Protein engineering strategies for microbial production of isoprenoids

• Published in: Metabolic engineering communications Vol. 11; p. e00129
• Main Authors: Daletos, Georgios, Stephanopoulos, Gregory
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2020; Elsevier
• Subjects: Activity; Enzyme engineering; Isoprenoids; Microbial hosts; Promiscuity; Selectivity; Special issue on The Natural Product Issue edited by Greg Stephanopoulos, Anthony Sinskey and Kang Zhou; Microbial hosts; Activity; Selectivity; Enzyme engineering; Promiscuity; Isoprenoids
• ISSN: 2214-0301; 2214-0301
• DOI: 10.1016/j.mec.2020.e00129

Isoprenoids comprise one of the most chemically diverse family of natural products with high commercial interest. The structural diversity of isoprenoids is mainly due to the modular activity of three distinct classes of enzymes, including prenyl diphosphate synthases, terpene synthases, and cytochrome P450s. The heterologous expression of these enzymes in microbial systems is suggested to be a promising sustainable way for the production of isoprenoids. Several limitations are associated with native enzymes, such as low stability, activity, and expression profiles. To address these challenges, protein engineering has been applied to improve the catalytic activity, selectivity, and substrate turnover of enzymes. In addition, the natural promiscuity and modular fashion of isoprenoid enzymes render them excellent targets for combinatorial studies and the production of new-to-nature metabolites. In this review, we discuss key individual and multienzyme level strategies for the successful implementation of enzyme engineering towards efficient microbial production of high-value isoprenoids. Challenges and future directions of protein engineering as a complementary strategy to metabolic engineering are likewise outlined. •Isoprenoid enzymes are attractive biocatalysts for protein engineering.•Isoprenoid enzymes can be engineered for broader substrate promiscuity.•Protein engineering can lead to the production of non-natural isoprenoids.•Protein engineering can promote co-localization of isoprenoid pathway enzymes.•Protein engineering supplements combinatorial biosynthesis for isoprenoid synthesis.