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

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2582-2596
Number of pages15
JournalChemistry and Biodiversity
Volume9
Issue number11
DOIs
StatePublished - Nov 1 2012

Keywords

  • Antituberculous activity
  • Enzyme inhibition
  • Fatty acid synthase I (FAS I)
  • NADPH
  • Pyrazinamide
  • Saturation Transfer Difference (STD) NMR

ASJC Scopus subject areas

  • Bioengineering
  • Biochemistry
  • Chemistry(all)
  • Molecular Medicine
  • Molecular Biology

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