Modern agricultural practices rely on herbicides to reduce yield losses.Herbicide-resistant weeds threaten herbicide utility and,hence,food security.New herbicide modes of action and integrated pest-management practic...Modern agricultural practices rely on herbicides to reduce yield losses.Herbicide-resistant weeds threaten herbicide utility and,hence,food security.New herbicide modes of action and integrated pest-management practices are vital to mitigate this threat.As the antimalarials that target the bifunctional enzyme dihydrofolate reductase–thymidylate synthase(DHFR-TS)have been shown to be herbicidal,DHFR-TS might represent a mode-of-action target for the development of herbicides.Here,we present the crystal structure of a DHFR-TS(AtDHFR-TS1)from the model dicot Arabidopsis thaliana.It shows a divergent DHFR active site and a linker domain that challenges previous classifications of bifunctional DHFR-TS proteins.This plant-conserved architecture enabled us to develop highly selective herbicidal inhibitors of AtDHFR-TS1 over human DHFR and identify inhibitors with unique scaffolds via a large-library virtual screen.These results suggest that DHFR-TS is a viable herbicide target.展开更多
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supported in part by Oracle Cloud credits and related resources provided by the Oracle for Research programsupported by an Australian Research Council Discovery Project to J.S.M.,K.A.S.,and J.H.(DP190101048)+1 种基金an Australian Research Council Discovery Early Career Researcher award to J.H.(DE180101445)an Australian Research Council Linkage Infrastructure,Equipment and Facilities grant to C.S.B.and J.S.M.(LE230100156).
文摘Modern agricultural practices rely on herbicides to reduce yield losses.Herbicide-resistant weeds threaten herbicide utility and,hence,food security.New herbicide modes of action and integrated pest-management practices are vital to mitigate this threat.As the antimalarials that target the bifunctional enzyme dihydrofolate reductase–thymidylate synthase(DHFR-TS)have been shown to be herbicidal,DHFR-TS might represent a mode-of-action target for the development of herbicides.Here,we present the crystal structure of a DHFR-TS(AtDHFR-TS1)from the model dicot Arabidopsis thaliana.It shows a divergent DHFR active site and a linker domain that challenges previous classifications of bifunctional DHFR-TS proteins.This plant-conserved architecture enabled us to develop highly selective herbicidal inhibitors of AtDHFR-TS1 over human DHFR and identify inhibitors with unique scaffolds via a large-library virtual screen.These results suggest that DHFR-TS is a viable herbicide target.
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.
