Affinage

PRPSAP2

Phosphoribosyl pyrophosphate synthase-associated protein 2 · UniProt O60256

Round 2 corrected
Length
369 aa
Mass
40.9 kDa
Annotated
2026-04-28
41 papers in source corpus 4 papers cited in narrative 4 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PRPSAP2 (PAP41) is a non-catalytic 41 kDa subunit of the mammalian phosphoribosyl pyrophosphate synthetase (PRPS) complex that assembles with PRPS1, PRPS2, and PRPSAP1 into large heterogeneous multimeric complexes required for de novo nucleotide biosynthesis (PMID:9003449, PMID:9545573). Although PRPSAP2 shares ~49% sequence identity with the catalytic PRPS subunits, it lacks the PRPP binding site and instead functions as a regulatory component: the presence of associated proteins including PRPSAP2 attenuates the sensitivity of the complex to allosteric nucleotide (ADP/GDP) feedback inhibition compared with isolated catalytic subunits (PMID:9748490). Loss of PRPSAP2 together with PRPS2 and PRPSAP1 forces PRPS1 into aberrant homo-oligomers with reduced nucleotide biosynthetic flux and impaired cell proliferation, establishing PRPSAP2 as essential for proper PRPS complex assembly and metabolic function (PMID:39411161).

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 1997 Medium

    Identification of PRPSAP2 as a distinct non-catalytic subunit of the PRPS complex resolved the question of whether the associated proteins represent separate gene products or modified forms of the catalytic subunits, establishing PRPSAP2 as a dedicated regulatory component.

    Evidence cDNA cloning and sequencing of rat PAP41 from liver PRPS complex

    PMID:9003449

    Open questions at the time
    • Single-lab cloning without independent confirmation at the time
    • No direct functional assay of PRPSAP2 in isolation from the complex
    • Mechanism by which PRPSAP2 contributes to complex function was unknown
  2. 1998 Medium

    Cloning of human PRPSAP2 and demonstration that the native PRPS complex modulates allosteric inhibition established the regulatory principle: associated proteins including PRPSAP2 dampen nucleotide feedback inhibition of the catalytic subunits, linking PRPSAP2 to metabolic control of purine/pyrimidine biosynthesis.

    Evidence Human cDNA cloning with expression analysis across cell lines; kinetic enzyme assays comparing purified native liver PRPS complex versus isolated catalytic subunits under controlled Mg²⁺ conditions

    PMID:9545573 PMID:9748490

    Open questions at the time
    • The individual contribution of PRPSAP2 versus PRPSAP1 to allosteric modulation was not resolved
    • No loss-of-function or reconstitution experiment to test PRPSAP2 necessity
    • In vivo relevance of altered allosteric sensitivity was not demonstrated
  3. 2024 High

    Combinatorial genetic ablation demonstrated that PRPSAP2 is required for proper PRPS complex assembly, answering whether the associated proteins are dispensable scaffolds or essential architectural subunits; their loss drives PRPS1 into dysfunctional homo-oligomers with reduced nucleotide flux and impaired proliferation.

    Evidence (preprint) Isogenic fibroblast knockout clones in all viable individual and combinatorial assembly states; quantitative proteomics, biochemical fractionation, metabolic flux analysis, cell proliferation assays

    PMID:39411161

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Individual PRPSAP2-only knockout phenotype versus combinatorial loss not fully delineated in the timeline
    • Structural basis of PRPSAP2-mediated complex assembly remains undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The precise structural contacts through which PRPSAP2 integrates into the PRPS multimer and the tissue-specific consequences of PRPSAP2 loss in vivo remain undefined.
  • No high-resolution structure of the intact PRPS complex including PRPSAP2
  • No animal model targeting PRPSAP2 specifically
  • Whether PRPSAP2 and PRPSAP1 are functionally redundant or have distinct regulatory roles is unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 2
Partners
PRPS1PRPS2PRPSAP1
Complex memberships
PRPS complex

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Rat PAP41 (ortholog of human PRPSAP2) was cloned and sequenced; the deduced protein of 369 amino acids shares ~49% identity with the catalytic PRS I and PRS II subunits and ~79% identity with the other associated protein PAP39, establishing PRPSAP2 as a member of the PRPS-associated protein subfamily that lacks catalytic PRPP-synthesizing activity but is a core component of the rat liver PRPS complex. cDNA cloning, sequence analysis, Northern blot Biochimica et biophysica acta Medium 9003449
1998 Human cDNA encoding PAP41 (PRPSAP2) was cloned; the predicted 369-amino-acid protein (MW ~40,925) shares 98.9% identity with rat PAP41 and 72.2% identity with human PAP39, is expressed as a single ~2.1 kb mRNA across five human cell lines, and its gene exists as a single copy in the human genome. The protein lacks the PRPP binding site, consistent with a non-catalytic regulatory role. cDNA cloning from EST clones, Southern blot, Northern blot, sequence analysis Biochimica et biophysica acta Medium 9545573
1998 The native rat liver PRPS complex (comprising PRS I, PRS II, PAP39, and PAP41/PRPSAP2) shows weaker sensitivity to allosteric nucleotide (ADP/GDP) inhibition than its isolated catalytic subunits alone, indicating that the associated proteins PAP39 and PAP41 modulate the regulatory response of the complex to inhibitory nucleotides. Free Mg²⁺ can largely overcome nucleotide inhibition at the regulatory site of PRS I, and the native liver enzyme (including PAP41) responds similarly but with a smaller inhibitory effect than isolated PRS I. Kinetic enzyme assays with purified native liver PRPS complex under controlled free Mg²⁺ concentrations; comparison of isolated subunits vs. native complex Biochimica et biophysica acta Medium 9748490
2024 PRPSAP2, together with PRPS2 and PRPSAP1, is required for proper assembly of the mammalian PRPS complex into high-molecular-weight multimeric configurations. Cells lacking PRPS2, PRPSAP1, and PRPSAP2 render PRPS1 into aberrant homo-oligomeric assemblies with diminished metabolic flux through the nucleotide synthesis pathway and impaired proliferative capacity. The study defines preferential subunit interactions within the complex and demonstrates translational control mechanisms that regulate PRPS assembly and activity. Isogenic fibroblast knockout clones in all viable individual and combinatorial assembly states; quantitative proteomics, biochemical fractionation, metabolic flux analysis, cell proliferation assays bioRxivpreprint High 39411161

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
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
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
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
2014 A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. Cell 325 25036637
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
2022 A comprehensive SARS-CoV-2-human protein-protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets. Nature biotechnology 140 36217030
2011 Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein. The Journal of biological chemistry 131 21832049
2010 Genome-wide association study of pancreatic cancer in Japanese population. PloS one 119 20686608
2021 Systematically defining selective autophagy receptor-specific cargo using autophagosome content profiling. Molecular cell 105 33545068
2018 Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. Molecular & cellular proteomics : MCP 101 30021884
2017 Cell cycle-dependent phosphorylation regulates RECQL4 pathway choice and ubiquitination in DNA double-strand break repair. Nature communications 89 29229926
2015 Systematic proteomics of the VCP-UBXD adaptor network identifies a role for UBXN10 in regulating ciliogenesis. Nature cell biology 81 26389662
2017 Assembly of the U5 snRNP component PRPF8 is controlled by the HSP90/R2TP chaperones. The Journal of cell biology 78 28515276
2018 Deubiquitinating enzyme PSMD14 promotes tumor metastasis through stabilizing SNAIL in human esophageal squamous cell carcinoma. Cancer letters 72 29331416
2021 Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy. Acta pharmaceutica Sinica. B 66 35256949
2015 Temporal proteomics of NGF-TrkA signaling identifies an inhibitory role for the E3 ligase Cbl-b in neuroblastoma cell differentiation. Science signaling 61 25921289
2020 Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D. Nature communications 60 31980649
2011 Cytoplasmic Metadherin (MTDH) provides survival advantage under conditions of stress by acting as RNA-binding protein. The Journal of biological chemistry 53 22199357
2012 Identification of novel candidate oncogenes in chromosome region 17p11.2-p12 in human osteosarcoma. PloS one 37 22292074
2016 Oncogenic Properties of Candidate Oncogenes in Chromosome Region 17p11.2p12 in Human Osteosarcoma. Cytogenetic and genome research 22 27846620
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
2024 Evolutionary origins and innovations sculpting the mammalian PRPS enzyme complex. bioRxiv : the preprint server for biology 3 39411161
2021 Evaluating the Neuroimaging-Genetic Prediction of Symptom Changes in Individuals with ADHD. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference 2 34891669
2008 [Increased activity of PRPP synthetase]. Nihon rinsho. Japanese journal of clinical medicine 2 18409517
2025 Proteome-Wide and Immune Cell Phenotype Mendelian Randomization Highlights Immune Involvement in Genetic Generalized Epilepsy. Brain and behavior 1 40495522