title: A pathogenic fungi diphenyl ether phytotoxin targets plant enoyl (acyl carrier protein) reductase.
abstract: Cyperin is a natural diphenyl ether phytotoxin produced by several fungal plant pathogens. At high concentrations, this metabolite inhibits protoporphyrinogen oxidase, a key enzyme in porphyrin synthesis. However, unlike its herbicide structural analogs, the mode of action of cyperin is not light dependent, causing loss of membrane integrity in the dark. We report that this natural diphenyl ether inhibits Arabidopsis (Arabidopsis thaliana) enoyl (acyl carrier protein) reductase (ENR). This enzyme is also sensitive to triclosan, a synthetic antimicrobial diphenyl ether. Whereas cyperin was much less potent than triclosan on this target site, their ability to cause light-independent disruption of membrane integrity and inhibition of ENR is similar at their respective phytotoxic concentrations. The sequence of ENR is highly conserved within higher plants and a homology model of Arabidopsis ENR was derived from the crystal structure of the protein from Brassica napus. Cyperin mimicked the binding of triclosan in the binding pocket of ENR. Both molecules were stabilized by the pi-pi stacking interaction between one of their phenyl rings and the nicotinamide ring of the NAD(+). Furthermore, the side chain of tyrosine is involved in hydrogen bonding with a phenolic hydroxy group of cyperin. Therefore, cyperin may contribute to the virulence of the pathogens by inhibiting ENR and destabilizing the membrane integrity of the cells surrounding the point of infection.
authors.affiliation: Natural Products Utilization Research Unit, U.S. Department of Agriculture, Agricultural Research Services, University, Mississippi 38677, USA. franck.dayan@ars.usda.gov
authors.forename: Franck E
authors.initials: FE
authors.lastname: Dayan
authors.forename: Daneel
authors.initials: D
authors.lastname: Ferreira
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Wang
authors.forename: Ikhlas A
authors.initials: IA
authors.lastname: Khan
authors.forename: John A
authors.initials: JA
authors.lastname: McInroy
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Pan
mesh_terms: D017360:Arabidopsis / Q000187:drug effects* / Q000201:enzymology; D020134:Catalytic Domain; D003408:Cresols / Q000494:pharmacology*; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors*; D054872:Fatty Acid Synthesis Inhibitors / Q000494:pharmacology*; D006540:Herbicides / Q000494:pharmacology; D008958:Models, Molecular; D009183:Mycotoxins / Q000494:pharmacology*; D010647:Phenyl Ethers / Q000494:pharmacology*; D014260:Triclosan / Q000494:pharmacology*
chemical_list: D003408:Cresols; D054872:Fatty Acid Synthesis Inhibitors; D006540:Herbicides; D009183:Mycotoxins; D010647:Phenyl Ethers; C531339:cyperin; D014260:Triclosan; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)