Production of the sesquiterpene bisabolene from one-carbon compounds in an engineered Methanosarcina acetivorans

The isoprenoid bisabolene, one of the simplest monocyclic sesquiterpenes, is a natural plant product that, in addition to its biological function, serves as a precursor for many industrial products. Due to the low concentration of bisabolene and the long harvest cycle, industrial production of this isoprenoid in plants is economically challenging. Chemical synthesis of bisabolene also suffers from significant disadvantages, such as low yields, toxic side products and high costs. Archaea appear suitable producers of isoprenoids, as their membrane lipids consist of isoprenoid ethers, which are synthesized via a variant of the mevalonate pathway. Archaeal model species have versatile metabolic capacities, which makes them suitable candidates for biotechnological applications. Here, we engineered Methanosarcina acetivorans for production of -bisabolene from one-carbon substrates by introducing a bisabolene synthase from Abies grandis. Expression of a codon-optimized bisabolene synthase gene in a M. acetivorans wild-type strain resulted in 10.6 mg bisabolene/liter of culture. Overexpressing genes of the mevalonate pathway only slightly increased bisabolene yields, which, however, were reached much earlier during incubations than in the corresponding wild-type strain. The data presented argue for the suitability of M. acetivorans for the biotechnical production of certain isoprenoids.