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.
Highlights
Federico Cesi, founder of the Accademia dei Lincei and a keen observer of his local environment, first attempted the scientific classification of organisms
While only a few of the genes required for de novo purine biosynthesis have been characterized in C. albicans, BLASTp analysis using C. neoformans orthologs reveals genes thought to encode the ten enzymatic activities required for the conversion of phosphoribosyl pyrophosphate to Inosine monophosphate (IMP): PRP transferase (C1_07710C), GAR synthetase/AIR synthetase (C1_07890C), GAR transformlyase (C2_03090C), FGAM synthetase (CR_04740C), AIR carboxylase (C3_04520C), SAICAR synthetase (CR_06150C), ADS lyase (CR_06150C) and AICAR transformylase/inosine cyclohydrolase (ATIC)
While purine metabolism has not been well characterized in A. fumigatus, more extensive characterization of the pathway in Aspergillus species has been carried out in Aspergillus nidulans, with all enzyme-encoding genes believed to be associated with degradation, salvage, and de novo biosynthesis of purines identified in this species [87,88,89,90]
Summary
Federico Cesi, founder of the Accademia dei Lincei and a keen observer of his local environment, first attempted the scientific classification of organisms. Almost 100 years later, mycologists Christian Hendrik Persoon and Elias Magnus Fries addressed these shortcomings by classifying fungi sent by leading scientists from around the world [4,5,6] Combined, these extensive works that took place over four centuries identified thousands of fungi that expanded well beyond Cesi’s Italian mushrooms to include more diverse species inhabiting a wide range of environments. Bird excreta contains high concentrations of the insoluble hetrocyclic compound uric acid, a strategy that reduces water loss compared to the mammalian excretion of nitrogen as its soluble derivative urea [26] Fresh plant matter such as cauliflower has a purine content of approximately 0.4 mg/g [27]; when living organisms, such as plants, decompose, purines become enriched in soil and so are available to fungi such as C. neoformans and A. fumigatus [28]. The concentrations of purines in the gastrointestinal tract inhabited by C. albicans are dependent on the host’s diet, whereas the cerebral spinal fluid to which C. neoformans disseminates is a purine-poor environment [29,30,31]
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