Herbicides are vital formodern agriculture,but their utility is threatened by genetic or metabolic resistance in weeds,as well as regulatory barriers.Of the known herbicide modes of action,7,8-dihydropterin synthase(D...Herbicides are vital formodern agriculture,but their utility is threatened by genetic or metabolic resistance in weeds,as well as regulatory barriers.Of the known herbicide modes of action,7,8-dihydropterin synthase(DHPS),which is involved in folate biosynthesis,is targeted by just one commercial herbicide,asulam.A mimic of the substrate para-aminobenzoic acid,asulam is chemically similar to sulfonamide antibiotics,and although it is still in widespread use,asulam has faced regulatory scrutiny.With an entire mode of action represented by just one commercial agrochemical,we sought to improve the understanding of its plant target.Here we solve a 2.3A°resolution crystal structure for Arabidopsis thaliana DHPS that is conjoined to 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase(HPPK),and we reveal a strong structural conservation with bacterial counterparts at the sulfonamide-bindingpocket of DHPS.We demonstrate that asulamand the antibiotic sulfamethoxazole have herbicidal as well as antibacterial activity,andwe explore the structural basis of their potency by modeling these compounds in mitochondrial HPPK/DHPS.Our findings suggest limited opportunity for the rational design of plant selectivity fromasulamand indicate that pharmacokinetic or delivery differences between plants andmicrobesmight be the bestways to safeguard thismode of action.展开更多
基金K.V.S.was supported by the Australian Research Training Program scholarshipG.V.supported by Australian Research Council grant DP190101048 to J.S.M.,K.A.S.,J.H.,who was also supported by an ARC Discovery Early Career Researcher Award(grant no.DE180101445).
文摘Herbicides are vital formodern agriculture,but their utility is threatened by genetic or metabolic resistance in weeds,as well as regulatory barriers.Of the known herbicide modes of action,7,8-dihydropterin synthase(DHPS),which is involved in folate biosynthesis,is targeted by just one commercial herbicide,asulam.A mimic of the substrate para-aminobenzoic acid,asulam is chemically similar to sulfonamide antibiotics,and although it is still in widespread use,asulam has faced regulatory scrutiny.With an entire mode of action represented by just one commercial agrochemical,we sought to improve the understanding of its plant target.Here we solve a 2.3A°resolution crystal structure for Arabidopsis thaliana DHPS that is conjoined to 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase(HPPK),and we reveal a strong structural conservation with bacterial counterparts at the sulfonamide-bindingpocket of DHPS.We demonstrate that asulamand the antibiotic sulfamethoxazole have herbicidal as well as antibacterial activity,andwe explore the structural basis of their potency by modeling these compounds in mitochondrial HPPK/DHPS.Our findings suggest limited opportunity for the rational design of plant selectivity fromasulamand indicate that pharmacokinetic or delivery differences between plants andmicrobesmight be the bestways to safeguard thismode of action.
