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，环境友好型害虫防治产品的有前途的途径。其中一种激素“幼体激素”（JH）在昆虫的发育和繁殖中起着关键作用。在幼虫发育过程中抑制其生物合成可以触发过早的（通常是致命的）转化为成虫形式（即变态），而在成虫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的昆虫特异性酶以及其他几种酶，这些酶在其他生物体中参与产生常见的代谢物，如胆固醇。在后一组酶中，我们发现了一种具有鳞翅目昆虫（毛虫、飞蛾、蝴蝶）特有特征的酶。这种鳞翅目酶，法尼酯二磷酸合成酶（FPPS），对乙基取代底物表现出选择性，乙基取代底物是这些昆虫中发现的不寻常的JHs分子的前体；鳞翅目JHs与其他分类群的不同之处在于，它们的碳骨架具有在该科相关化合物中很少见到的乙基分支。拟开展的研究重点是对该酶的鳞翅目版本进行表征，包括(i)鉴定其活性形式，（ii）研究其在JH生物合成和其他代谢途径中的精确作用，以及（iii）鉴定赋予同源底物选择性的结构特征。通过这项研究产生的知识有望为合理设计专门针对鳞翅目的FPPS抑制剂铺平道路；这些化合物可以成为新型的、针对特定目标的害虫防治产品的基础。

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.