Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0064292
Title: Characterization of the Complete Uric Acid Degradation Pathway in the Fungal Pathogen Cryptococcus neoformans
Authors: Lee I.R. 
Yang L.
Sebetso G.
Allen R.
Doan T.H.N.
Blundell R.
Lui E.Y.L.
Morrow C.A.
Fraser J.A.
Keywords: uric acid
animal experiment
animal model
article
controlled study
Cryptococcus neoformans
DAL1 gene
DAL2 3 3 gene
female
fungal gene
fungal metabolism
fungal virulence
gene function
gene identification
mouse
nonhuman
open reading frame
purine metabolism
recombination repair
URE1 gene
URO1 gene
URO2 gene
URO3 gene
Agrobacterium
Animals
Caenorhabditis elegans
Computational Biology
Cryptococcosis
Cryptococcus neoformans
Fungal Capsules
Fungal Proteins
Gene Deletion
Host-Pathogen Interactions
Humans
Hydrolases
Melanins
Metabolic Networks and Pathways
Mice
Mutagenesis, Insertional
Nitrogen
Phenotype
Purines
Reproducibility of Results
Reproduction
Reverse Genetics
Temperature
Urease
Uric Acid
Issue Date: 2013
Publisher: Public Library of Science
Citation: Lee I.R., Yang L., Sebetso G., Allen R., Doan T.H.N., Blundell R., Lui E.Y.L., Morrow C.A., Fraser J.A. (2013). Characterization of the Complete Uric Acid Degradation Pathway in the Fungal Pathogen Cryptococcus neoformans. PLoS ONE 8 (5) : e64292. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0064292
Abstract: Degradation of purines to uric acid is generally conserved among organisms, however, the end product of uric acid degradation varies from species to species depending on the presence of active catabolic enzymes. In humans, most higher primates and birds, the urate oxidase gene is non-functional and hence uric acid is not further broken down. Uric acid in human blood plasma serves as an antioxidant and an immune enhancer; conversely, excessive amounts cause the common affliction gout. In contrast, uric acid is completely degraded to ammonia in most fungi. Currently, relatively little is known about uric acid catabolism in the fungal pathogen Cryptococcus neoformans even though this yeast is commonly isolated from uric acid-rich pigeon guano. In addition, uric acid utilization enhances the production of the cryptococcal virulence factors capsule and urease, and may potentially modulate the host immune response during infection. Based on these important observations, we employed both Agrobacterium-mediated insertional mutagenesis and bioinformatics to predict all the uric acid catabolic enzyme-encoding genes in the H99 genome. The candidate C. neoformans uric acid catabolic genes identified were named: URO1 (urate oxidase), URO2 (HIU hydrolase), URO3 (OHCU decarboxylase), DAL1 (allantoinase), DAL2,3,3 (allantoicase-ureidoglycolate hydrolase fusion protein), and URE1 (urease). All six ORFs were then deleted via homologous recombination; assaying of the deletion mutants' ability to assimilate uric acid and its pathway intermediates as the sole nitrogen source validated their enzymatic functions. While Uro1, Uro2, Uro3, Dal1 and Dal2,3,3 were demonstrated to be dispensable for virulence, the significance of using a modified animal model system of cryptococcosis for improved mimicking of human pathogenicity is discussed. © 2013 Lee et al.
Source Title: PLoS ONE
URI: https://scholarbank.nus.edu.sg/handle/10635/166575
ISSN: 19326203
DOI: 10.1371/journal.pone.0064292
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