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 IC50 value of 43 μm, paving the way to hit-to-lead process.

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

Stefano Sainas;Marco L Lolli;Donatella Boschi;
2023-01-01

Abstract

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 IC50 value of 43 μm, paving the way to hit-to-lead process.
2023
597
16
2119
2132
https://febs.onlinelibrary.wiley.com/doi/10.1002/1873-3468.14680
Mycobacterium tuberculosis; dihydroorotate dehydrogenase; drug discovery; pyrimidine biosynthesis; tuberculosis.
Marta Alberti , Stefano Sainas , Erika Ronchi , Marco L Lolli , Donatella Boschi, Menico Rizzi, Davide M Ferraris , Riccardo Miggiano
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1941090
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