BIOSYNTHESIS OF PURINE NUCLEOTIDES 1
During de novo synthesis of pyrimidine nucleotides, UMP is synthesized first which in turn becomes the precursor for UDP, UTP and CTP biosynthesis . Thus, when de novo synthesis is perturbed, there is a reduction in the entire pyrimidine nucleotide pool which is replenished with the restoration of the pathway in the URA5 complement. In contrast, the salvage pathway utilizes pyrimidine bases cytosine, cytidine and uridine for the synthesis of their respective nucleotides. Thus, the supplementation of ura− mutant with uracil alone would mainly result in the replenishment of UMP, UDP and UTP pools, whereas reduced cytidine nucleotide pools may persist. A unique feature of C. neoformans is its large polysaccharide capsule. UDP sugars like UDP-galactose, UDP-xylose and UDP-glucuronic acid are the activated donors and precursors of capsular polysaccharide whereas UDP - glucose and UDP-N-Acetylglucosamine serve the same purpose in cell wall biosynthesis . Deletion of UGD1 and USX1 genes that encode for C. neoformans UDP-glucose dehydrogenase and UDP-xylose synthase respectively leads to acapsular, temperature sensitive and avirulent phenotypes. URA5 mutants are also less virulent in mice . Given the importance of uridine nucleotides in cryptococcal structural development, virulence and pathogenesis, it is likely that the influx of uracil in the ura− mutant is prioritized toward the synthesis of UMP and UDP leaving the pyrimidine pools imbalanced. This reliance on pyrimidine pools for pathogenesis reinforces the potential of pyrimidine biosynthesis as a drug target in C. neoformans.
Regulation of pyrimidine nucleotide biosynthesis;
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Chapter 21 : Biosynthesis of Amino Acids, Nucleotides, …
The polyene antifungal agent Amphotericin B exhibits potent and broad spectrum fungicidal activity. However, high nephrotoxicity can hinder its administration in resource poor settings. Quantification of early fungicidal activity in studies of HIV patients with cryptococcosis demonstrate that 5-Fluorocytosine therapy in combination with Amphotericin B results in faster clearance than with Amphotericin B alone. In vitro synergy between the two drugs has also been reported but the mechanism by which 5-Fluorocytosine synergizes with Amphotericin B has not been delineated. In this study we set out to investigate the effect of genetic mutation or pharmacologic repression of de novo pyrimidine and purine biosynthesis pathways on the Amphotericin B susceptibility of Cryptococcus neoformans. We demonstrate that a ura- derivative of wild type Cryptococcus neoformans strain H99 is hypersensitive to Amphotericin B. This sensitivity is remediated by re-introduction of a wild type URA5 gene, but not by addition of exogenous uracil to supplement the auxotrophy. Repression of guanine biosynthesis by treatment with the inosine monophosphate dehydrogenase inhibitor, mycophenolic acid, was synergistic with Amphotericin B as determined by checkerboard analysis. As in Cryptococcus neoformans, a ura− derivative of Candida albicans was also hypersensitive to Amphotericin B, and treatment of Candida albicans with mycophenolic acid was likewise synergistic with Amphotericin B. In contrast, neither mycophenolic acid nor 5-FC had an effect on the Amphotericin B susceptibility of Aspergillus fumigatus. These studies suggest that pharmacological targeting of nucleotide biosynthesis pathways has potential to lower the effective dose of Amphotericin B for both C. neoformans and C. albicans. Given the requirement of nucleotide and nucleotide sugars for growth and pathogenesis of Cryptococcus neoformans, disrupting nucleotide metabolic pathways might thus be an effective mechanism for the development of novel antifungal drugs.
De novo biosynthesis of purine nucleotides
Metabolism1.0 Global and overview maps1.1 Carbohydrate metabolism1.2 Energy metabolism1.3 Lipid metabolism1.4 Nucleotide metabolism1.5 Amino acid metabolism1.6 Metabolism of other amino acids1.7 Glycan biosynthesis and metabolism1.8 Metabolism of cofactors and vitamins1.9 Metabolism of terpenoids and polyketides1.10 Biosynthesis of other secondary metabolites1.11 Xenobiotics biodegradation and metabolism1.12 Chemical structure transformation maps