Pyrazinamide, but not pyrazinoic acid, is a competitive inhibitor of NADPH binding to Mycobacterium tuberculosis fatty acid synthase i

Halimah Sayahi, Oren Zimhony, William R. Jacobs, Alexander Shekhtman, John T. Welch

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4804-4807
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number16
DOIs
StatePublished - Aug 15 2011

Fingerprint

Pyrazinamide
Fatty Acid Synthases
Glycogen Synthase
NADP
Mycobacterium tuberculosis
Binding Sites
Nuclear magnetic resonance
Competitive Binding
Chemotherapy
X-Ray Diffraction
Crystal orientation
Tuberculosis
Single crystals
Drug Therapy
X ray diffraction
pyrazinoic acid

Keywords

  • Enzyme inhibition
  • Fatty acid synthase I (FAS I)
  • NADPH
  • Pyrazinamide
  • STD NMR

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Pyrazinamide, but not pyrazinoic acid, is a competitive inhibitor of NADPH binding to Mycobacterium tuberculosis fatty acid synthase i. / Sayahi, Halimah; Zimhony, Oren; Jacobs, William R.; Shekhtman, Alexander; Welch, John T.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 21, No. 16, 15.08.2011, p. 4804-4807.

Research output: Contribution to journalArticle

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