Reconstruction of diaminopimelic acid biosynthesis allows characterisation of Mycobacterium tuberculosis N-succinyl-L,L-diaminopimelic acid desuccinylase

Sci Rep. 2016 Mar 15:6:23191. doi: 10.1038/srep23191.

Abstract

With the increased incidence of tuberculosis (TB) caused by Mycobacterium tuberculosis there is an urgent need for new and better anti-tubercular drugs. N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) is a key enzyme in the succinylase pathway for the biosynthesis of meso-diaminopimelic acid (meso-DAP) and L-lysine. DapE is a zinc containing metallohydrolase which hydrolyses N-succinyl L,L diaminopimelic acid (L,L-NSDAP) to L,L-diaminopimelic acid (L,L-DAP) and succinate. M. tuberculosis DapE (MtDapE) was cloned, over-expressed and purified as an N-terminal hexahistidine ((His)6) tagged fusion containing one zinc ion per DapE monomer. We redesigned the DAP synthetic pathway to generate L,L-NSDAP and other L,L-NSDAP derivatives and have characterised MtDapE with these substrates. In contrast to its other Gram negative homologues, the MtDapE was insensitive to inhibition by L-captopril which we show is consistent with novel mycobacterial alterations in the binding site of this drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors
  • Amidohydrolases / chemistry*
  • Amidohydrolases / metabolism
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Captopril / pharmacology
  • Diaminopimelic Acid / chemistry
  • Diaminopimelic Acid / metabolism*
  • Histidine / chemistry
  • Mycobacterium tuberculosis / enzymology*
  • Oligopeptides / chemistry
  • Zinc / chemistry

Substances

  • Bacterial Proteins
  • His-His-His-His-His-His
  • Oligopeptides
  • Histidine
  • Diaminopimelic Acid
  • Captopril
  • Amidohydrolases
  • Zinc