Diversifying Isoprenoid Platforms via Atypical Carbon Substrates and Non-model Microorganisms

Abstract

Isoprenoid compounds are biologically ubiquitous, and their characteristic modularity has afforded products ranging from pharmaceuticals to biofuels. Isoprenoid production has been largely successful in Escherichia coli and Saccharomyces cerevisiae with metabolic engineering of the mevalonate (MVA) and methylerythritol phosphate (MEP) pathways coupled with the expression of heterologous terpene synthases. Yet conventional microbial chassis pose several major obstacles to successful commercialization including the affordability of sugar substrates at scale, precursor flux limitations, and intermediate feedback-inhibition. Now, recent studies have challenged typical isoprenoid paradigms by expanding the boundaries of terpene biosynthesis and using non-model organisms including those capable of metabolizing atypical C1 substrates. Conversely, investigations of non-model organisms have historically informed optimization in conventional microbes by tuning heterologous gene expression. Here, we review advances in isoprenoid biosynthesis with specific focus on the synergy between model and non-model organisms that may elevate the commercial viability of isoprenoid platforms by addressing the dichotomy between high titer production and inexpensive substrates.

Farnesyl pyrophosphate compartmentalization in the green microalga Chlamydomonas reinhardtii during heterologous (E)-α-bisabolene production

“…Engineering fermentative heterotrophs for isoprenoid production has developed into a mature technology, relying on high growth rates of these organisms on sugar or other organic carbon substrates to very high cell densities. Unconventional host organisms like eukaryotic green algae can offer several advantages to their fermentative counterparts [ 4 ] including a high basal turnover of precursors, consumption of inexpensive waste CO 2 as a carbon substrate, and the high similarity of their metabolic structure and intracellular environments to plants [ 5 ]. In microalgae, metabolic precursors of cytosolic C 15 farnesyl pyrophosphate and plastidic C 5 as well as C 20 geranylgeranyl pyrophosphate have been demonstrated to be freely available for conversion to heterologous terpenoid products by expression and localization of heterologous terpene synthases to respective cellular compartments [ 6 – 8 ].…”

Recent Advances on Key Enzymes of Microbial Origin in the Lycopene Biosynthesis Pathway

“…15,36,128 Similarly, Deinococcus radiodurans also has a strong carbon flux in the carotenoid biosynthesis pathway and an abundant intracellular NAD(P)H pool. 50,129 In addition, Pseudomonas putida is capable of tolerating high concentrations of isoprenoids, 130,131 while the photosynthetic bacterium Rhodobacter sphaeroides has an abundant membrane system. 51,132 Finally, at the level of spatial organization, several forms of scaffolds such as DNA origami, RNA scaffolds, and lipid droplets can be designed and introduced to balance the expression of multiple enzymes and optimize metabolic pathways, as well as explore multienzyme assembly strategies that can be applied to other complex metabolic pathways.…”

Antioxidant Potential and Capacity of Microorganism-Sourced C30 Carotenoids—A Review

“…Like most carotenoids, the isoprene units that comprise C 30 carotenoids are constructed from the isopentyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) precursors from the mevalonate (MVA) pathway in plants and microalgae ( Figure 1 ), and the methylerythritol phosphate (MEP) pathway in bacteria and fungi ( Figure 2 ) [ 18 ]. The biosynthesis of C 30 carotenoids occurs via either the condensation of two C 15 farnesyl diphosphate (FPP) molecules, or the condensation of C 10 geranyl diphosphate (GPP) and C 20 geranylgeranyl diphosphate (GGPP).…”