Properties and functions of farnesyl diphosphate synthase paralogs in the Lepidoptera

传统的化学杀虫剂往往对包括人类在内的非目标生物产生有害影响。因此，限制它们在林业和农业中的使用的压力越来越大。目前为发现更安全的替代品而实施的策略之一是开发能够破坏特定昆虫群体的生化过程的分子，因为这些分子不太可能对非目标生物产生严重的负面影响。然而，在开发这些分子之前，必须首先确定可被致命破坏的生理和生化过程，并发展对潜在机制的全面了解，包括将被破坏的目标蛋白质（通常是酶或受体）的表征。目前的研究重点是一种酶（法尼酯二磷酸合成酶或FPPS），它在几个生理过程中起着关键作用，包括调节昆虫的变态和繁殖。因此，这种酶对“幼体激素”（JH）的合成至关重要，JH是一种控制昆虫形态发生和卵子成熟的萜类化合物。JH生物合成是一个合适的破坏目标，因为它的抑制对这两个过程有深远的影响。在一组被称为鳞翅目的昆虫（毛虫、飞蛾、蝴蝶）中，我们分离出了两种截然不同的fpps，它们表现出与其他“传统”形式的这种酶不同的特征。因此，有可能开发出鳞翅目FPPSs特异性抑制剂（即对其他生物体中的相应酶没有或几乎没有影响）。然而，我们必须首先更好地了解这两种fpps是如何相互作用的，确定它们在JH生物合成和其他生理过程中的各自作用，并了解它们独特的结构特征，以便我们能够设计针对它们的抑制剂。这些抑制剂可以形成新的鳞翅目特异性杀虫剂的基础。

Conventional chemical insecticides tend to have detrimental impacts on non-target organisms, including humans. For this reason, there is increasing pressure to limit their use in forestry and agriculture. One of the strategies currently implemented for the discovery of safer alternatives involves the development of molecules that disrupt biochemical processes that are specific to a group of insects, because such molecules are unlikely to have serious negative effects on non-target organisms. Before developing these molecules, however, one must first identify physiological and biochemical processes that are amenable to being fatally disrupted, and develop a thorough knowledge of the underlying mechanisms, including a characterization of the proteins (typically enzymes or receptors) that will be targeted for disruption. The present research focuses on an enzyme (farnesyl diphosphate synthase or FPPS) that plays a critical role in several physiological processes, including the regulation of metamorphosis and reproduction in insects. As such, this enzyme is essential to the synthesis of "juvenile hormone" (JH), a terpenoid compound that controls insect morphogenesis and egg maturation. JH biosynthesis is an appropriate target for disruption because its inhibition has profound effects on these two processes. In a group of insects known as the Lepidoptera (caterpillars, moths, butterflies), we have isolated two very distinct FPPSs, exhibiting features that set them apart from other, "conventional" forms of this enzyme. For this reason, the development of inhibitors that are specific to lepidopteran FPPSs (i.e., with no or little effect on the corresponding enzyme in other organisms) appears possible. However, we must first acquire a better understanding of how these two FPPSs interact with one another, identify their respective roles in JH biosynthesis and other physiological processes, and develop knowledge about their unique structural features, so that we can design inhibitors that are specific to them. Such inhibitors could form the basis of novel, lepidoptera-specific insecticides.