The phosphoribosyl pyrophosphate synthetase (PRPS) enzyme plays a central role in core biochemical pathways across all life, reflecting its deep evolutionary significance. Here, we present a pan-domain analysis of more than 35,000 non-redundant protein sequences that defines the fundamental features of PRPS at the roots of both domains of life and at critical branchpoints in the tree of life, including during early eukaryogenesis. Combining protein language modeling with maximum likelihood phylogenetic analysis, we identify entirely new PRPS enzyme classes and reveal how neofunctionalization of the canonical class I (bacteria-derived) or class III (archaea-derived) enzymes proceeds via genetic drift or gene duplication. We further demonstrate that multiple PRPS classes from distinct bacterial ancestries were transferred to the eukaryotic genome prior to supergroup radiation, and we provide biochemical and structural characterization of representative examples to clarify their roles in eukaryotic metabolism. Finally, we identify over 30 independent instances of PRPS pseudoenzyme formation across nearly all major eukaryotic lineages and PRPS orthologs, revealing a widespread but underappreciated mechanism of PRPS regulation. Together, this systems-level investigation resolves some of the earliest genetic events shaping life on Earth and offers detailed insight into the evolutionary mechanisms that sculpt enzyme structure and function.
Karki, B. R., Meller, J., Cunningham, J. T.
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