title: Comprehensive understanding of acetohydroxyacid synthase inhibition by different herbicide families.
abstract: Five commercial herbicide families inhibit acetohydroxyacid synthase (AHAS, E.C. 2.2.1.6), which is the first enzyme in the branched-chain amino acid biosynthesis pathway. The popularity of these herbicides is due to their low application rates, high crop vs. weed selectivity, and low toxicity in animals. Here, we have determined the crystal structures ofArabidopsis thalianaAHAS in complex with two members of the pyrimidinyl-benzoate (PYB) and two members of the sulfonylamino-carbonyl-triazolinone (SCT) herbicide families, revealing the structural basis for their inhibitory activity. Bispyribac, a member of the PYBs, possesses three aromatic rings and these adopt a twisted "S"-shaped conformation when bound toA. thalianaAHAS (AtAHAS) with the pyrimidinyl group inserted deepest into the herbicide binding site. The SCTs bind such that the triazolinone ring is inserted deepest into the herbicide binding site. Both compound classes fill the channel that leads to the active site, thus preventing substrate binding. The crystal structures and mass spectrometry also show that when these herbicides bind, thiamine diphosphate (ThDP) is modified. When the PYBs bind, the thiazolium ring is cleaved, but when the SCTs bind, ThDP is modified to thiamine 2-thiazolone diphosphate. Kinetic studies show that these compounds not only trigger reversible accumulative inhibition of AHAS, but also can induce inhibition linked with ThDP degradation. Here, we describe the features that contribute to the extraordinarily powerful herbicidal activity exhibited by four classes of AHAS inhibitors.
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, QLD, Australia.
authors.forename: Mario D
authors.identifier: 0000-0001-8378-7475
authors.initials: MD
authors.lastname: Garcia
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, QLD, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Nouwens
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, QLD, Australia.
authors.forename: Thierry G
authors.initials: TG
authors.lastname: Lonhienne
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, QLD, Australia luke.guddat@uq.edu.au.
authors.forename: Luke W
authors.initials: LW
authors.lastname: Guddat
mesh_terms: D000095:Acetolactate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D029681:Arabidopsis Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006540:Herbicides / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D013453:Sulfonylurea Compounds / Q000737:chemistry / Q000494:pharmacology; D013835:Thiamine Pyrophosphate / Q000378:metabolism; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D029681:Arabidopsis Proteins; D001565:Benzoates; D006540:Herbicides; D007093:Imidazoles; D011743:Pyrimidines; D011804:Quinolines; D013453:Sulfonylurea Compounds; D013876:Thiophenes; D014230:Triazoles; C471815:propoxycarbazone; C401888:pyrithiobac sodium; C057728:imazaquin; C549011:bispyribac; C112343:chlorimuron ethyl; D000095:Acetolactate Synthase; D013835:Thiamine Pyrophosphate
keywords: ThDP; acetohydroxyacid synthase; acetolactate synthase; crystal structure; herbicide