TY - JOUR
T1 - Acetohydroxyacid synthase from Mycobacterium avium and its inhibition by sulfonylureas and imidazolinones
AU - Zohar, Yehudit
AU - Einav, Monica
AU - Chipman, David M.
AU - Barak, Ze'ev
N1 - Funding Information:
This work was partially funded by BGU Seed Grant no. 81824101. We are grateful to Dr. Giovanna Riccardi for the gift of plasmids carrying M. avium DNA. We thank M. Vyazmensky for her assistance.
PY - 2003/6/26
Y1 - 2003/6/26
N2 - Tuberculosis (TB) remains one of the world's leading causes of death from infectious disease. It is caused by infection with Mycobacterium tuberculosis or sometimes, particularly in immune-compromised patients, Mycobacterium avium. The aim of this study was to create a tool that could be used in the search for new anti-TB drugs that inhibit branched-chain amino acid (BCAA) biosynthesis, as these are essential amino acids that are not available to a mycobacterium during growth in an infected organism. To this end, we cloned, overexpressed, purified and characterised for the first time an acetohydroxyacid synthase (AHAS), a key enzyme in the pathway to the biosynthesis of the BCAAs, from the genus Mycobacterium. Nine commercial herbicides of the sulfonylurea and imidazolinone classes were tested for their influence on this enzyme. Four of the sulfonylureas were potent inhibitors of the enzyme. The relative potency of the different inhibitors towards the M. avium enzyme was unlike their potency towards other AHASs whose inhibitor profile has been reported, emphasising the advantage of using a mycobacterial enzyme as a tool in the search for new anti-TB drugs.
AB - Tuberculosis (TB) remains one of the world's leading causes of death from infectious disease. It is caused by infection with Mycobacterium tuberculosis or sometimes, particularly in immune-compromised patients, Mycobacterium avium. The aim of this study was to create a tool that could be used in the search for new anti-TB drugs that inhibit branched-chain amino acid (BCAA) biosynthesis, as these are essential amino acids that are not available to a mycobacterium during growth in an infected organism. To this end, we cloned, overexpressed, purified and characterised for the first time an acetohydroxyacid synthase (AHAS), a key enzyme in the pathway to the biosynthesis of the BCAAs, from the genus Mycobacterium. Nine commercial herbicides of the sulfonylurea and imidazolinone classes were tested for their influence on this enzyme. Four of the sulfonylureas were potent inhibitors of the enzyme. The relative potency of the different inhibitors towards the M. avium enzyme was unlike their potency towards other AHASs whose inhibitor profile has been reported, emphasising the advantage of using a mycobacterial enzyme as a tool in the search for new anti-TB drugs.
KW - Acetohydroxyacid synthase
KW - Acetolactate synthase
KW - Imidazolinone
KW - Mycobacterium
KW - Sulfonylurea
KW - Tuberculosis
UR - http://www.scopus.com/inward/record.url?scp=0043123259&partnerID=8YFLogxK
U2 - 10.1016/S1570-9639(03)00160-2
DO - 10.1016/S1570-9639(03)00160-2
M3 - Article
AN - SCOPUS:0043123259
SN - 1570-9639
VL - 1649
SP - 97
EP - 105
JO - Biochimica et Biophysica Acta - Proteins and Proteomics
JF - Biochimica et Biophysica Acta - Proteins and Proteomics
IS - 1
ER -