Microbial Production of Lutein

Escherichia coli was metabolically engineered to produce lutein with high productivity. This is important as lutein is used to protect the eyes from oxidative damage caused by radiation and reduces the risk of macular degeneration and cataracts.

Article | Spring 2023

Lutein is classified as a xanthophyll chemical that is abundant in egg yolk, fruits, and vegetables. It protects the eyes from oxidative damage caused by radiation and reduces the risk of eye diseases including macular degeneration and cataracts. Commercialized products featuring lutein are derived from the extracts of the marigold flower, which is known to harbor abundant amounts of lutein. However, the drawback of lutein production from nature is that it takes a long time to grow and harvest marigold flowers. Furthermore, it requires additional physical and chemical-based extractions with a low yield, which makes it economically unfeasible in terms of productivity. The quality of lutein, the high cost, and the low yield of these bioprocesses have made it difficult to readily meet the demand for lutein.

These challenges inspired the metabolic engineers at KAIST, including researchers Dr. Seon Young Park, Ph.D. Candidate Hyunmin Eun, and Distinguished Professor Sang Yup Lee from the Department of Chemical and Biomolecular Engineering. The team’s study entitled “Metabolic engineering of Escherichia coli with electron channeling for the production of natural products” was published in Nature Catalysis on August 4^th, 2022.

This study details the ability to produce lutein from E. coli with a high yield using a cheap carbon source, glycerol, via systems metabolic engineering. The research group focused on solving the bottlenecks of the biosynthetic pathway for lutein production constructed within an individual cell. Initially, using systems metabolic engineering, which is an integrated technology to engineer the metabolism of a microorganism, lutein was produced when the lutein biosynthesis pathway was introduced, albeit in very small amounts.

To improve the productivity of lutein production, the bottleneck enzymes within the metabolic pathway were first identified. It was revealed that metabolic reactions that involve a promiscuous enzyme, an enzyme that is involved in two or more metabolic reactions, and electron-requiring cytochrome P450 enzymes are the main bottleneck steps of the pathway inhibiting lutein biosynthesis.

To overcome these challenges, substrate channeling, a strategy to artificially recruit enzymes in physical proximity within the cell in order to increase the local concentrations of substrates that can be converted into products, was employed. Using this strategy helped to channel more metabolic flux towards the target chemical while reducing the formation of unwanted byproducts as shown in Figure 1.

 

Dr. Seon Young Park stated “It is expected that this microbial cell factory-based production of lutein will be able to replace the current plant extraction-based process.” She explained that another important point of the research is that integrated metabolic engineering strategies developed from this study can be generally applied to make production process efficient of other natural products that may be useful in pharmaceuticals or nutraceuticals.

“As maintaining good health in an aging society is becoming increasingly important, we expect that the technology and strategies developed here will play pivotal roles in producing other valuable natural products of medical or nutritional importance,” explained Distinguished Professor Sang Yup Lee.