Characterisation of Potential Antimicrobial Targets for Tuberculosis - II. Branched-Chain Amino Acid Aminotransferase and Methionine Regeneration in Mycobacterium Tuberculosis

PDF

Authors
  1. Venos, E.S.
  2. Knodel, M.H.
  3. Radford, C.L.
  4. Berger, B.J.
Corporate Authors
Defence R&D Canada - Suffield, Ralston ALTA (CAN)
Abstract
Tuberculosis remains an important problem for the Canadian Forces in many of its overseas deployments. With the spread of drug-resistant strains of Mycobacterium tuberculosis, there is an increased need to characterise novel drug targets in the organism. The final step of methionine recycling from methylthioadenosine has been examined in M. tuberculosis, and has been found to be catalysed by a branched-chain amino acid aminotransferase. The enzyme was found to be a member of the aminotransferase IIIa subfamily, and closely related to the corresponding aminotransferase in Bacillus subtilis, but not to that found in B. anthracis or B. cereus (Berger et al., Journal of Bacteriology, 185, p. 2418-2431, 2003). The amino donor preference for the formation of methionine from ketomethiobutyrate was isoleucine, leucine, valine, glutamate, and phenylalanine. The enzyme catalysed branched-chain amino acid and ketomethiobutyrate transamination with a Km of 1.77 – 7.44 mM and a Vmax of 2.17 – 5.70 Mu mol/min/mg protein, and transamination of ketoglutarate with a Km of 5.79 – 6.95 mM and a Vmax of 11.82 – 14.35 Mu mol/min/mg protein. Aminooxy compounds were examined as potential enzyme inhibitors, with O-benzylhydroxylamine, O-t-butylhydroxylamine, carboxymethoxylamine, and O-allylhydroxylamine yielding mixed-type inhibition with Ki values of 8.20 – 21.61 MuM. These same compounds were examined as antimycobacterial agents in a M. marinum model and were found to completely prevent

Il y a un résumé en français ici.

Keywords
Methionine adenosyltransferase;Mycobacterium smegmatis;Mycobacterium tuberculosis;Tuberculosis
Report Number
DRDC-SUFFIELD-TR-2003-147 — Technical Report
Date of publication
01 Dec 2003
Number of Pages
36
DSTKIM No
CA023704
CANDIS No
521040
Format(s):
Hardcopy;CD ROM

Permanent link

Document 1 of 1

Date modified: