Affinage

GMPS

GMP synthase [glutamine-hydrolyzing] · UniProt P49915

Length
693 aa
Mass
76.7 kDa
Annotated
2026-06-10
12 papers in source corpus 7 papers cited in narrative 8 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

GMPS catalyzes the final, glutamine-amide-dependent step of de novo GMP synthesis, converting XMP to GMP, and this catalytic activity supports cancer cell proliferation and reshapes glutamine metabolism, as shown by isotope tracing and the growth defects following GMPS inhibition or knockdown in prostate cancer (PMID:33768538). Beyond its metabolic role, GMPS has a nuclear, non-catalytic function in p53 regulation: nuclear GMPS recruits the deubiquitinase USP7 into a complex with p53, decreasing p53 ubiquitination and stabilizing the protein (PMID:33742136). GMPS subcellular partitioning is therefore the key control point — cytoplasmic GMPS is targeted by the E3 ligase TRIM21 for ubiquitination and degradation, with SERPINB5 acting as an adaptor that prevents nuclear entry and recruits TRIM21, while SNORD50A/B small nucleolar RNAs further promote the TRIM21–GMPS interaction and cytoplasmic sequestration; loss of these restraints releases GMPS to the nucleus to stabilize p53 (PMID:33742136, PMID:32005234). GMPS additionally moonlights as a scaffold that bridges the Sec61 channel and the oligosaccharyltransferase subunit STT3A to enhance N-glycosylation and stability of PD-L1 in hepatocellular carcinoma (PMID:39690246), and promotes lung cancer cell migration through a DNMT1/SERPINB2/uPA axis (PMID:40498285). The GATase subunit of the enzyme adopts a defined fold with a surface mediating Mg2+ binding and contact with the ATPPase subunit, as resolved in an archaeal ortholog (PMID:23724776).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2000 Medium

    Established the GMPS chromosomal locus and showed it can be disrupted by oncogenic translocation, the first link between GMPS and malignancy.

    Evidence cDNA panhandle PCR and Southern blot identifying an in-frame MLL-GMPS fusion in treatment-related AML

    PMID:11110714

    Open questions at the time
    • Single patient with no functional characterization of the fusion protein
    • Does not establish whether GMPS contributes function to the chimera
  2. 2013 Medium

    Resolved the structural basis of the GATase subunit's Mg2+ binding and its interaction surface with the ATPPase subunit, defining intersubunit coupling within the synthetase.

    Evidence Solution NMR structure, backbone relaxation and chemical shift perturbation mapping of archaeal (M. jannaschii) GMPS GATase

    PMID:23724776

    Open questions at the time
    • Archaeal rather than mammalian enzyme
    • Does not address full-length holoenzyme catalysis or nuclear moonlighting functions
  3. 2020 High

    Defined how cytoplasmic GMPS is restrained, showing TRIM21-mediated ubiquitination and SERPINB5-adaptor-controlled nuclear exclusion link GMPS localization to TP53 expression.

    Evidence Mass spectrometry, Co-IP, overexpression/knockout cell lines and xenografts

    PMID:32005234

    Open questions at the time
    • Does not resolve the structural basis of SERPINB5-GMPS-TRIM21 assembly
    • Mechanism of nuclear import upon adaptor loss not detailed
  4. 2021 High

    Identified SNORD50A/B snoRNAs as upstream modulators that promote TRIM21–GMPS complex formation and cytoplasmic sequestration, and confirmed the nuclear GMPS–USP7–p53 stabilizing complex.

    Evidence Reciprocal Co-IP, immunofluorescence translocation assays, and KO/OE functional studies in breast cancer cells

    PMID:33742136

    Open questions at the time
    • How snoRNAs physically template the TRIM21-GMPS interaction is not structurally defined
    • Quantitative contribution of nuclear GMPS to total p53 pool unclear
  5. 2021 Medium

    Provided direct metabolic evidence that GMPS catalytic glutamine-amide transfer drives guanylate synthesis required for cancer cell growth.

    Evidence siRNA knockdown, pharmacological inhibition, [15N]-/[U-13C5]-glutamine isotope tracing, and PC-3 xenografts

    PMID:33768538

    Open questions at the time
    • Single tumor type and lab
    • Does not separate catalytic from scaffolding contributions to the growth phenotype
  6. 2024 Medium

    Revealed a catalysis-independent scaffolding role in which GMPS bridges the Sec61 channel and STT3A to enhance PD-L1 N-glycosylation and stability.

    Evidence Proteomics/scRNA-seq, Co-IP, angustmycin A inhibition, and in vivo tumor models in HCC

    PMID:39690246

    Open questions at the time
    • The bridging mechanism between Sec61 and STT3A is inferred, not reconstituted
    • Single-lab finding without orthogonal structural validation
  7. 2025 Medium

    Placed GMPS in a pro-migratory pathway acting through DNMT1 to regulate the SERPINB2-uPA axis in lung cancer.

    Evidence Lentiviral KO/OE cell lines, RNA-seq, western blot, and animal experiments in NSCLC

    PMID:40498285

    Open questions at the time
    • Direct biochemical link between GMPS and DNMT1 not established
    • Single lab; mechanism of DNMT1 regulation of SERPINB2 not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GMPS catalytic guanylate output, nuclear p53 stabilization, and ER scaffolding functions are coordinately switched in a single cell remains unresolved.
  • No structural model of the mammalian holoenzyme in its nuclear moonlighting state
  • Regulatory hierarchy among localization, catalysis, and scaffolding undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 2 GO:0016874 ligase activity 1 GO:0060090 molecular adaptor activity 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-1430728 Metabolism 1

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 SNORD50A/B small nucleolar RNAs enhance the interaction between E3 ubiquitin ligase TRIM21 and GMPS by forming a complex among them, promoting GMPS ubiquitination and cytoplasmic sequestration; loss of SNORD50A/B releases GMPS to translocate into the nucleus, where GMPS recruits USP7 and forms a complex with p53, decreasing p53 ubiquitination and stabilizing p53 protein. Co-immunoprecipitation, western blot, immunofluorescence, functional overexpression/knockout studies in breast cancer cells Cell death and differentiation High 33742136
2020 TRIM21 acts as an E3 ubiquitin ligase that mediates GMPS ubiquitination and degradation, thereby reducing nuclear GMPS availability and suppressing TP53 expression; SERPINB5 serves as an adaptor protein that prevents GMPS from entering the nucleus and recruits TRIM21 for GMPS ubiquitination. Co-immunoprecipitation, western blot, mass spectrometry identification of GMPS as TRIM21 target, immunofluorescence, overexpression/knockout cell lines, in vivo xenograft models Journal of biomedical science High 32005234
2024 GMPS promotes PD-L1 expression in hepatocellular carcinoma by enhancing the interaction between PD-L1 and the catalytic subunit STT3A of oligosaccharyltransferase (OST), acting as an additional module connecting the Sec61 channel complex and STT3A, thereby facilitating translocation and N-glycosylation of PD-L1 and reducing its ubiquitination-mediated degradation. Proteomic and scRNA-seq analyses, co-immunoprecipitation, western blot, pharmacological inhibition with angustmycin A, in vivo tumor models Cell death and differentiation Medium 39690246
2021 GMPS functions in the de novo purine biosynthesis pathway utilizing a glutamine amide to synthesize guanosine monophosphate; pharmacological inhibition or knockdown of GMPS significantly decreases prostate cancer cell growth and alters glutamine metabolism, as demonstrated by [15N-(amide)]glutamine and [U-13C5]glutamine metabolic tracing. siRNA knockdown, pharmacological inhibition, isotope metabolic tracing ([15N]-glutamine, [U-13C5]-glutamine), PC-3 xenograft mouse model The Journal of pathology Medium 33768538
2000 GMPS (Guanosine 5'-Monophosphate Synthetase) gene on chromosome 3q24 is fused in-frame with MLL in a t(3;11)(q25;q23) translocation in treatment-related acute myeloid leukemia, producing a chimeric MLL-GMPS fusion transcript that is alternatively spliced. cDNA panhandle PCR, reverse transcription, Southern blot analysis Blood Medium 11110714
2013 The GATase subunit of archaeal (Methanocaldococcus jannaschii) GMPS has a solution structure with a seven-stranded mixed β-sheet fenced by five α-helices; NMR chemical shift perturbation mapping identified a common surface on GATase responsible for both Mg2+ binding and interaction with the ATPPase subunit, with GATase-Mg2+ having Kd ~1 mM and GATase-ATPPase interaction falling in intermediate chemical exchange. Solution NMR structure determination, 15N backbone relaxation, NMR chemical shift perturbation mapping, gel filtration chromatography Biochemistry Medium 23724776
2025 GMPS promotes lung cancer cell migration through the SERPINB2-uPA axis, with DNMT1 serving as an intermediate factor by which GMPS regulates SERPINB2 expression; knockdown of GMPS inhibits tumor progression in NSCLC. Lentiviral overexpression and knockout cell lines, RNA sequencing, western blot, animal experiments Cellular oncology (Dordrecht, Netherlands) Medium 40498285
2025 Extracellular matrix (ECM) bio-scaffolds enhance guanylate production in pancreatic ductal adenocarcinoma cells via upregulation of GMPS (and IMPDH) expression, with increased guanylates alleviating oxaliplatin-induced DNA damage; GMPS expression correlates with matrisomal and DNA repair gene expression in PDAC patient samples. In vitro ECM bio-scaffolds, multi-omics integration, metabolic tracing, gene expression correlation in patient samples bioRxivpreprint Low

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Inhibition of cyclic GMP-dependent protein kinase-mediated effects by (Rp)-8-bromo-PET-cyclic GMPS. British journal of pharmacology 99 8719784
2021 The noncoding RNAs SNORD50A and SNORD50B-mediated TRIM21-GMPS interaction promotes the growth of p53 wild-type breast cancers by degrading p53. Cell death and differentiation 49 33742136
2020 TRIM21-SERPINB5 aids GMPS repression to protect nasopharyngeal carcinoma cells from radiation-induced apoptosis. Journal of biomedical science 43 32005234
2011 Bone marrow-derived CMPs and GMPs represent highly functional proangiogenic cells: implications for ischemic cardiovascular disease. Blood 42 21828132
2021 Inhibition of guanosine monophosphate synthetase (GMPS) blocks glutamine metabolism and prostate cancer growth. The Journal of pathology 35 33768538
2000 t(3;11) translocation in treatment-related acute myeloid leukemia fuses MLL with the GMPS (GUANOSINE 5' MONOPHOSPHATE SYNTHETASE) gene. Blood 23 11110714
2024 A STT3A-dependent PD-L1 glycosylation modification mediated by GMPS drives tumor immune evasion in hepatocellular carcinoma. Cell death and differentiation 21 39690246
2009 Genetic variations in the HGPRT, ITPA, IMPDH1, IMPDH2, and GMPS genes in Japanese individuals. Drug metabolism and pharmacokinetics 20 20045992
1999 Diminishing Dynamic Motion Problems of Platinum Anticancer Drug Adducts of Guanine Derivatives with the Hybrid Ligand Approach: Evidence for Cis Interligand Interactions Especially between 3'-GMP's. Inorganic chemistry 12 11670875
2021 Discovery of Novel GMPS Inhibitors of Candidatus Liberibacter Asiaticus by Structure Based Design and Enzyme Kinetic. Biology 6 34203217
2013 Solution nuclear magnetic resonance structure of the GATase subunit and structural basis of the interaction between GATase and ATPPase subunits in a two-subunit-type GMPS from Methanocaldococcus jannaschii. Biochemistry 6 23724776
2025 GMPS inhibits the proliferation and migration of non-small cell lung cancer via the regulation of the DNMT 1/SERPINB2 axis. Cellular oncology (Dordrecht, Netherlands) 0 40498285

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