Inhibition of mycobacterium tuberculosis transaminase BioA by aryl hydrazines and hydrazides

Ran Dai, Daniel J. Wilson, Todd W. Geders, Courtney C. Aldrich, Barry C. Finzel

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

7,8-Diaminopelargonic acid synthase (BioA) of Mycobacterium tuberculosis is a recently validated target for therapeutic intervention in the treatment of tuberculosis (TB). Using biophysical fragment screening and structural characterization of compounds, we have identified a potent aryl hydrazine inhibitor of BioA that reversibly modifies the pyridoxal-5′-phosphate (PLP) cofactor, forming a stable quinonoid. Analogous hydrazides also form covalent adducts that can be observed crystallographically but are incapable of inactivating the enzyme. In the X-ray crystal structures, small molecules induce unexpected conformational remodeling in the substrate binding site. We compared these conformational changes to those induced upon binding of the substrate (7-keto-8-aminopelargonic acid), and characterized the inhibition kinetics and the X-ray crystal structures of BioA with the hydrazine compound and analogues to unveil the mechanism of this reversible covalent modification. TB or not TB: 7,8-Diaminopelargonic acid synthase (BioA) of Mycobacterium tuberculosis (Mtb) is a recently validated target in therapeutic interventions for tuberculosis (TB). In this paper, an aryl hydrazine Mtb BioA inhibitor is described that reversibly reacts with the PLP cofactor to form a stable cis-azo quinonoid species, which was structurally characterized by X-ray crystallography.

Original languageEnglish (US)
Pages (from-to)575-586
Number of pages12
JournalChemBioChem
Volume15
Issue number4
DOIs
StatePublished - Mar 3 2014

Keywords

  • X-ray crystal structures
  • hydrazine
  • reversible covalent inhibitors
  • transaminase
  • tuberculosis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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