Tailor-Made Terpenoids: Exploring and Exploiting Natures Magic Methyl Effect

Objective

TAILOMET will explore and exploit the hidden magic methyl effect in nature to develop genetically programmable biocatalytic systems for the production of tailor-made terpenoids. Given the immense pharmaceutical and industrial importance of terpene natural products, methodologies for strategic structure modifications to fine-tune physicochemical properties are of vast interest. Introduction of a single methyl group can have dramatic impact on a drug lead’s potency, selectivity, or pharmacokinetics, and can alter olfactory reception of aroma compounds. The influence of methylations on the bioactivity of terpenes has, however, never been systematically investigated due to the limited availability of suitable methodologies to introduce such structural modifications into terpene scaffolds. Our recent discovery on a novel general pathway to homoterpenes, together with bioinformatic analyses indicates widespread interkingdom occurrence of terpene C-methylations in nature. The findings suggest a readily available and vast treasure trove for the discovery of novel enzymology to develop biocatalytic systems for selective methyl installation into terpene backbones. By exploration, exploitation, and re-design of these naturally available enzymes, TAILOMET will develop a comprehensive toolbox to close current knowledge gaps and unlock rapid access to terpenoids with fine-tuned or even novel properties. Besides synthetic advancements, comprehensive insights into the biological function of terpene methylations in nature might shed novel lights on intra- and interspecies communication with potentially valuable implications for chemical ecology and natural product discovery.