Crystal structure of Arabidopsis thaliana HPPK/DHPS, a bifunctional enzyme and target of the herbicide asulam

Grishma Vadlamani; Kirill V Sukhoverkov; Joel Haywood; Karen J Breese; Mark F Fisher; Keith A Stubbs; Charles S Bond; Joshua S Mylne

doi:10.1016/j.xplc.2022.100322

Crystal structure of Arabidopsis thaliana HPPK/DHPS, a bifunctional enzyme and target of the herbicide asulam

Plant Commun. 2022 Jul 11;3(4):100322. doi: 10.1016/j.xplc.2022.100322. Epub 2022 Apr 9.

Authors

Grishma Vadlamani¹, Kirill V Sukhoverkov², Joel Haywood¹, Karen J Breese³, Mark F Fisher⁴, Keith A Stubbs³, Charles S Bond³, Joshua S Mylne⁵

Affiliations

¹ School of Molecular Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia; The ARC Centre of Excellence in Plant Energy Biology, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia; Centre for Crop and Disease Management, School of Molecular and Life Sciences, Curtin University, Bentley, WA 6102, Australia.
² School of Molecular Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia; The ARC Centre of Excellence in Plant Energy Biology, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia.
³ School of Molecular Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia.
⁴ Centre for Crop and Disease Management, School of Molecular and Life Sciences, Curtin University, Bentley, WA 6102, Australia.
⁵ School of Molecular Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia; The ARC Centre of Excellence in Plant Energy Biology, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia; Centre for Crop and Disease Management, School of Molecular and Life Sciences, Curtin University, Bentley, WA 6102, Australia. Electronic address: josh.mylne@curtin.edu.au.

Abstract

Herbicides are vital for modern 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 2.3 Å 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-binding pocket of DHPS. We demonstrate that asulam and the antibiotic sulfamethoxazole have herbicidal as well as antibacterial activity, and we 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 from asulam and indicate that pharmacokinetic or delivery differences between plants and microbes might be the best ways to safeguard this mode of action.

Keywords: folate metabolism; mode of action; structural biology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / metabolism
Arabidopsis* / genetics
Arabidopsis* / metabolism
Carbamates
Dihydropteroate Synthase / chemistry
Dihydropteroate Synthase / genetics
Dihydropteroate Synthase / metabolism
Herbicides* / pharmacology
Sulfonamides / chemistry

Substances

Anti-Bacterial Agents
Carbamates
Herbicides
Sulfonamides
asulam
Dihydropteroate Synthase