Enzymatic adaptations for the biosynthesis of ethyl-substituted juvenile hormones

长期以来，激素功能的中断一直被视为开发针对昆虫的、环境友好的虫害防治产品的一条很有前途的途径。其中一种名为“保幼激素”(JH)的荷尔蒙在昆虫的发育和繁殖中起着至关重要的作用。在幼虫发育期间抑制其生物合成可引发过早--通常是致命的--向成虫形式的转变(即变态)，而成虫的类似抑制可抑制生殖。JH是一种萜类化合物，其生物合成涉及一些后期昆虫特有的酶以及其他几种酶，在其他生物中，这些酶参与产生常见代谢物，如胆固醇。在后一组酶中，我们发现了一种明显具有鳞翅目昆虫(毛虫、蛾、蝴蝶)特有特征的酶。鳞翅目昆虫的这种酶，法尼基二磷酸合成酶(FPPS)，对乙基取代底物具有选择性，乙基取代底物是在这些昆虫中发现的不寻常的JHS分子的前体；鳞翅目JHS与其他类群中观察到的不同之处在于，它们的碳骨架上有乙基分支，在这一家族的相关化合物中很少见。建议的研究重点是该酶的鳞翅目版本的特征，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精确作用的研究，以及(Iii)给予同源底物选择性的结构特征的鉴定。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；这种化合物可能形成新的、靶标特定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.