Analogs of the antituberculous agent pyrazinamide are competitive inhibitors of NADPH binding to M. tuberculosis fatty acid synthase I.

Halimah Sayahi, Kaitlin M Pugliese, Oren Zimhony, William R Jacobs, Alexander Shekhtman, John T Welch

Department of Chemistry, University at Albany, SUNY, 1400 Washington Ave, Albany, NY 12222, USA.

Chemistry & biodiversity 2012 Nov

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Analogs of pyrazinamide (=pyrazine-2-carboxamide; PZA), an essential component of short-course antituberculous chemotherapy, such as 5-chloropyrazinamide (5-Cl-PZA) act as competitive inhibitors of NADPH binding to purified mycobacterial fatty acid synthase I (FAS I) as shown by Saturation Transfer Difference (STD) NMR studies. In addition, pyrazinoic acid esters (POE) and 5-Cl-POE reversibly bind to FAS I with the relatively greater affinity of longer-chain esters for FAS I, clear from the STD amplification factors. The competitive binding of PZA and 5-Cl-PZA clearly illustrates that both agents bind FAS. In contrast to PZA, at low NADPH concentrations 5-Cl-PZA is a cooperative inhibitor of NADPH binding. Copyright © 2012 Verlag Helvetica Chimica Acta AG, Zürich.

Citation

Halimah Sayahi, Kaitlin M Pugliese, Oren Zimhony, William R Jacobs, Alexander Shekhtman, John T Welch. Analogs of the antituberculous agent pyrazinamide are competitive inhibitors of NADPH binding to M. tuberculosis fatty acid synthase I. Chemistry & biodiversity. 2012 Nov;9(11):2582-96