Amongst 1.5 million fatal mycoses of humans occurring annually [1], the vast majority involve the human lung as the primary site of pathogenesis, and are derived from organisms which occupy environmental niches. On entry into the respiratory system pathogenic fungi must draw upon metabolic versatility for survival and proliferation as the mammalian lung is a nutritionally limiting environment. The nutritional stresses encountered have exposed vulnerabilities which have long been viewed as potential antifungal targets, since humans lack several of the metabolic pathways which fungi rely upon for pathogenic growth. However the ability of saprophytic fungi to proteolytically liberate amino acids from exogenous protein sources, and the differential availabilities of amino acids in diverse host niches have undermined confidence in amino acid metabolism as a target for selectively toxic antifungal therapies. Recent studies have reopened this debate by revealing a number of anabolic amino acid pathways in pathogenic fungi as being essential for viability per se. This review examines new knowledge on fungal amino acid metabolism in fungal pathogens of the human lung with a view to highlighting important new advances and gaps in understanding.
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Role of amino acid metabolism in fungal pathogenicityThroughout the kingdoms of life, amino acids are important building blocks of proteins and critical sources of macroelements such as nitrogen and sulphur which, if not acquired via intrinsic anabolic metabolism, must be sourced from extrinsic sources. Although fungi can biosynthesise all 20 of the proteinogenic amino acids the uptake of exogenous amino acids is significantly energetically preferable [2]. Accordingly, saprophytic fungal genomes harbour a multitude of protease and peptidase, and amino acid transporter encoding genes to ensure the liberation and uptake of amino acids from exogenous proteinaceous substrates.Amongst the hierarchy of preferred nitrogen sources the nitrogen-rich amino acids glutamine and arginine are dominant, but other amino acids can also be utilised when starvation threatens. Several wide domain regulatory mechanisms operate to ensure that starvation for nitrogen, carbon or amino acids is met with an appropriate metabolic response. In response to intracellular glutamine levels AreA-type GATA factors interact with other transcription factors specific for the biosynthesis of alternative nitrogen sources eg proline [3,4], while amino acid starvation increases translation of the transcriptional activator CpcA to generate a broad-acting cellular response governing amino acid biosynthesis and uptake [5]. Cellular levels of cysteine and methionine reflect intracellular sulphur content and modulate sulphur uptake via sulphur metabolite repression involving the positive-acting