Abstract
Fungal microorganisms, including the human pathogenic yeast and filamentous fungi, are able to synthesize all proteinogenic amino acids, including nine that are essential for humans. A number of enzymes catalyzing particular steps of human-essential amino acid biosynthesis are fungi specific. Numerous studies have shown that auxotrophic mutants of human pathogenic fungi impaired in biosynthesis of particular amino acids exhibit growth defect or at least reduced virulence under in vivo conditions. Several chemical compounds inhibiting activity of one of these enzymes exhibit good antifungal in vitro activity in minimal growth media, which is not always confirmed under in vivo conditions. This article provides a comprehensive overview of the present knowledge on pathways of amino acids biosynthesis in fungi, with a special emphasis put on enzymes catalyzing particular steps of these pathways as potential targets for antifungal chemotherapy.
Highlights
Among 20 proteinogenic amino acids, nine are regarded as essential for humans: phenylalanine, valine, threonine, tryptophan, isoleucine, methionine, leucine, lysine, and histidine
Enzymes involved in inter alia L-glutamine, L-glutamic acid, l-cysteine, or l-proline biosynthesis have been proposed as targets for several compounds with antifungal activity
We have summarized the present state of knowledge on pathways of amino acids biosynthesis in human pathogenic fungi as a source of targets for antifungal chemotherapy and on compounds inhibiting particular enzymes of these pathways as potential antifungals
Summary
Among 20 proteinogenic amino acids, nine are regarded as essential for humans: phenylalanine, valine, threonine, tryptophan, isoleucine, methionine, leucine, lysine, and histidine. The mutant was virulent when injected intravenously, but its virulence was strongly attenuated in the murine model of bronchopulmonary aspergillosis Despite those ambiguous results of gene disruption studies, homocitric synthase (Lys21p and Lys22p isoforms from C. albicans, Lys20p and Lys21p isoforms from S. cerevisiae), homoaconitase (Lys4p), and homoisocitric dehydrogenase (Lys12p) catalyzing biosynthetic reactions present only in fungal cells, and having no counterparts in mammalian cells, are the most obvious candidates for molecular targets. On the other hand, Becker et al (2010) provided evidence that ilv (a gene encoding enzyme catalyzing the second step in the common part of the branched-chain amino acid biosynthesis) was non-essential for C. albicans virulence in a murine infection model. Histidine biosynthesis antibacterial activity (Abdo et al 2011 and references cited therein) but their antifungal potential is not known
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