Inhibition of Stenotrophomonas maltophilia dihydrofolate reductase by methotrexate: A single slow-binding process

Authors: Navarro-Martínez, M. D.1; Cabezas-Herrera, J.2; García-Cánovas, F.1; Rodríguez-López, J. N.1

Source: Journal of Enzyme Inhibition and Medicinal Chemistry, Volume 22, Number 4, August 2007 , pp. 377-382(6)

Publisher: Informa Healthcare

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Abstract:

Although antifolates such as trimethoprim are used in the clinical treatment of Stenotrophomonas maltophilia infection, the dihydrofolate reductase (DHFR) of this microorganism is scarcely known because it has never been isolated. Here, we describe the purification of this enzyme and kinetically characterize its inhibition by methotrexate (MTX). Upon MTX treatment, time-dependent, slow-binding inhibition was observed due to the generation of a long-lived, slowly dissociating enzyme-NADPH-inhibitor complex. Kinetic analysis revealed a one-step inhibition mechanism [image omitted]  with an association rate constant (ki) of 3.8 × 107 M- 1s- 1. Possible mechanisms for MTX binding to S. maltophilia DHFR are discussed.

Keywords: Stenotrophomonas maltophilia; antifolates; dihydrofolate reductase; methotrexate; slow-binding inhibitors

Document Type: Research Article

DOI: http://dx.doi.org/10.1080/14756360601141653

Affiliations: 1: Grupo de Investigación de Enzimología, Departamento de Bioquímica y Biología Molecular A, Facultad de Biología, Universidad de Murcia, Espinardo, Murcia, Spain 2: Servicio de Análisis Clínicos, Hospital, Universitario Virgen de la Arrixaca, Murcia, Spain

Publication date: August 1, 2007

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