Enzymatic adaptations for the biosynthesis of ethyl-substituted juvenile hormones

长期以来，激素功能的破坏一直被视为开发昆虫特异性、环境友好型害虫控制产品的有希望的途径。保幼激素（juvenile hormone，JH）在昆虫的发育和繁殖中起着重要作用。在幼虫发育过程中抑制其生物合成可引发过早-并且通常是致命的-转化为成虫形式（即，变态），而在成年人中类似的抑制可以抑制繁殖。JH是一种萜类化合物，其生物合成涉及一些后期步骤，昆虫特异性酶以及其他几种酶，在其他生物体中，这些酶参与产生常见的代谢物，如胆固醇。在后一组酶中，我们确定了一种酶，它显示出一组被称为鳞翅目（毛虫，飞蛾，蝴蝶）的昆虫所特有的特征。这种鳞翅目酶，法呢基二磷酸合酶（FPPS），显示选择性乙基取代的底物，这是不寻常的JHS分子在这些昆虫中发现的前体;鳞翅目JHS不同于其他类群中观察到的，他们的碳骨架带有乙基分支很少看到这个家庭的相关化合物。拟议的研究重点是这种酶的鳞翅目版本的表征，包括（i）其活性形式的鉴定，（ii）其在JH生物合成和其他代谢途径中的确切作用的研究，以及（iii）赋予同源底物的选择性的结构特征的鉴定。通过这项研究产生的知识，预计将铺平道路的FPPS抑制剂，专门针对鳞翅目昆虫的合理设计，这些化合物可以形成新的，目标特定的害虫控制产品的基础。

The disruption of hormone functions has long been viewed as a promising avenue for the development of insect-specific, environmentally friendly pest control products. One such hormone, "juvenile hormone" (JH), plays critical roles in insect development and reproduction. Inhibition of its biosynthesis during larval development can trigger the premature - and typically fatal - transformation into the adult form (i.e., metamorphosis), while a similar inhibition in adults can suppress reproduction. JH is a terpenoid compound whose biosynthesis involves some late-step, insect-specific enzymes as well as several other enzymes that, in other organisms, are involved in the production of common metabolites such as cholesterol. Among the latter group of enzymes, we identified one that displays features apparently unique to a group of insects known as the Lepidoptera (caterpillars, moths, butterflies). This lepidopteran enzyme, farnesyl diphosphate synthase (FPPS), displays selectivity for ethyl-substituted substrates, which are the precursors of the unusual JHs molecules found in these insects; the lepidopeteran JHs differ from those observed in other taxa in that their carbon skeletons bear ethyl branches rarely seen in related compounds of this family. The proposed research focuses on the characterization of the lepidopteran version of this enzyme, including (i) the identification of its active form, (ii) the study of its precise roles in JH biosynthesis and other metabolic pathways, and (iii) the identification of the structural features that confer selectivity for homologous substrates. The knowledge generated through this research is expected to pave the way to the rational design of FPPS inhibitors that specifically target the Lepidoptera; such compounds could form the basis of novel, target-specific pest control products.