title: Pyrazinamide, but not pyrazinoic acid, is a competitive inhibitor of NADPH binding to Mycobacterium tuberculosis fatty acid synthase I.
abstract: Pyrazinamide (PZA), an essential component of short-course anti-tuberculosis chemotherapy, was shown by Saturation Transfer Difference (STD) NMR methods to act as a competitive inhibitor of NADPH binding to purified Mycobacterium tuberculosis fatty acid synthase I (FAS I). Both PZA and pyrazinoic acid (POA) reversibly bind to FAS I but at different binding sites. The competitive binding of PZA and NADPH suggests potential FAS I binding sites. POA was not previously known to have any specific binding interactions. The STD NMR of NADPH bound to the mycobacterial FAS I was consistent with the orientation reported in published single crystal X-ray diffraction studies of fungal FAS I. Overall the differences in binding between PZA and POA are consistent with previous recognition of the importance of intracellular accumulation of POA for anti-mycobacterial activity.
authors.affiliation: Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA.
authors.forename: Halimah
authors.initials: H
authors.lastname: Sayahi
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: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D009249:NADP / Q000737:chemistry / Q000494:pharmacology; D011718:Pyrazinamide / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D011718:Pyrazinamide; C005296:pyrazinoic acid; D009249:NADP; D064429:Fatty Acid Synthases; C413881:fatty acid synthase I, mycobacteria