathway, and its loss completely abolishes intracellular GDP-fucose and cellular fucosylation, which can be rescued by exogenous L-fucose via the salvage pathway (PMID:17559959, PMID:18047682, PMID:32748555). GMDS-dependent fucosylation is required for TRAIL- and CD95-induced apoptosis through formation of the secondary FADD/caspase-8/cFLIP complex (complex II), independently of direct death receptor fucosylation, and loss-of-function GMDS mutations in colon cancer cells enable escape from NK cell–mediated immune surveillance (PMID:19361506, PMID:22027835). GMDS regulates Notch protein stability through the GDP-fucose/OFUT1 axis, as demonstrated by genetic epistasis in Drosophila and pharmacological Notch inhibition epistasis in zebrafish, where loss of gmds increases neuromast hair cell number and accelerates regeneration (PMID:21720678, PMID:41097001). GMDS is cell-intrinsically required for T cell development beyond the double-negative thymic stage, as shown by competitive bone marrow chimera experiments in mice carrying a point mutation in Gmds (PMID:40642090).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2007 High

    Establishing GMDS as the rate-limiting enzyme of de novo GDP-fucose biosynthesis resolved how mammalian cells generate the universal fucose donor nucleotide sugar.

    Evidence siRNA knockdown and gene knockout in CHO cells with direct GDP-fucose measurement, glycan mass spectrometry, and L-fucose salvage rescue

    PMID:17559959 PMID:18047682

    Open questions at the time
    • Crystal structure–based catalytic mechanism in human GMDS not defined in these studies
    • Regulation of GMDS expression or enzymatic activity under physiological conditions unknown
    • Whether GMDS is rate-limiting in all mammalian cell types was not tested
  2. 2009 High

    Discovery that GMDS loss-of-function mutations occur naturally in human colon cancer and that restoring GMDS rescues TRAIL sensitivity and NK cell killing linked the fucosylation pathway to tumor immune evasion.

    Evidence Mutational analysis of HCT116 cells, wild-type GMDS transfection rescue, TRAIL apoptosis assay, in vivo xenograft with NK cell depletion

    PMID:19361506

    Open questions at the time
    • The specific fucosylated target(s) mediating TRAIL sensitization were not identified
    • Frequency and spectrum of GMDS mutations across broader cancer cohorts not established
    • Whether fucosylation loss affects additional immune surveillance mechanisms beyond NK/TRAIL was untested
  3. 2011 High

    Mechanistic dissection revealed that GMDS deficiency blocks TRAIL and CD95 apoptosis at the level of secondary complex II (FADD/caspase-8/cFLIP) assembly rather than at primary DISC formation, and that this effect is independent of direct death receptor fucosylation.

    Evidence Co-immunoprecipitation of DISC and complex II components, caspase-8 activity assays, lectin pull-down for DR4/DR5 fucosylation status

    PMID:22027835

    Open questions at the time
    • The identity of the fucosylated protein(s) required for complex II assembly remains unknown
    • Whether this mechanism operates in non-cancer primary cells was not examined
  4. 2011 Medium

    Genetic epistasis in Drosophila established that GMD/GDP-fucose levels regulate Notch protein stability through OFUT1, linking the fucosylation pathway to a major developmental signaling axis.

    Evidence Drosophila GMD mutants and UAS/Gal4 system, genetic epistasis with OFUT1, Notch protein and Abruptex mutant analysis

    PMID:21720678

    Open questions at the time
    • Whether this Notch stability mechanism is conserved in mammalian GMDS/POFUT1 was not shown
    • Biochemical mechanism by which OFUT1 degrades unfucosylated Notch was not defined
  5. 2020 Medium

    CRISPR knockout of GMDS in mammalian CHO cells confirmed its role as the de novo pathway bottleneck and demonstrated that complete loss of Fc fucosylation enhances FcγRIIIa binding and ADCC, validating GMDS as a glycoengineering target.

    Evidence CRISPR/Cas9 knockout in CHOZN cells, glycan mass spectrometry, FcγRIIIa binding and ADCC assays

    PMID:32748555

    Open questions at the time
    • Long-term stability of the afucosylated glycan phenotype in manufacturing-scale culture not assessed
    • Effects of GMDS loss on non-antibody glycoprotein function in the same cells not examined
  6. 2025 Medium

    A mouse ENU point mutation in Gmds revealed a cell-intrinsic requirement for GMDS-dependent fucosylation in T cell development from the double-negative to double-positive transition, while B cell development was unaffected.

    Evidence ENU mutagenesis, immunophenotyping by flow cytometry, competitive mixed bone marrow chimera transplantation

    PMID:40642090

    Open questions at the time
    • The fucosylated substrate(s) essential for the DN-to-DP transition remain unidentified
    • Whether this reflects Notch fucosylation requirements (known for thymocyte development) was not tested
    • Only a single point mutation was studied; full knockout phenotype in mice is unknown
  7. 2025 Medium

    Studies in zebrafish gmds mutants extended the Notch connection by showing that GMDS-dependent fucosylation suppresses neuromast hair cell regeneration partially through Notch signaling, and separately implicated GMDS haploinsufficiency in retinal ganglion cell loss and ocular stress response.

    Evidence CRISPR/Cas9 zebrafish knockouts, neomycin hair cell ablation with pharmacological Notch inhibition epistasis, RNA-seq and histological analysis of eye

    PMID:40571142 PMID:41097001

    Open questions at the time
    • Direct demonstration that Notch is hypofucosylated in gmds zebrafish mutants was not provided
    • Whether the ocular phenotype is Notch-dependent or reflects a distinct fucosylation target is unknown
    • Mammalian relevance of the hair cell and RGC phenotypes has not been tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of the specific fucosylated substrate(s) that mediate GMDS-dependent effects on death receptor complex II assembly, T cell development, and Notch signaling in mammals remains the central unresolved question.
  • No direct identification of the fucosylated target required for complex II formation
  • No structural or enzymological study of human GMDS regulation in the timeline
  • Tissue-specific physiological consequences of GMDS loss in a full mammalian knockout model have not been reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016829 lyase activity 3
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2
Partners
FUT8OFUT1

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 GMD (GDP-mannose 4,6-dehydratase) is an essential enzyme in the de novo GDP-fucose biosynthesis pathway; siRNA knockdown of GMDS in CHO antibody-producing cells reduced intracellular GDP-fucose and core fucosylation of antibody Fc oligosaccharides, demonstrating that GMDS and FUT8 collaborate synergistically in intracellular oligosaccharide fucosylation. siRNA loss-of-function, mRNA expression analysis, glycan mass spectrometry on antibody Fc BMC biotechnology High 18047682
2007 GMDS knockout CHO cells are completely devoid of intracellular GDP-fucose and produce fully non-fucosylated antibodies; fucosylation is rescued through the salvage pathway upon addition of exogenous L-fucose, confirming GMDS is the rate-limiting enzyme in the de novo GDP-fucose biosynthetic pathway. Gene knockout (CHO/DG44), HPLC measurement of GDP-fucose, glycan analysis of antibody products, L-fucose rescue experiment Journal of biotechnology High 17559959
2009 Loss-of-function mutations in GMDS found in human colon cancer (HCT116 cells) result in virtually complete deficiency of cellular fucosylation; transfection of wild-type GMDS into HCT116 cells restored cellular fucosylation and rendered cells highly susceptible to TRAIL-induced apoptosis, while GMDS-deficient cells escaped NK cell-mediated tumor surveillance in vivo. Mutational analysis, wild-type GMDS transfection rescue, in vitro TRAIL apoptosis assay, in vivo xenograft transplantation into athymic mice with NK cell depletion, anti-TRAIL blocking antibody Gastroenterology High 19361506
2011 GMDS deficiency inhibits formation of the secondary FADD-dependent complex II (comprising caspase-8 and cFLIP) downstream of TRAIL receptor and CD95 death-inducing signaling complex (DISC), without affecting primary DISC formation or caspase-8 recruitment/activation; this inhibition is independent of direct fucosylation of DR4 or DR5, as DR5-mediated apoptosis was also blocked despite DR5 not being fucosylated. Co-immunoprecipitation of DISC components, caspase-8 activity assays, DR4/DR5 fucosylation analysis, lectin pull-down, siRNA knockdown of GMDS The Journal of biological chemistry High 22027835
2011 In Drosophila, GMD (GDP-mannose dehydratase, ortholog of GMDS) activity and GDP-fucose levels are required to stabilize Notch protein; under low GMD expression, Notch degradation is mediated by OFUT1, demonstrating that the GDP-fucose/OFUT1 balance regulates Notch stability and signaling pathway activity. Drosophila genetics (mutants, UAS/Gal4 overexpression and knockdown), genetic epistasis with OFUT1, Notch protein level analysis, Notch Abruptex mutant analysis Biological research Medium 21720678
2018 Lentiviral shRNA-mediated knockdown of GMDS in human lung adenocarcinoma cells (A549 and H1299) impaired cell proliferation and colony formation, induced cell cycle arrest and apoptosis in vitro, and inhibited xenograft tumorigenesis in vivo; transcriptome analysis implicated the CASP8-CDKN1A axis as a downstream effector. Lentiviral shRNA knockdown, cell proliferation assay, colony formation assay, flow cytometry (cell cycle and apoptosis), xenograft mouse model, microarray transcriptome analysis BMC cancer Medium 29843634
2025 A point mutation in GMDS in mice results in reduced double-positive, CD4 single-positive, and CD8 single-positive T cells in the thymus despite normal double-negative cell numbers; mixed bone marrow chimera experiments demonstrated a cell-intrinsic requirement for GMDS from the double-positive stage of T cell development onward, while B cell subsets were not affected. ENU mutagenesis mouse model, immunophenotyping by flow cytometry, Rag1 bone marrow reconstitution, mixed bone marrow chimera competitive transplantation Frontiers in immunology Medium 40642090
2025 CRISPR/Cas9 gmds haploinsufficiency in zebrafish leads to downregulation of stress response genes (including crystallins) and upregulation of cell death genes, retinal ganglion cell layer thinning, RGC loss, and reduced optic nerve head width, implicating GMDS-dependent fucosylation in the regulation of ocular stress response and glaucoma-related pathology. CRISPR/Cas9 zebrafish knockout (haploinsufficient), RNA-seq, histological/morphological analysis of eye Experimental eye research Medium 40571142
2025 Loss of gmds function in zebrafish increases neuromast hair cell number and accelerates hair cell regeneration after neomycin ablation; pharmacological Notch inhibition further enhanced regeneration in wild-type but less so in gmds mutants, indicating GMDS-dependent fucosylation partially suppresses hair cell regeneration through Notch signaling. CRISPR/Cas9 zebrafish gmds mutants, neomycin chemical ablation, hair cell counting, pharmacological Notch inhibition (gamma-secretase inhibitor), epistasis analysis International journal of molecular sciences Medium 41097001
2020 Knockout of Gmds in CHOZN cells depletes GDP-fucose biosynthesis via the de novo pathway, resulting in complete loss of fucose modification on recombinant antibody N-glycans and significantly enhanced FcγRIIIa binding and ADCC activity, demonstrating GMDS as the rate-limiting step in the de novo GDP-fucose pathway in mammalian cells. CRISPR/Cas9 knockout, glycan mass spectrometry, FcγRIIIa binding assay, ADCC assay Biotechnology progress Medium 32748555

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 GMD@CSB.DB: the Golm Metabolome Database. Bioinformatics (Oxford, England) 945 15613389
2007 Double knockdown of alpha1,6-fucosyltransferase (FUT8) and GDP-mannose 4,6-dehydratase (GMD) in antibody-producing cells: a new strategy for generating fully non-fucosylated therapeutic antibodies with enhanced ADCC. BMC biotechnology 114 18047682
2007 Establishment of a GDP-mannose 4,6-dehydratase (GMD) knockout host cell line: a new strategy for generating completely non-fucosylated recombinant therapeutics. Journal of biotechnology 91 17559959
2009 Deficiency of GMDS leads to escape from NK cell-mediated tumor surveillance through modulation of TRAIL signaling. Gastroenterology 85 19361506
2019 LncRNA GMDS-AS1 inhibits lung adenocarcinoma development by regulating miR-96-5p/CYLD signaling. Cancer medicine 51 31860169
2011 GDP-mannose-4,6-dehydratase (GMDS) deficiency renders colon cancer cells resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor- and CD95-mediated apoptosis by inhibiting complex II formation. The Journal of biological chemistry 39 22027835
2009 The structural basis for catalytic function of GMD and RMD, two closely related enzymes from the GDP-D-rhamnose biosynthesis pathway. The FEBS journal 39 19459932
2018 GMDS knockdown impairs cell proliferation and survival in human lung adenocarcinoma. BMC cancer 26 29843634
2001 Cloning and expression of Helicobacter pylori GDP-l-fucose synthesizing enzymes (GMD and GMER) in Saccharomyces cerevisiae. European journal of biochemistry 22 11737200
2016 Correlations of AFAP1, GMDS and PTGFR gene polymorphisms with intra-ocular pressure response to latanoprost in patients with primary open-angle glaucoma. Journal of clinical pharmacy and therapeutics 18 27862086
2024 Decitabine in older patients with AML: quality of life results of the EORTC-GIMEMA-GMDS-SG randomized phase 3 trial. Blood 14 38717861
2012 GMD: measuring the distance between histograms with applications on high-throughput sequencing reads. Bioinformatics (Oxford, England) 14 22345619
2022 lncRNA GMDS‑AS1 upregulates IL‑6, TNF‑α and IL‑1β, and induces apoptosis in human monocytic THP‑1 cells via miR‑96‑5p/caspase 2 signaling. Molecular medicine reports 13 34981821
2015 Disruptions in a cluster of computationally identified enhancers near FOXC1 and GMDS may influence brain development. Neurogenetics 12 26382291
2013 Human GMDS gene fragment hypermethylation in chronic high level of arsenic exposure with and without arsenic induced cancer. SpringerPlus 12 24255851
2023 lncRNA GMDS-AS1 restrains lung adenocarcinoma progression via recruiting TAF15 protein to stabilize SIRT1 mRNA. Epigenomics 10 37309595
2020 Generation of FX-/- and Gmds-/- CHOZN host cell lines for the production of afucosylated therapeutic antibodies. Biotechnology progress 10 32748555
2023 Establishment and Application of an Indirect ELISA for the Detection of Antibodies to Porcine Streptococcus suis Based on a Recombinant GMD Protein. Animals : an open access journal from MDPI 8 36830506
2019 Gastric mucosal devitalization (GMD): translation to a novel endoscopic metabolic therapy. Endoscopy international open 7 31788546
2023 Epigenetic inhibition of lncRNA GMDS-AS1 by methyltransferase ESET promoted cell viability and metastasis of hepatocellular carcinoma. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 4 36737533
2011 The balance between GMD and OFUT1 regulates Notch signaling pathway activity by modulating Notch stability. Biological research 4 21720678
2021 Interactions between the Prophage 919TP and Its Vibrio cholerae Host: Implications of gmd Mutation for Phage Resistance, Cell Auto-Aggregation, and Motility. Viruses 3 34960610
2025 Genomic analysis of glaucoma pathogenesis due to gmds mutation in zebrafish. Experimental eye research 2 40571142
2024 The Indispensable Roles of GMDS and GMDS-AS1 in the Advancement of Cancer: Fucosylation, Signal Pathway and Molecular Pathogenesis. Mini reviews in medicinal chemistry 1 38591197
2025 Essential cell-intrinsic requirement for GMDS in T cell development. Frontiers in immunology 0 40642090
2025 Mutation of the GDP-Fucose Biosynthesis Gene gmds Increases Hair Cell Number and Neuromast Regenerative Capacity in Zebrafish. International journal of molecular sciences 0 41097001