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Structure-based functional annotation of hypothetical proteins from Candida dubliniensis: a quest for potential drug targets.

ABSTRACT: Candida dubliniensis is an emerging pathogenic yeast in humans and infections are usually restricted to mucosal parts of the body. However, its presence in specimens of immunocompromised individuals, especially in HIV-positive patients, is of major medical concern. There is a large fraction of genomes of C. dubliniensis in the database which are uncharacterized for their biochemical, biophysical, and/or cellular functions, and are identified as hypothetical proteins (HPs). Function annotation of Candida genome is, therefore, essentially required to facilitate the understanding of mechanisms of pathogenesis and biochemical pathways important for selecting novel therapeutic target. Here, we carried out an extensive analysis to explain the functional properties of genome, using available protein structure and function analysis tools. We successfully modeled the structures of eight HPs for which a template with moderate sequence similarity was available in the protein data bank. All modeled structures were analyzed and we found that these proteins may act as transporter, kinase, transferase, ketosteroid, isomerase, hydrolase, oxidoreductase, and binding targets for DNA and RNA. Since these unique HPs of Candida showed no homologs in humans, these proteins are expected to be a potential target for future antifungal therapy.

SUBMITTER: Kumar K

PROVIDER: S-EPMC4522726 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Candida dubliniensis is a recently described opportunistic fungal pathogen that is closely related to Candida albicans. Candida dubliniensis readily develops resistance to the azole antifungal agent fluconazole, both in vitro and in infected patients, and this resistance is usually associated with upregulation of the CdMDR1 gene, encoding a multidrug efflux pump of the major facilitator superfamily. To determine the role of CdMDR1 in drug resistance in C. dubliniensis, we constructed an mdr1 null mutant from the fluconazole-resistant clinical isolate CM2, which overexpressed the CdMDR1 gene. Sequential deletion of both CdMDR1 alleles was performed by the MPA(R)-flipping method, which is based on the repeated use of a dominant mycophenolic acid resistance marker for selection of integrative transformants and its subsequent deletion from the genome by FLP-mediated, site-specific recombination. In comparison with its parental strain, the mdr1 mutant showed decreased resistance to fluconazole but not to the related drug ketoconazole. In addition, we found that CdMDR1 confers resistance to the structurally unrelated drugs 4-nitroquinoline-N-oxide, cerulenin, and brefeldin A, since the enhanced resistance to these compounds of the parent strain CM2 compared with the matched susceptible isolate CM1 was abolished in the mdr1 mutant. In contrast, CdMDR1 inactivation did not cause increased susceptibility to amorolfine, terbinafine, fluphenazine, and benomyl, although overexpression of CdMDR1 in a hypersusceptible Saccharomyces cerevisiae strain had previously been shown to confer resistance to these compounds. The effect of CdMDR1 inactivation was identical to that seen in two similarly constructed C. albicans mdr1 mutants. Therefore, despite species-specific differences in the amino acid sequences of the Mdr1 proteins, overexpression of CaMDR1 and CdMDR1 in clinical C. albicans and C. dubliniensis strains seems to confer the same drug resistance profile in both species.

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Structure-based functional annotation of hypothetical proteins from Candida dubliniensis: a quest for potential drug targets.

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