Purine Acquisition and Synthesis by Human Fungal Pathogens

Abstract

While members of the Kingdom Fungi are found across many of the world’s most hostile environments, only a limited number of species can thrive within the human host. The causative agents of the most common invasive fungal infections are Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans. During the infection process, these fungi must not only combat the host immune system while adapting to dramatic changes in temperature and pH, but also acquire sufficient nutrients to enable growth and dissemination in the host. One class of nutrients required by fungi, which is found in varying concentrations in their environmental niches and the human host, is the purines. These nitrogen-containing heterocycles are one of the most abundant organic molecules in nature and are required for roles as diverse as signal transduction, energy metabolism and DNA synthesis. The most common life-threatening fungal pathogens can degrade, salvage and synthesize de novo purines through a number of enzymatic steps that are conserved. While these enable them to adapt to the changing purine availability in the environment, only de novo purine biosynthesis is essential during infection and therefore an attractive antimycotic target.

Genome-Wide Detection of Genes Under Positive Selection in Worldwide Populations of the Barley Scald Pathogen

“…Uptake of nucleoside and nitrogenous compounds are important for pathogenicity in Candida albicans, Xenorhabdus nemaptophila and obligate parasitic protozoan ( de Koning et al. 2005 ; Orchard and Goodrich-Blair 2005 ; Chitty and Fraser 2017 ). We also identified a GNAT acyltransferase that plays a role in multiple biological processes including the regulation of growth, morphogenesis, cellulase expression, and stress–response pathways related to the host and abiotic environment ( O’Meara et al.…”

Grf10 and Bas1 Regulate Transcription of Adenylate and One-Carbon Biosynthesis Genes and Affect Virulence in the Human Fungal Pathogen Candida albicans

“…C. albicans is adapted to the human host, colonizing different sites such as skin, mucosal tissue, and the bloodstream. Purine bases and nucleosides in plasma and extracellular fluids are found in low, virtually constant levels of ~4 μM ( 48 , 49 ); high basal gene expression and feedback inhibition of the biosynthetic pathway could be sufficient to maintain intracellular nucleotide pools. In the intestine, there is intense competition among the microbial communities for nutrients released upon digestion.…”

A Molecular Window into the Biology and Epidemiology of Pneumocystis spp

“…This is unusual for a highly compact genome, since the de novo biosynthetic pathways involve substantially more chemical reactions and thus require more energy than those for salvage pathways. In fact, although de novo nucleotide synthesis is a fundamental biological process that is highly conserved in fungi and other organisms, most organisms, including all known human fungal pathogens, also maintain functional salvage and degradation pathways (154). The exception to this are the intracellular fungal pathogen Microsporidia (155,156) and parasitic protozoa (157,158), which lack de novo nucleotide synthesis pathways but preserve the nucleotide salvage and degradation pathways.…”