德国慕尼黑工业大学Groll, Michael团队报道了金属依赖性酶对称性引导萜烯前体的生物合成通量。相关研究成果发表在2023年6月12日出版的《自然—化学》。

萜类化合物占所有天然产物的60%以上，其碳骨架来源于常见的不同长度的类异戊二烯单元，如香叶基焦磷酸和法尼基焦磷酸。

该文中，研究人员通过结构和功能分析表征了叶甲Phaedon cochleae中的一种金属依赖性双功能异戊二烯基二磷酸合成酶。同源二聚体中的分子间和分子内协同作用强烈依赖于所提供的金属离子，并调节萜烯前体的生物合成流量，以进行生物防御或生理发育。引人注目的是，一个独特的链长决定结构域通过改变酶的对称性和两个亚基之间的配体亲和力来形成香叶基或法尼基焦磷酸。此外，还鉴定了一个变构香叶基焦磷酸特异性结合位点，该位点与人法尼基焦磷酸合成酶的最终产物抑制相似。

研究的综合发现阐明了P.cochleae异戊二烯基二磷酸合酶中一种深度交织的反应机制，该机制整合了底物、产物和金属离子浓度，以利用其动态潜力。叶甲Phaedon cochleae的金属依赖性双功能异戊二烯基二磷酸合酶PcIDS1整合了底物、产物和金属离子浓度，以调节其动态反应性。现在，结构和功能分析表明，这种酶利用两个催化中心形成香叶基焦磷酸，而一个结构域在法尼基焦磷酸的生产过程中失活。

附：英文原文

Title: Metal-dependent enzyme symmetry guides the biosynthetic flux of terpene precursors

Author: Ecker, Felix, Vattekkatte, Abith, Boland, Wilhelm, Groll, Michael

Issue&Volume: 2023-06-12

Abstract: Terpenoids account for more than 60% of all natural products, and their carbon skeletons originate from common isoprenoid units of different lengths such as geranyl pyrophosphate and farnesyl pyrophosphate. Here we characterize a metal-dependent, bifunctional isoprenyl diphosphate synthase from the leaf beetle Phaedon cochleariae by structural and functional analyses. Inter- and intramolecular cooperative effects in the homodimer strongly depend on the provided metal ions and regulate the biosynthetic flux of terpene precursors to either biological defence or physiological development. Strikingly, a unique chain length determination domain adapts to form geranyl or farnesyl pyrophosphate by altering enzyme symmetry and ligand affinity between both subunits. In addition, we identify an allosteric geranyl-pyrophosphate-specific binding site that shares similarity with end-product inhibition in human farnesyl pyrophosphate synthase. Our combined findings elucidate a deeply intertwined reaction mechanism in the P. cochleariae isoprenyl diphosphate synthase that integrates substrate, product and metal-ion concentrations to harness its dynamic potential. The metal-dependent, bifunctional isoprenyl diphosphate synthase PcIDS1 from the leaf beetle Phaedon cochleariae integrates substrate, product and metal-ion concentrations to tune its dynamic reactivity. Now structural and functional analyses reveal that this enzyme uses both catalytic centres to form geranyl pyrophosphate, while one domain is inactivated during farnesyl pyrophosphate production.

DOI: 10.1038/s41557-023-01235-9

Source: https://www.nature.com/articles/s41557-023-01235-9