The progress of the biosynthesis of vitamin E

Abstract

Vitamin E is a fat-soluble compound with powerful antioxidative and anticancer activity, which constitutes eight isoforms, namely α-, β-, γ-, δ-tocopherol and α-, β-, γ-, δ-tocotrienol. With the wide use of vitamin E in food, medicine, cosmetics and other fields, the demand of vitamin E in market is huge. Currently in the market, vitamin E is about 80% from chemical synthesis and 20% from extraction of oil distillates derived from plants or seeds. However, chemical synthesis of vitamin E suffered from the use of toxic catalysts, making the process environmentally unfriendly and unsustainable. In addition, the chemical synthesis technologies mainly synthesized the racemate of vitamin E and the enantiomerically pure vitamin E is mostly extracted from limited agricultural resources. Recently, using microorganisms to heterologously express metabolic pathways originated from plants is an attractive strategy due to the environmentally friendly, economic and easily scalable. Moreover, the progress of synthetic biology and metabolic engineering enabled the genetically tractable microorganisms such as Escherichia coli and Saccharomyces cerevisiae to successfully produce many natural compounds. As the natural pathways and related enzymes to synthesize vitamin E have been found in the last decades, it is feasible to engineer microorganisms to produce vitamin E. δ-tocotrienol, one isoform of vitamin E, was de novo heterologously synthesized in Escherichia coli and Saccharomyces cerevisiae with the production of 15 μg/(g cdw) and the titer of 4.10 mg/L (1.3 mg/(g cdw)), respectively. In this review, we firstly summarized the natural pathways and the recent progress on the enhanced biosynthesis of Vitamin E. Then the pathways and the recent advances on metabolically engineering strategies for the enhanced key intimidates (homogentisate and geranylgeranyl diphosphate) in industrial model microorganism was summarized. Specifically, we reviewed the advances on the shikimate pathway and the 2-C-methyl-d-erythritol-4-phosphate (MEP) and mevalonic acid (MVA) pathway in different chassis. Finally, we summarized the present situation and prospected the potential of biosynthesis of vitamin E in microorganisms. Based on the current researches on the improving production of vitamin E in microorganisms, in addition to enhance the supply of the precursors (homogentisate and geranylgeranyl diphosphate) by metabolic engineering, more attention needs to be paid to improve the enzyme activities of the key enzymes like homogentisate phytyl transferase (HPT) and tocopherol/tocotrienol cyclase (TC), which restricted the conversion rate of the precursors to the target product vitamin E. In the future, biotechnology such as genetic engineering, metabolic engineering and synthetic biology can be combined with the natural pathway of vitamin E to biosynthesize specific monomer or mixture of vitamin E in different model microorganisms. To further improve the production of vitamin E in the engineered microorganism, diverse genes and enzymes from multiple species involved in the biosynthesis of vitamin E needs to be characterized and functionalized. Enzyme engineering could also be used to improve the enzyme activities and consequently enhance the production of vitamin E.