Surveying purine biosynthesis across the domains of life unveils promising drug targets in pathogens

Abstract

Purines play an integral role in cellular processes such as energy metabolism, cell signaling and encoding the genetic makeup of all living organisms—ensuring that the purine metabolic pathway is maintained across all domains of life. To gain a deeper understanding of purine biosynthesis via the de novo biosynthetic pathway, the genes encoding purine metabolic enzymes from 35 archaean, 69 bacterial and 99 eukaryotic species were investigated. While the classic elements of the canonical purine metabolic pathway were utilized in all domains, a subset of familiar biochemical roles was found to be performed by unrelated proteins in some members of the Archaea and Bacteria. In the Bacteria, a major differentiating feature of de novo purine biosynthesis is the increasing prevalence of gene fusions, where two or more purine biosynthesis enzymes that perform consecutive biochemical functions in the pathway are encoded by a single gene. All species in the Eukaryota exhibited the most common fusions seen in the Bacteria, in addition to new gene fusions to potentially increase metabolic flux. This complexity is taken further in humans, where a reversible biomolecular assembly of enzymes known as the purinosome has been identified, allowing short‐term regulation in response to metabolic cues while expanding on the benefits that can come from gene fusion. By surveying purine metabolism across all domains of life, we have identified important features of the purine biosynthetic pathway that can potentially be exploited as prospective drug targets.

The purine nucleoside phosphorylase pnp-1 regulates epithelial cell resistance to infection in C. elegans

“…Here, we describe a role for purine metabolism in regulating intestinal epithelial cell defense against pathogen infection in the nematode C. elegans (Fig 6). Purine metabolism pathways are conserved from prokaryotes to humans and include the energy-expensive de novo synthesis pathway and the less energy-costly salvage pathway that recycles nucleotides (S3A Fig) [34]. While recent reports have implicated purine metabolism in C. elegans longevity and development, specific characterization of the salvage pathway has not previously been reported [35,36].…”

The purine nucleoside phosphorylase pnp-1 regulates epithelial cell resistance to infection in C. elegans

“…Here, we describe a role for purine metabolism in regulating intestinal epithelial cell defense against pathogen infection in the nematode C. elegans (Fig 6). Purine metabolism pathways are conserved from prokaryotes to humans and include the energy-expensive de novo synthesis pathway and the less energy-costly salvage pathway that recycles nucleotides (S2A Fig) [34]. While recent reports have implicated purine metabolism in C. elegans longevity and development, specific characterization of the salvage pathway has not previously been reported [35, 36].…”

Structural features of Cryptococcus neoformans bifunctional GAR/AIR synthetase may present novel antifungal drug targets

“…Unlike a number of de novo purine biosynthesis enzymes that have alternative enzymes that can perform equivalent biochemical roles, there are no alternative enzymes that perform the role of GARS or AIRS (21). In the Archaea and the Bacteria, these conserved GARS or AIRS proteins are almost exclusively encoded by individual genes.…”

“…While these first five enzymes in de novo purine biosynthesis mostly exist as monofunctional proteins in the Archaea and Bacteria, in many Eukaryotes the genes encoding these enzymes have fused to encode multifunctional proteins consisting of up to three components of the pathway in a single open reading frame (21). One of these multifunctional proteins consists of GARS, responsible for the second step of the pathway, fused at its C terminus to AIRS, which performs the fifth step.…”