Expanding the Terpene Universe: Synthetic Biology and Non-Natural Chemistry in Engineered Microorganisms.

Terpenes, representing one of the most extensive classes of natural products, hold significant value in the fields of pharmaceuticals, fragrances, and biofuels. Extracting these compounds from natural sources is often environmentally unsustainable, and the structural diversity found in nature is inherently limited. Metabolic engineering using microbial hosts offers a scalable and sustainable alternative, utilizing optimized biosynthetic pathways-such as the mevalonate (MVA) and the methylerythritol phosphate (MEP) pathways-to achieve high-yield production of natural terpene scaffolds. This review focuses on the various strategies in developing microbial cell factories, ranging from enhancing precursor supply to optimizing terpene synthase systems. A new and promising frontier is the increase in structural diversity of terpenes by integration of non-biological chemical transformations into engineered biosynthetic pathways. We discuss the use of artificial metalloenzymes such as engineered cytochrome P450 variants that catalyze non-natural carbene transfer reactions (cyclopropanation). The merging of synthetic biology and synthetic chemistry goes beyond the normal synthesizing capabilities found in nature, which may pave the way for the design of "non-natural" terpenoids that contain new additions and better capabilities.