Nov 9, 2018

The distinct biochemical property enables thymidylate kinase as a drug target and participates in pyrimidine drug sensitivity in Candida albicans

BioRxiv : the Preprint Server for Biology
Chang Yu Huang

Abstract

The ability to overcome drug resistance in outbreaks of Candida albicans infection is an unmet need in health management. Here, we investigated CDC8, which encodes thymidylate kinase (TMPK), as a potential drug target for the treatment of C. albicans infection. In this study, we found that the specific region spanning amino acids 106-123, namely, the Ca-loop of C. albicans TMPK (CaTMPK) contributes to the hyperactivity of this enzyme compared to the human enzyme (hTMPK) and to the utilization of deoxy-uridine monophosphate (dUMP)/ deoxy-5-Fluorouridine monophosphate (5-FdUMP) as a substrate. Notably, CaTMPK but not hTMPK enables dUTP/5-FdUTP-mediated DNA toxicity in yeast. CRISPR-mediated deletion of this Ca-loop in C. albicans demonstrated the critical role of this Ca-loop in fungal growth and susceptibility to 5-Fluorouridine (5-FUrd). Moreover, pathogenic and drug-resistant C. albicans clones were similarly sensitive to 5-FUrd. Thus, this study not only identified a target site for the development of CaTMPK-selective drugs but also revealed 5-FUrd to be a potential drug for the treatment of C. albicans infection.

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Mentioned in this Paper

Study
Candida albicans
Cyclodictyon albicans
Daiotyla albicans
CRISPR-Cas Systems
Pathogenic Organism
Cineraria albicans
Amino Acids, I.V. solution additive
Carex albicans
Codia albicans

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