Metabolic engineering of Yarrowia lipolytica for high‑level polyketide production

Background

The field of biotechnology has seen significant advancements in the use of genetically modified organisms to produce valuable compounds. Polyketides, a diverse class of secondary metabolites, are of particular interest due to their wide-ranging applications in pharmaceuticals, bioactive compounds, and renewable chemicals. Traditional methods of producing polyketides involve extraction from plants and microorganisms, which often results in low yields and high costs. The use of genetically modified oleaginous yeast, such as Yarrowia lipolytica, offers a promising alternative due to their ability to be engineered for high production levels of these compounds. The need for efficient and scalable production methods is driven by the increasing demand for renewable and sustainable sources of chemicals and pharmaceuticals.

Current approaches to polyketide production face several challenges. Traditional chemical synthesis methods are often inefficient and struggle with the complexity of polyketide structures, especially those with challenging chiral centers. Natural producers of polyketides, such as certain plants and bacteria, typically yield low concentrations, making industrial-scale production impractical. While some progress has been made using industrial yeast strains like Saccharomyces cerevisiae, the yields remain insufficient for large-scale applications. Additionally, the use of arable land for plant-based production is not feasible for meeting global demands. These limitations highlight the need for improved genetic and metabolic engineering strategies to enhance the production capabilities of microbial hosts like Yarrowia lipolytica, which can potentially overcome these bottlenecks and achieve commercially viable production levels.

Technology description

This technology leverages genetically modified oleaginous yeast strains, particularly Yarrowia lipolytica, to produce Type III polyketides such as triacetic acid lactone (TAL) at industrially relevant levels. The yeast cells are engineered to express heterologous genes encoding Type III polyketide synthases from various sources, including plants like Gerbera hybrida and bacteria such as Streptomyces griseus. Key genetic modifications involve integrating multiple copies of polyketide synthase genes into the yeast genome and overexpressing genes that increase the availability of essential precursors like acetyl-CoA and malonyl-CoA. Additional modifications include enhancing beta-oxidation pathways and reducing or eliminating genes that divert carbon flux away from polyketide synthesis. The production process involves culturing these engineered yeast cells in growth media with specific carbon sources, such as glucose, and isolating the desired polyketides. This method provides a scalable approach to producing high yields of polyketides, which have applications in pharmaceuticals, bioactive compounds, and renewable chemicals.

The differentiation of this technology lies in its ability to produce high titers of polyketides using a renewable, microbial-based method. Traditional methods of polyketide production often involve complex chemical synthesis or extraction from plants, which are not scalable for industrial applications due to low yields and high costs. By genetically modifying Yarrowia lipolytica, this technology harnesses the yeast's natural lipid metabolism to redirect precursor molecules toward polyketide synthesis. The use of oleaginous yeast enables the accumulation of significant amounts of acetyl-CoA and malonyl-CoA, essential building blocks for polyketides, thereby achieving production levels that exceed those of previous recombinant organisms. This innovative approach not only enhances the efficiency and scalability of polyketide production but also opens up new possibilities for using these compounds as chemical feedstocks in various industries, including pharmaceuticals and material sciences.

Benefits

Scalable production method for high yields of polyketides
Applications in pharmaceuticals, bioactive compounds, and renewable chemicals
Use of genetically modified oleaginous yeast strains like Yarrowia lipolytica
Integration of polyketide synthase genes to enhance production
Overexpression of genes to increase acetyl-CoA and malonyl-CoA availability
Elimination or reduction of genes that divert carbon flux away from polyketide synthesis
Production of polyketides at industrially relevant levels
Potential for renewable sorbic acid production from triacetic acid lactone (TAL)
Enabling technology for the use of polyketides in chemical and material science industries
Production of diverse polyketide structures with various useful properties