Affinage

PRPSAP1

Phosphoribosyl pyrophosphate synthase-associated protein 1 · UniProt Q14558

Round 2 corrected
Length
356 aa
Mass
39.4 kDa
Annotated
2026-04-28
51 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PRPSAP1 (PAP39) is a non-catalytic regulatory subunit of the mammalian PRPP synthetase complex that inhibits phosphoribosyl pyrophosphate synthesis in proportion to its stoichiometric abundance within the complex (PMID:8132556, PMID:9366267). It physically associates with the catalytic subunits PRPS1 and PRPS2 with equal affinity and is required for proper oligomeric assembly of the complex; its absence drives catalytic subunits into aberrant homo-oligomeric states with diminished metabolic flux and impaired cell proliferation (PMID:9366267, PMID:39411161). Beyond nucleotide metabolism, PRPSAP1 functions in early histone maturation and chromatin assembly independently of its role in PRPP synthesis, coordinating nucleotide supply with chromatin formation (PMID:41344329).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 1994 High

    Identification of PAP39 as a physically associated, non-catalytic inhibitory component of PRPP synthetase resolved how the native enzyme complex is negatively regulated beyond allosteric nucleotide feedback.

    Evidence cDNA cloning, covalent cross-linking, co-immunoprecipitation, and enzymatic activity assays after PAP39 depletion from rat liver complex

    PMID:8132556

    Open questions at the time
    • Stoichiometry of PAP39 within the native complex not determined
    • Whether PAP39 alters substrate affinity vs. Vmax not resolved
    • No structural information on how PAP39 contacts catalytic subunits
  2. 1997 High

    Reconstitution of PRPS–PAP39 complexes in E. coli established that PAP39 binds PRS I and PRS II equally and exerts dose-dependent inhibition, answering whether its regulatory effect is stoichiometric rather than allosteric.

    Evidence Recombinant GST-PAP39 pulldown and co-expression reconstitution in E. coli with quantitative activity measurements

    PMID:9366267

    Open questions at the time
    • Whether PAP39 competes with PAP41 for the same binding site on catalytic subunits
    • No mammalian cell reconstitution performed
    • Structural basis of inhibition unknown
  3. 1998 Medium

    Kinetic analysis of the native complex revealed that the presence of associated proteins including PAP39 modulates nucleotide inhibition sensitivity of PRPP synthetase, extending PAP39's role from simple activity suppression to shaping the enzyme's allosteric regulation.

    Evidence Kinetic enzymatic assays with controlled free Mg²⁺ and nucleotide inhibitor concentrations on native rat liver complex

    PMID:9748490

    Open questions at the time
    • PAP39-specific contribution was inferred from complex composition rather than isolated manipulation
    • Whether PAP39 vs. PAP41 differentially influences nucleotide inhibition not dissected
    • No mutagenesis of PAP39 residues involved in allosteric modulation
  4. 2024 High

    Systematic genetic dissection using combinatorial knockout fibroblast clones demonstrated that PRPSAP1 is required for proper oligomeric assembly of the PRPS complex, with its loss leading to aberrant homo-oligomers, reduced metabolic flux, and impaired proliferation.

    Evidence Isogenic fibroblast KO clones with native complex analysis, metabolic flux assays, and proliferation assays (preprint)

    PMID:39411161

    Open questions at the time
    • Preprint; not yet peer-reviewed
    • Relative contributions of PRPSAP1 vs. PRPSAP2 to assembly not fully delineated
    • Structural basis for how PRPSAP1 prevents aberrant oligomerization unknown
  5. 2025 High

    Acute degradation of PRPSAP1 revealed a nucleotide-biosynthesis-independent function in histone maturation and chromatin assembly, fundamentally expanding its role beyond metabolic regulation.

    Evidence Rapid degron-mediated depletion in multiple human cell lines with histone availability and chromatin assembly readouts

    PMID:41344329

    Open questions at the time
    • Molecular mechanism linking PRPSAP1 to histone maturation not defined
    • Whether this function requires interaction with PRPS catalytic subunits or occurs independently is unclear
    • No structural or interactome data for the chromatin-related role

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular mechanism by which PRPSAP1 promotes histone maturation independently of nucleotide biosynthesis, and the structural basis for its inhibitory and assembly roles within the PRPS complex, remain unresolved.
  • No atomic-resolution structure of PRPSAP1 or PRPSAP1-containing complex
  • Specific protein partners mediating the chromatin assembly function not identified
  • In vivo physiological consequences of PRPSAP1 loss in animal models not reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4
Localization
GO:0005829 cytosol 3
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-4839726 Chromatin organization 1
Partners
PRPS1PRPS2PRPSAP2
Complex memberships
PRPP synthetase complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 PRPSAP1 (PAP39), a 39-kDa protein, was cloned from rat liver and found to physically interact with PRPP synthetase catalytic subunits (PRS I and PRS II) via covalent cross-linking and immunoprecipitation experiments. Removal of PAP39 from the native complex (by gel filtration with MgCl2 or mild trypsin treatment) increased catalytic activity, demonstrating a negative regulatory role for PAP39 on PRPP synthetase activity. cDNA cloning, covalent cross-linking, immunoprecipitation, enzymatic activity assays after PAP39 depletion The Journal of biological chemistry High 8132556
1995 PAP39 (PRPSAP1) is a component of the high-molecular-weight rat liver PRPP synthetase complex composed of PRS I, PRS II, PAP39, and a 41-kDa protein. PAP39 shows ~48% amino acid identity with the catalytic subunits, lacks catalytic activity, and inhibits PRPP synthesis. Its mRNA is expressed in a tissue-differential manner, indicating that complex composition and hence enzyme properties vary by tissue. cDNA cloning, Northern blot, biochemical fractionation, activity assays Advances in enzyme regulation High 7572345
1997 Recombinant PAP39 (PRPSAP1) expressed as a GST fusion protein in E. coli bound equally to dissociated PRS I and PRS II catalytic subunits. Co-expression of PAP39 with PRS I or PRS II in E. coli reconstituted soluble complexes of variable composition; higher relative PAP39 content lowered specific catalytic activity in an amount-dependent manner, providing strong evidence that PAP39 has no catalytic activity but exerts inhibitory effects proportional to its abundance in the complex. Recombinant protein expression, GST pulldown, in situ reconstitution in E. coli, enzymatic activity assays Biochimica et biophysica acta High 9366267
1998 Kinetic analysis of the native rat liver PRPP synthetase complex (containing PRS I, PRS II, PAP39, and PAP41) showed weaker nucleotide inhibition sensitivity than expected from the composition of its catalytic subunits alone. High free Mg2+ concentrations nullified inhibition by MgGDP almost completely and partly that by MgADP on PRS I, with the native liver enzyme (including PAP39-containing complex) showing an intermediate response, indicating that PAPs modulate the regulatory properties of the enzyme complex. Kinetic enzymatic assays under controlled free Mg2+ and nucleotide concentrations Biochimica et biophysica acta Medium 9748490
1996 The promoter region of the rat PAP39 (PRPSAP1) gene is GC-rich and contains putative binding sites for regulatory transcription factors. Transfection of a promoter-CAT reporter construct into rat PC12 cells demonstrated promoter activity, establishing the regulatory region of the PRPSAP1 gene. Gene isolation, sequencing, CAT reporter transfection assay Biochimica et biophysica acta Medium 8611622
2014 In U87 glioma cells, hypoxia suppressed PRPSAP1 and PRPSAP2 gene expression only when ERN1 (endoplasmic reticulum stress kinase/endoribonuclease) was knocked down, whereas PRPS1 and PRPS2 were suppressed by hypoxia regardless of ERN1 status. This indicates that ERN1-mediated ER stress signaling modulates PRPSAP1 expression under hypoxic conditions, placing PRPSAP1 downstream of the ERN1 pathway. ERN1 knockdown in glioma cells, real-time RT-PCR under hypoxia and ER stress conditions Ukrainian biochemical journal Low 25816608
2024 Using isogenic fibroblast clones in combinatorial PRPS complex assembly states, PRPSAP1 was shown to be required for proper oligomeric assembly of the PRPP synthetase complex: cells lacking PRPS2, PRPSAP1, and PRPSAP2 drove PRPS1 into aberrant homo-oligomeric assemblies with diminished metabolic flux and impaired proliferative capacity. PRPSAP1 was defined as preferentially interacting with specific subunits, and translational control mechanisms were identified as enabling fine-tuned regulation of PRPS complex assembly and activity. Isogenic fibroblast KO clones, native complex analysis, metabolic flux assays, proliferation assays bioRxivpreprint High 39411161
2025 Using a rapid degron system in multiple human cell lines, depletion of PRPSAP1 was shown to limit histone availability and disrupt chromatin assembly independently of its role in nucleotide biosynthesis, revealing a previously unrecognized function of PRPSAP1 in early histone maturation and coordinating nucleotide metabolism with chromatin formation. Rapid protein degradation (degron) system, histone availability assays, chromatin assembly assays in multiple cell lines Molecular cell High 41344329
2022 Fructose treatment increased the gene expression, protein expression, and fluorescence intensity of PRPSAP1 in mouse livers via increased mTOR expression, placing PRPSAP1 regulation downstream of the mTOR pathway in the context of fructose-induced purine de novo synthesis and hyperuricemia. RNA-seq, immunofluorescence, Western blotting in hepatic cells and mouse livers with fructose treatment Frontiers in nutrition Low 36601078

Source papers

Stage 0 corpus · 51 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2012 Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nature genetics 657 23263486
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2016 Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics. Cell reports 306 27342126
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2012 MMS19 assembles iron-sulfur proteins required for DNA metabolism and genomic integrity. Science (New York, N.Y.) 230 22678362
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2015 A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning. eLife 198 26673895
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2019 A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nature immunology 159 30833792
2022 A comprehensive SARS-CoV-2-human protein-protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets. Nature biotechnology 140 36217030
2021 Protein interaction landscapes revealed by advanced in vivo cross-linking-mass spectrometry. Proceedings of the National Academy of Sciences of the United States of America 113 34349018
1995 Mammalian phosphoribosyl-pyrophosphate synthetase. Advances in enzyme regulation 41 7572345
2022 Dietary intake of fructose increases purine de novo synthesis: A crucial mechanism for hyperuricemia. Frontiers in nutrition 38 36601078
2003 Identification of differentially expressed genes in skeletal muscle of non-diabetic insulin-resistant and insulin-sensitive Pima Indians by differential display PCR. Diabetologia 38 14576983
1994 A novel 39-kDa phosphoribosylpyrophosphate synthetase-associated protein of rat liver. Cloning, high sequence similarity to the catalytic subunits, and a negative regulatory role. The Journal of biological chemistry 33 8132556
2019 Identification of novel epithelial ovarian cancer loci in women of African ancestry. International journal of cancer 23 31469419
1998 Molecular cloning of a human cDNA for the 41-kDa phosphoribosylpyrophosphate synthetase-associated protein. Biochimica et biophysica acta 18 9545573
1997 Cloning and sequencing of rat cDNA for the 41-kDa phosphoribosylpyrophosphate synthetase-associated protein has a high homology to the catalytic subunits and the 39-kDa associated protein. Biochimica et biophysica acta 14 9003449
1998 Rat liver phosphoribosylpyrophosphate synthetase is activated by free Mg2+ in a manner that overcomes its inhibition by nucleotides. Biochimica et biophysica acta 8 9748490
2011 Hyperuricemia cosegregating with osteogenesis imperfecta is associated with a mutation in GPATCH8. Human genetics 6 21594610
2014 Expression of phosphoribosyl pyrophosphate synthetase genes in U87 glioma cells with ERN1 knockdown: effect of hypoxia and endoplasmic reticulum stress. Ukrainian biochemical journal 5 25816608
2019 Prostatic adenocarcinoma with novel NTRK3 gene fusion: a case report. American journal of clinical and experimental urology 4 31763365
1997 Partial reconstitution of mammalian phosphoribosylpyrophosphate synthetase in Escherichia coli cells. Coexpression of catalytic subunits with the 39-kDa associated protein leads to formation of soluble multimeric complexes of various compositions. Biochimica et biophysica acta 4 9366267
2024 Exosomal mRNA in plasma serves as a predictive marker for microvascular invasion in hepatocellular carcinoma. Journal of gastroenterology and hepatology 3 38972728
2024 Evolutionary origins and innovations sculpting the mammalian PRPS enzyme complex. bioRxiv : the preprint server for biology 3 39411161
1996 [PRPP synthetase superactivity]. Nihon rinsho. Japanese journal of clinical medicine 3 8976111
2008 [Increased activity of PRPP synthetase]. Nihon rinsho. Japanese journal of clinical medicine 2 18409517
2025 Rate-limiting enzymes in nucleotide metabolism synchronize nucleotide biosynthesis and chromatin formation. Molecular cell 1 41344329
2024 NTRK3-Rearranged Prostatic Acinar Adenocarcinoma: Report of a Patient and Review of the Literature. International journal of surgical pathology 1 38772598
1996 Promoter region of the rat phosphoribosylpyrophosphate synthetase-associated protein 39. Biochimica et biophysica acta 1 8611622
2026 Comprehensive insights into sepsis-induced cardiac dysfunction through proteomics and metabolomics. BMC research notes 0 41566375
1986 [Cloning of DNA fragments of the genetic transfer factor pAP39]. Molekuliarnaia genetika, mikrobiologiia i virusologiia 0 3025681