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

Chem Biodivers. 2012 Nov;9(11):2582-96. doi: 10.1002/cbdv.201200291.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / metabolism*
  • Fatty Acid Synthases / antagonists & inhibitors
  • Fatty Acid Synthases / metabolism*
  • Humans
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / enzymology*
  • NADP / metabolism*
  • Protein Binding / drug effects
  • Pyrazinamide / analogs & derivatives*
  • Pyrazinamide / pharmacology*
  • Tuberculosis / drug therapy
  • Tuberculosis / microbiology

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Pyrazinamide
  • NADP
  • Fatty Acid Synthases
  • fatty acid synthase I, mycobacteria