Crystal structures of two novel sulfonylurea herbicides in complex with Arabidopsis thaliana acetohydroxyacid synthase.
Acetohydroxyacid synthase (AHAS; EC 2.2.1.6) is the first enzyme in the biosynthetic pathway of the branched-chain amino acids. It catalyzes the conversion of two molecules of pyruvate into 2-acetolactate or one molecule of pyruvate and one molecule of 2-ketobutyrate into 2-aceto-2-hydroxybutyrate. AHAS requires the cofactors thiamine diphosphate (ThDP), Mg(2+) and FAD for activity. The herbicides that target this enzyme are effective in protecting a broad range of crops from weed species. However, resistance in the field is now a serious problem worldwide. To address this, two new sulfonylureas, monosulfuron and monosulfuron ester, have been developed as commercial herbicides in China. These molecules differ from the traditional sulfonylureas in that the heterocyclic ring attached to the nitrogen atom of the sulfonylurea bridge is monosubstituted rather than disubstituted. The structures of these compounds in complex with the catalytic subunit of Arabidopsis thaliana AHAS have been determined to 3.0 and 2.8 A, respectively. In both complexes, these molecules are bound in the tunnel leading to the active site, such that the sole substituent of the heterocyclic ring is buried deepest and oriented towards the ThDP. Unlike the structures of Arabidopsis thaliana AHAS in complex with the classic disubstituted sulfonylureas, where ThDP is broken, this cofactor is intact and present most likely as the hydroxylethyl intermediate.
Wang
Jian-Guo
JG
State Key Laboratory of Elemento-Organic Chemistry, National Pesticide Engineering Research Center, Nankai University, Tianjin, China.
Lee
Patrick K-M
PK
Dong
Yu-Hui
YH
Pang
Siew Siew
SS
Duggleby
Ronald G
RG
Li
Zheng-Ming
ZM
Guddat
Luke W
LW
D000095:Acetolactate Synthase / Q000737:chemistry* / Q000378:metabolism; D017360:Arabidopsis / Q000201:enzymology* / Q000378:metabolism; D029681:Arabidopsis Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D006540:Herbicides / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000737:chemistry* / Q000378:metabolism; D013835:Thiamine Pyrophosphate / Q000737:chemistry / Q000378:metabolism; D014227:Triazines / Q000737:chemistry / Q000378:metabolism
D029681:Arabidopsis Proteins; D006540:Herbicides; D013449:Sulfonamides; D013453:Sulfonylurea Compounds; D014227:Triazines; D000095:Acetolactate Synthase; C037137:chlorsulfuron; D013835:Thiamine Pyrophosphate