Proteome-wide profiling of isoniazid targets in Mycobacterium tuberculosis

Argyrides Argyrou, Lianji Jin, Linda Siconilfi-Baez, Ruth H. Angeletti, John S. Blanchard

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Isoniazid (INH) is an essential drug used to treat tuberculosis. The mycobactericidal agents are INH adducts [INH-NAD(P)] of the pyridine nucleotide coenzymes, which are generated in vivo after INH activation and which bind to, and inhibit, essential enzymes. The NADH-dependent enoyl-ACP reductase (InhA) and the NADPH-dependent dihydrofolate reductase (DfrA) have both been shown to be inhibited by INH-NAD(P) adducts with nanomolar affinity. In this paper, we profiled the Mycobacterium tuberculosis proteome using both the INH-NAD and INH-NADP adducts coupled to solid supports and identified, in addition to InhA and DfrA, 16 other proteins that bind these adducts with high affinity. The majority of these are predicted to be pyridine nucleotide-dependent dehydrogenases/ reductases. They are involved in many cellular processes, including 5-adenosylmethionine-dependent methyl transfer reactions, pyrimidine and valine catabolism, the arginine degradative pathway, proton and potassium transport, stress response, lipid metabolism, and riboflavin biosynthesis. The targeting of multiple enzymes could, thus, account for the pleiotropic effects of, and powerful mycobactericidal properties of, INH.

Original languageEnglish (US)
Pages (from-to)13947-13953
Number of pages7
JournalBiochemistry
Volume45
Issue number47
DOIs
Publication statusPublished - Nov 28 2006

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ASJC Scopus subject areas

  • Biochemistry

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