Journal
NATURE BIOTECHNOLOGY
Volume 27, Issue 8, Pages 753-U107Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nbt.1557
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Funding
- UC Berkeley
- QB3 Institute
- National Science Foundation (NSF)
- Synthetic Biology Engineering Research Center [EEC-0540879]
- NSF [CBET-0756801]
- Bill and Melinda Gates Foundation
- Joint BioEnergy Institute
- Office of Naval Research Young Investigator Program [N000140510656]
- Directorate For Engineering [0756801] Funding Source: National Science Foundation
- Div Of Chem, Bioeng, Env, & Transp Sys [0756801] Funding Source: National Science Foundation
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Engineered metabolic pathways constructed from enzymes heterologous to the production host often suffer from flux imbalances, as they typically lack the regulatory mechanisms characteristic of natural metabolism. In an attempt to increase the effective concentration of each component of a pathway of interest, we built synthetic protein scaffolds that spatially recruit metabolic enzymes in a designable manner. Scaffolds bearing interaction domains from metazoan signaling proteins specifically accrue pathway enzymes tagged with their cognate peptide ligands. The natural modularity of these domains enabled us to optimize the stoichiometry of three mevalonate biosynthetic enzymes recruited to a synthetic complex and thereby achieve 77-fold improvement in product titer with low enzyme expression and reduced metabolic load. One of the same scaffolds was used to triple the yield of glucaric acid, despite high titers (0.5 g/I) without the synthetic complex. These strategies should prove generalizeable to other metabolic pathways and programmable for fine-tuning pathway flux.
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