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PreprintCited by 11Biochemical and Molecular ResearchRNA and protein synthesis mechanismsGenomics and Phylogenetic Studies

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Evolutionary origins and innovations sculpting the mammalian PRPS enzyme complex

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Karki, Bibek R., Macmillan, Austin C., Vicente-Muñoz, Sara, Greis, Kenneth D., Romick, Lindsey E., Cunningham, J. Tom·2024·Nature Communications
DOI 10.1101/2024.10.01.616059PMC PMC12238573

Preprint — published as 10.1038/s41467-025-61216-z · Paper page

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Abstract

The phosphoribosyl pyrophosphate synthetase (PRPS) enzyme conducts a chokepoint reaction connecting central carbon metabolism and nucleotide production pathways, making it essential for life 1,2 . Here, we show that the presence of multiple PRPS-encoding genes is a hallmark trait of eukaryotes, and we trace the evolutionary origins and define the individual functions of each of the five mammalian PRPS homologs – three isozymes (one testis-restricted) 3,4 and two non-enzymatic associated proteins (APs) 5,6 – which we demonstrate operate together as a large molecular weight complex capable of attaining a heterogeneous array of functional multimeric configurations. Employing a repertoire of isogenic fibroblast clones in all viable individual or combinatorial assembly states, we define preferential interactions between subunits, and we show that cells lacking PRPS2, PRPSAP1, and PRPSAP2 render PRPS1 into aberrant homo-oligomeric assemblies with diminished metabolic flux and impaired proliferative capacity. We demonstrate how numerous evolutionary innovations in the duplicated genes have created specialized roles for individual complex members and identify translational control mechanisms that enable fine-tuned regulation of PRPS assembly and activity, which provide clues into the positive and negative selective pressures that facilitate metabolic flexibility and tissue specialization in advanced lifeforms. Collectively, our study demonstrates how evolution has transformed a single PRPS gene into a multimeric complex endowed with functional and regulatory features that govern cellular biochemistry.

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Metadata

Authors
Karki, B. R., Macmillan, A. C., Vicente-Muñoz, S., Greis, K. D., Romick, L. E., & Cunningham, J. T.
Affiliations
  • University of Cincinnati (US)
  • Cincinnati Children's Hospital Medical Center (US)
Corresponding author
Cunningham, J. Tom
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2024-10-01
Volume
16
Issue
1
Pages
6076-6076
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2024.10.01.616059
PMC
PMC12238573
OpenAlex
W4412102667
Cited by
11
References
2
Citations by year
2026: 7 · 2025: 4
FWCI
3.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health and Human Services (S10OD026717, R35GM133561, R01CA230904)
  • Cincinnati Children's Hospital Medical Center
  • University of Cincinnati
  • National Institutes of Health (1s10od026717-01)
  • National Cancer Institute (R01CA230904)
  • National Institute of General Medical Sciences (R35GM133561)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
Keywords
phosphoribosylpyrophosphate synthetase, gene duplication, complex assembly, nucleotide synthesis, eukaryotic evolution, isogenic cell lines, enzyme regulation, mammalian metabolism

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