Methods for decoupling yield and productivity of a non-catabolic compound produced by a host cell
Inventors
CHUA, Penelope R. • LERMAN, Joshua Adam • SCHERBART, Thomas Jon • Thakker, Chandresh • Tsong, Annie Ening • Jiang, Hanxiao
Assignees
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Publication Number
US-12098407-B2
Publication Date
2024-09-24
Expiration Date
Abstract
Provided herein are compositions and methods for uncoupling the yield and productivity of an isoprenoid compound produced in a host cell. In some embodiments, the yield and productivity are uncoupled by genetically modifying the host cell to reduce flux through the citric acid cycle (TCA). In other embodiments, the yield and productivity are uncoupled by reducing the levels of ATP in the host cell.
Core Innovation
The invention relates to decoupling yield and productivity of an isoprenoid produced in a yeast cell capable of making the isoprenoid. The method comprises adding one or more ATP depleting agents to the yeast cell and reducing ATP levels during production of the isoprenoid.
A further aspect of the invention is that ATP levels can be lowered not only by adding ATP depleting agents such as weak organic acids, but also by genetic mechanisms that dissipate or uncouple ATP. The document describes ATP-diphosphohydrolase, NADH oxidase (NOX), alternative oxidase (AOX), and related mechanisms that reduce ATP levels during isoprenoid production.
Another aspect is to decouple yield and productivity by introducing futile cycles to reduce ATP levels, and by reducing carbon flux through the TCA cycle. The document describes futile-cycle approaches and reducing carbon flux through the citric acid cycle, including decreasing expression or activity of CIT1 and pyruvate carboxylase and citrate synthase, to lower ATP during isoprenoid production.
Claims Coverage
The provided independent claim set includes one independent claim. The claim coverage focuses on reducing ATP during isoprenoid production in a yeast cell by ATP depleting agents, with dependent refinements that specify genetic ATP dissipation or uncoupling, futile-cycle strategies, and routes that reduce carbon flux through the TCA cycle.
Adding ATP depleting agents to reduce ATP levels during isoprenoid production
A method of decoupling yield and productivity of an isoprenoid produced in a yeast cell capable of making the isoprenoid, comprising adding one or more ATP depleting agents to the yeast cell and reducing ATP levels during production of the isoprenoid.
Across the provided independent claim and its dependents, inventive coverage centers on decoupling yield and productivity by reducing ATP levels in the yeast cell during isoprenoid production, either via adding ATP depleting agents or via genetic and metabolic strategies that lower ATP.
Stated Advantages
Decoupling yield and productivity of an isoprenoid produced in a yeast cell.
Reducing rate-yield coupling by lowering ATP levels during isoprenoid production.
Documented Applications
Producing non-catabolic isoprenoids, including farnesene, in host cells such as yeast while decoupling yield and productivity.
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