Mechanism for the inhibition of the carboxyltransferase domain of acetyl-coenzyme A carboxylase by pinoxaden

Abstract

Acetyl-CoA carboxylases (ACCs) are crucial metabolic enzymes and have been targeted for drug development against obesity, diabetes, and other diseases. The carboxyltransferase (CT) domain of this enzyme is the site of action for three different classes of herbicides, as represented by haloxyfop, tepraloxydim, and pinoxaden. Our earlier studies have demonstrated that haloxyfop and tepraloxydim bind in the CT active site at the interface of its dimer. However, the two compounds probe distinct regions of the dimer interface, sharing primarily only two common anchoring points of interaction with the enzyme. We report here the crystal structure of the CT domain of yeast ACC in complex with pinoxaden at 2.8-Å resolution. Despite their chemical diversity, pinoxaden has a similar binding mode as tepraloxydim and requires a small conformational change in the dimer interface for binding. Crystal structures of the CT domain in complex with all three classes of herbicides confirm the importance of the two anchoring points for herbicide binding. The structures also provide a foundation for understanding the molecular basis of the herbicide resistance mutations and cross resistance among the herbicides, as well as for the design and development of new inhibitors against plant and human ACCs.fatty acid metabolism | metabolic syndrome | structure-based drug design

The enzymes of biotin dependent CO2 metabolism: What structures reveal about their reaction mechanisms

“…All of the herbicides bind in the active site at the interface between the N-terminal domain of one subunit and the C-terminal domain of a neighboring monomer, and all block the acetyl-CoA binding site. [79][80][81] Obstructing the acetyl-CoA binding site is consistent with the observed competitive inhibition versus the product malonyl-CoA. 72 Earlier kinetic analyses with the aryloxyphenoxypropionates and the cyclohexandiones showed noncompetitive inhibition with respect to acetyl-CoA.…”

“…The significance of this interaction is underscored by the fact that mutation of Leu 1705 is often observed in plants resistant to the herbicides. 81 In addition to serving as herbicide targets, acetyl-CoA carboxylase has recently been implicated in anti-obesity agents, and molecules that inhibit its carboxyltransferase component are being actively investigated. Humans, like plants, have two isoforms of acetyl-CoA carboxylase.…”

The cyclic keto-enol insecticide spirotetramat inhibits insect and spider mite acetyl-CoA carboxylases by interfering with the carboxyltransferase partial reaction

“…It is a well-established molecular target site for commercially successful herbicides, including the aryloxyphenoxypropionates (FOPs), the cyclohexanediones (DIMs), and the more recently introduced pinoxaden (Devine, 2002, Wenger et al, 2012. Localization of herbicide-resistant mutations as well as structural studies have shown that the herbicidal ACC inhibitor classes bind to the carboxyltransferase (CT) domain of the multidomain ACC isoform in the plastids of grasses (Yu et al, 2007;Liu et al, 2007;Kaundun et al, 2013;Yu et al, 2010).…”

“…The herbicidal FOPs, DIMs and phenylpyrazolines all bind to the CT domain (Delye et al, 2005;Kaundun, 2010;Yu et al, 2010). However, the myxobacterial polyketide soraphen A was reported as a nanomolar inhibitor of the biotin carboxylase (BC) domains of fungal ACCs (Weatherly et al, 2004), probably by interfering with BC dimerization (Tong, 2013).…”

Mechanism of Resistance to Glyphosate in Lolium perenne from Argentina

“…The activity of herbicide target enzymes at different herbicide concentrations has been used to determine if a target site mechanism provokes low sensitivity in resistant plants (Baerson et al, 2002;Burke et al, 2006;Yu et al, 2010;Cruz-Hipolito et al, 2011). Following this approach, glyphosate-susceptible and -resistant models of EPSPS activity showed no significant differences in half maximal inhibitory concentration (I50) ( Table 2).…”