Abstract
Terpenoids are the largest and structurally most diverse class of natural products. They possess potent and specific biological activity in multiple assays and against diseases, including cancer and malaria as notable examples. Although the number of characterized terpenoid molecules is huge, our knowledge of how they are biosynthesized is limited, particularly when compared to the well-studied thiotemplate assembly lines. Bacteria have only recently been recognized as having the genetic potential to biosynthesize a large number of complex terpenoids, but our current ability to associate genetic potential with molecular structure is severely restricted. The canonical terpene biosynthetic pathway uses a single enzyme to form a cyclized hydrocarbon backbone followed by modifications with a suite of tailoring enzymes that can generate dozens of different products from a single backbone. This functional promiscuity of terpene biosynthetic pathways renders terpene biosynthesis susceptible to rational pathway engineering using the latest developments in the field of synthetic biology. These engineered pathways will not only facilitate the rational creation of both known and novel terpenoids, their development will deepen our understanding of a significant branch of biosynthesis. The biosynthetic insights gained will likely empower a greater degree of engineering proficiency for non-natural terpene biosynthetic pathways and pave the way towards the biotechnological production of high value terpenoids.
Highlights
Evolutionary diversification of terpene biosynthetic pathways has resulted in the largest and most structurally diverse class of specialized metabolites on the planet
The structural diversity and functional utility of this class of specialized metabolites have combined to encourage efforts to apply the tools of synthetic biology to engineer pathways that will expand molecular diversity, especially around scaffolds associated with high-value compounds
Despite the ubiquitous distribution of terpene biosynthetic pathways in bacteria, only a few terpenes of bacterial origin have been characterized, and their biosynthesis is for the most part poorly understood
Summary
Evolutionary diversification of terpene biosynthetic pathways has resulted in the largest and most structurally diverse class of specialized metabolites on the planet. As a result, producing and “screening” a large number of specialized metabolites for potent TCs that can generate multiple products from simple building blocks is a huge evolutionary advantage; even more so when combined with tailoring enzymes that have a broad substrate tolerance and catalyze multiple, sequential tailoring reactions [40] This diversification process resembles the strategy embedded in the construction of combinatorial libraries by organic chemists to generate chemical diversity. Plex terpenoids, 2) the lack of genome mining platforms for terpene biosynthetic gene clusters and the inability to perform rational structure predictions based on genome sequence information, and 3) low production titers of bacterial terpenoids under standard laboratory conditions These factors, in combination with general terpene properties such as lack of UV-absorbing functional groups, poor ionization properties, and ubiquitous odiferous terpenes that overshadow characteristic terpene signals (branching methyl groups) in NMR experiments, render the targeted isolation of terpenes highly challenging. The comparatively small number of characterized bacterial terpenes can likely be attributed to three factors: 1) the early misconception that bacteria are not capable of producing com-
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