Enzymatic adaptations for the biosynthesis of ethyl-substituted juvenile hormones

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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.