https://scholars.lib.ntu.edu.tw/handle/123456789/416772
Title: | The Ca-loop in thymidylate kinase is critical for growth and contributes to pyrimidine drug sensitivity of Candida albicans | Authors: | Huang, Chang-Yu YEE-CHUN CHEN Wu-Hsieh, Betty A Fang, J.-M. ZEE-FEN CHANG |
Keywords: | Candida albicans; DNA damage; drug resistance; nucleoside/nucleotide analogue; substrate specificity; thymidylate kinase | Issue Date: | 5-Jul-2019 | Publisher: | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC | Journal Volume: | 294 | Journal Issue: | 27 | Start page/Pages: | 10686 | Source: | The Journal of biological chemistry | Abstract: | The yeast Candida albicans is the most prevalent opportunistic fungal pathogen in humans. Drug resistance among C. albicans isolates poses a common challenge, and overcoming this resistance represents an unmet need in managing this common pathogen. Here, we investigated CDC8, encoding thymidylate kinase (TMPK), as a potential drug target for the management of C. albicans infections. We found that the region spanning amino acids 106-123, namely the Ca-loop of C. albicans TMPK (CaTMPK), contributes to the hyperactivity of this enzyme compared with the human enzyme (hTMPK) and to the utilization of deoxyuridine monophosphate (dUMP)/deoxy-5-fluorouridine monophosphate (5-FdUMP) as a substrate. Notably, expression of CaTMPK, but not of hTMPK, produced dUTP/5-FdUTP-mediated DNA toxicity in budding yeast (Saccharomyces cerevisiae). CRISPR-mediated deletion of this Ca-loop in C. albicans revealed that the Ca-loop is critical for fungal growth and susceptibility to 5-fluorouridine (5-FUrd). Of note, pathogenic and drug-resistant C. albicans clones were similarly sensitive to 5-FUrd, and we also found that CaTMPK is essential for the growth of C. albicans In conclusion, these findings not only identified a target site for the development of CaTMPK-selective drugs, but also revealed that 5-FUrd may have potential utility as drug for managing C. albicans infections. |
URI: | 10.1074/jbc.RA118.006798 https://scholars.lib.ntu.edu.tw/handle/123456789/416772 |
ISSN: | 00219258 | DOI: | 10.1074/jbc.RA118.006798 |
Appears in Collections: | 分子醫學研究所 |
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