GMP Synthase Is Required for Virulence Factor Production and Infection by Cryptococcus neoformans.

摘要: Over the last four decades HIV pandemic and advances in medical treatments that also cause immunosuppression have produced an ever-growing cohort of individuals susceptible to opportunistic pathogens. Of these, AIDS patients are particularly vulnerable infection by encapsulated yeast Cryptococcus neoformans. Most commonly found environment purine-rich bird guano, C. neoformans experiences a drastic change nutrient availability during host infection, ultimately disseminating colonize purine-poor central nervous system. Investigating consequences this challenge, we characterized GMP synthase, second enzyme guanylate branch de novo purine biosynthesis. We show absence becomes guanine auxotroph, production key virulence factors is compromised, ability infect nematodes mice abolished. Activity assays performed using recombinant protein unveiled differences substrate binding between human enzymes, with structural insights into these kinetic acquired via homology modeling. Collectively, data highlight potential synthase be exploited development new therapeutic agents for treatment disseminated, life-threatening fungal infections.