Inhibition of Mycobacterium tuberculosis transaminase BioA by aryl hydrazines and hydrazides

Chembiochem. 2014 Mar 3;15(4):575-86. doi: 10.1002/cbic.201300748. Epub 2014 Jan 31.


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.

Keywords: X-ray crystal structures; hydrazine; reversible covalent inhibitors; transaminase; tuberculosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry
  • Amino Acids / metabolism
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / metabolism*
  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray
  • Hydrazines / chemistry
  • Hydrazines / metabolism*
  • Kinetics
  • Molecular Docking Simulation
  • Mycobacterium tuberculosis / enzymology*
  • Transaminases / antagonists & inhibitors
  • Transaminases / metabolism*


  • Amino Acids
  • Bacterial Proteins
  • Hydrazines
  • hydrazine
  • 7-keto-8-aminopelargonic acid
  • Transaminases
  • BioA protein, bacteria