Biochemical characterization of Mycobacterium tuberculosis dihydroorotate dehydrogenase and identification of a selective inhibitor.

Autor: Alberti M; Department of Pharmaceutical Sciences, University of Eastern Piedmont, Novara, Italy., Sainas S; Department of Sciences and Drug Technology, University of Turin, Torino, Italy., Ronchi E; Department of Pharmaceutical Sciences, University of Eastern Piedmont, Novara, Italy., Lolli ML; Department of Sciences and Drug Technology, University of Turin, Torino, Italy., Boschi D; Department of Sciences and Drug Technology, University of Turin, Torino, Italy., Rizzi M; Department of Pharmaceutical Sciences, University of Eastern Piedmont, Novara, Italy., Ferraris DM; Department of Pharmaceutical Sciences, University of Eastern Piedmont, Novara, Italy., Miggiano R; Department of Pharmaceutical Sciences, University of Eastern Piedmont, Novara, Italy.
Jazyk: angličtina
Zdroj: FEBS letters [FEBS Lett] 2023 Aug; Vol. 597 (16), pp. 2119-2132. Date of Electronic Publication: 2023 Jun 15.
DOI: 10.1002/1873-3468.14680
Abstrakt: Mycobacterium tuberculosis (MTB) is the etiologic agent of tuberculosis (TB), an ancient disease which causes 1.5 million deaths worldwide. Dihydroorotate dehydrogenase (DHODH) is a key enzyme of the MTB de novo pyrimidine biosynthesis pathway, and it is essential for MTB growth in vitro, hence representing a promising drug target. We present: (i) the biochemical characterization of the full-length MTB DHODH, including the analysis of the kinetic parameters, and (ii) the previously unreleased crystal structure of the protein that allowed us to rationally screen our in-house chemical library and identify the first selective inhibitor of mycobacterial DHODH. The inhibitor has fluorescence properties, potentially instrumental to in cellulo imaging studies, and exhibits an IC 50 value of 43 μm, paving the way to hit-to-lead process.
(© 2023 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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