Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis

Science. 1998 Jan 2;279(5347):98-102. doi: 10.1126/science.279.5347.98.

Abstract

The preferred antitubercular drug isoniazid specifically targets a long-chain enoyl-acyl carrier protein reductase (InhA), an enzyme essential for mycolic acid biosynthesis in Mycobacterium tuberculosis. Despite the widespread use of this drug for more than 40 years, its precise mode of action has remained obscure. Data from x-ray crystallography and mass spectrometry reveal that the mechanism of isoniazid action against InhA is covalent attachment of the activated form of the drug to the nicotinamide ring of nicotinamide adenine dinucleotide bound within the active site of InhA.

Publication types

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

MeSH terms

  • Antitubercular Agents / metabolism
  • Antitubercular Agents / pharmacology*
  • Bacterial Proteins
  • Binding Sites
  • Biotransformation
  • Crystallography, X-Ray
  • Drug Resistance, Microbial
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
  • Fatty Acid Synthases / antagonists & inhibitors
  • Fatty Acid Synthases / chemistry
  • Fatty Acid Synthases / genetics
  • Fatty Acid Synthases / metabolism
  • Isoniazid / metabolism
  • Isoniazid / pharmacology*
  • Mass Spectrometry
  • Models, Molecular
  • Mutation
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Mycolic Acids / metabolism
  • NAD / chemistry
  • NAD / metabolism*
  • Oxidoreductases / antagonists & inhibitors*
  • Oxidoreductases / chemistry
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Mycolic Acids
  • NAD
  • Oxidoreductases
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
  • InhA protein, Mycobacterium
  • Fatty Acid Synthases
  • Isoniazid

Associated data

  • PDB/1ZID