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US 12,385,005 B2Granted
Compositions and methods for improved malonyl-CoA biosynthesis using 2-stage dynamic metabolic control
AssigneeDuke University
InventorsMichael Lynch, Jeovanna Rios
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Abstract
Methods and microorganisms for improved malonyl-CoA flux and production of products having malonyl-CoA as a precursor. The methods comprise dynamically regulating, in a stationary phase of a method, a nitrogen regulatory protein. The methods may dynamically regulate more than one gene.
Claims9
A genetically modified microorganism comprising:
- a first synthetic metabolic valve for dynamic and selective regulation of a nitrogen regulatory protein (glnB), the synthetic metabolic valve comprising:
- gene expression-silencing of a glnB gene,
- selective enzymatic degradation of a glnB protein, or
- a combination thereof,
- wherein the synthetic metabolic valve is selectively activated to silence a glnB gene and/or degrade a glnB protein in response to depletion of phosphate as a limiting nutrient in the growth media in which the genetically modified microorganism is growing.
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A bioprocess for production of a product from a genetically modified microorganism, the bioprocess comprising:
- (a) providing a genetically modified microorganism comprising:
- (i) a production pathway for a product, the production pathway having malonyl-CoA as a biosynthetic precursor of the product;
- (ii) a synthetic metabolic valve for dynamic and selective regulation of a nitrogen regulatory protein (glnB), the synthetic metabolic valve comprising:
- gene expression-silencing of a glnB gene,
- selective enzymatic degradation of a glnB protein, or
- a combination thereof;
- and
- (iii) an additional synthetic metabolic valve(s) for dynamic and selective regulation of one or more genes in addition to the glnB gene;
- or
- a selective enzymatic degradation of one or more proteins in addition to the glnB protein;
- (b) growing the genetically modified microorganism in a media;
- (c) transitioning from microorganism growth to stationary productive phase, the transition comprising:
- (i) reducing or stopping genetically modified microorganism growth at least partially by controlled depletion of phosphate as a limiting nutrient from the media
- (ii) activation of synthetic metabolic valves
- (iii) increasing the available malonyl-CoA pool;
- (d) producing a product in the stationary productive phase.
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Dependencies are inferred from the claim text.