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The Journal of biological chemistry v.292 no.7, 2017년, pp.3049 - 3059   SCI SCIE
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GMP Synthase Is Required for Virulence Factor Production and Infection by Cryptococcus neoformans

Chitty, Jessica L. (From the Australian Infectious Diseases Research Centre, School of Chemistry & Molecular Biosciences, ) ; Tatzenko, Tayla L. (From the Australian Infectious Diseases Research Centre, School of Chemistry & Molecular Biosciences, ) ; Williams, Simon J. (From the Australian Infectious Diseases Research Centre, School of Chemistry & Molecular Biosciences, ) ; Koh, Y. Q. Andre E. (From the Australian Infectious Diseases Research Centre, School of Chemistry & Molecular Biosciences, ) ; Corfield, Elizabeth C. (From the Australian Infectious Diseases Research Centre, School of Chemistry & Molecular Biosciences, ) ; Butler, Mark S. (the Institute for Molecular Bioscience, and ) ; Robertson, Avril A. B. (the Institute for Molecular Bioscience, and ) ; Cooper, Matthew A. (From the Australian Infectious Diseases Research Centre, School of Chemistry & Molecular Biosciences, ) ; Kappler, Ulrike (From the Australian Infectious Diseases Research Centre, School of Chemistry & Molecular Biosciences, ) ; Kobe, Bostjan (From the Australian Infectious Diseases Research Centre, School of Chemistry & Molecular Biosciences, ) ; Fraser, James A. (From the Australian Infectious Diseases Research Centre, School of Chemistry ) ;
  • 초록  

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


  • 주제어

    enzyme kinetics .   fungi .   nucleoside/nucleotide biosynthesis .   purine .   virulence factor .   GMP synthase.  

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