title: Analogs of the antituberculous agent pyrazinamide are competitive inhibitors of NADPH binding to M. tuberculosis fatty acid synthase I.
abstract: 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.
authors.affiliation: Department of Chemistry, University at Albany, SUNY, 1400 Washington Ave, Albany, NY 12222, USA.
authors.forename: Halimah
authors.initials: H
authors.lastname: Sayahi
authors.forename: Kaitlin M
authors.initials: KM
authors.lastname: Pugliese
authors.forename: Oren
authors.initials: O
authors.lastname: Zimhony
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.forename: Alexander
authors.initials: A
authors.lastname: Shekhtman
authors.forename: John T
authors.initials: JT
authors.lastname: Welch
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D009249:NADP / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011718:Pyrazinamide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D011718:Pyrazinamide; D009249:NADP; D064429:Fatty Acid Synthases; C413881:fatty acid synthase I, mycobacteria