Flavonoid-based inhibitors of the Phi-class glutathione transferase from black-grass to combat multiple herbicide resistance.
Flavonoid-based inhibitors of the Phi-class glutathione transferase from black-grass to combat multiple herbicide resistance.
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PHI级谷胱甘肽转移酶从黑草到对抗多种除草剂耐药性的基于类黄酮的抑制剂。
DOI：
10.1039/d1ob01802g
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发表时间：
2021-11-03
影响因子：
3.2
通讯作者：
Steel PG
中科院分区：
文献类型：
--
作者：
Schwarz M;Eno RFM;Freitag-Pohl S;Coxon CR;Straker HE;Wortley DJ;Hughes DJ;Mitchell G;Moore J;Cummins I;Onkokesung N;Brazier-Hicks M;Edwards R;Pohl E;Steel PG
禾本科杂草的多重除草剂抗性（MHR）的进化和发展继续威胁着全球谷物生产。虽然各种过程可以有助于抗性，但早期的工作已经确定phi类谷胱甘肽-S-转移酶（AmGSTF 1）作为黑草（大穗看麦娘）中MHR的功能性生物标志物。这项研究提供了进一步的见解AmGSTF 1在MHR中的作用，使用化学和结构生物学的组合。获得野生型AmGSTF 1的晶体结构，以及两种专门设计的变体，其允许与谷胱甘肽和AmGSTF 1抑制剂4-氯-7-硝基-苯并呋咱（NBD-Cl）的谷胱甘肽加合物测定共晶体结构。这些研究表明，NBD-Cl的抑制活性与活性位点的封闭和底物结合的障碍有关。寻找其他选择性抑制剂AmGSTF 1，使用配体捕捞实验，确定了一些黄酮类化合物作为潜在的配体。随后使用黑草提取物的实验发现了一种特定的类黄酮作为重组酶的天然配体。制备了一系列相关的合成黄酮类化合物，并研究了它们与AmGSTF 1的结合，显示出对带有O-5-癸基-α-羧酸酯的衍生物的高亲和力。基于高分辨率晶体结构的分子建模允许定义解释类黄酮结合特异性的结合姿势。重要的是，高结合亲和力与MHR黑草中除草剂抗性表型的逆转有关。总的来说，这些结果为开发除草剂增效剂以抵消杂草中的MHR提供了一个自然启发的新线索。自然启发的类黄酮衍生物结合AmGSTF 1，并克服多重除草剂抗性（MHR）黑草中的除草剂抗性。
The evolution and growth of multiple-herbicide resistance (MHR) in grass weeds continues to threaten global cereal production. While various processes can contribute to resistance, earlier work has identified the phi class glutathione-S-transferase (AmGSTF1) as a functional biomarker of MHR in black-grass (Alopecurus myosuroides). This study provides further insights into the role of AmGSTF1 in MHR using a combination of chemical and structural biology. Crystal structures of wild-type AmGSTF1, together with two specifically designed variants that allowed the co-crystal structure determination with glutathione and a glutathione adduct of the AmGSTF1 inhibitor 4-chloro-7-nitro-benzofurazan (NBD-Cl) were obtained. These studies demonstrated that the inhibitory activity of NBD-Cl was associated with the occlusion of the active site and the impediment of substrate binding. A search for other selective inhibitors of AmGSTF1, using ligand-fishing experiments, identified a number of flavonoids as potential ligands. Subsequent experiments using black-grass extracts discovered a specific flavonoid as a natural ligand of the recombinant enzyme. A series of related synthetic flavonoids was prepared and their binding to AmGSTF1 was investigated showing a high affinity for derivatives bearing a O-5-decyl-α-carboxylate. Molecular modelling based on high-resolution crystal structures allowed a binding pose to be defined which explained flavonoid binding specificity. Crucially, high binding affinity was linked to a reversal of the herbicide resistance phenotype in MHR black-grass. Collectively, these results present a nature-inspired new lead for the development of herbicide synergists to counteract MHR in weeds. Nature inspired flavonoid derivatives bind to AmGSTF1 and overcome herbicide resistance in multiple herbicide resistant (MHR) Black Grass.
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影响因子：
5.6
作者：
Chen J;Yu Q;Patterson E;Sayer C;Powles S
通讯作者：
Powles S
影响因子：
5.6
作者：
Franco-Ortega S;Goldberg-Cavalleri A;Walker A;Brazier-Hicks M;Onkokesung N;Edwards R
通讯作者：
Edwards R
影响因子：
2
作者：
Cavaliere, C;Foglia, P;Laganà, A
通讯作者：
Laganà, A
DOI：
10.1199/tab.0131
发表时间：
2010-01-01
期刊：
The arabidopsis book
影响因子：
--
作者：
Dixon, David P;Edwards, Robert
通讯作者：
Edwards, Robert
影响因子：
7.4
作者：
Clark, SM;Konermann, L
通讯作者：
Konermann, L