Journal
NATURE CHEMICAL BIOLOGY
Volume 11, Issue 7, Pages 465-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.1816
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Funding
- US Department of Energy Office of Science Early Career Research Program (Office of Biological and Environmental Research) [DE-SC0008084]
- US National Science Foundation
- US Department of Defense
- Genome Canada
- Genome Quebec
- Canada Research Chair
- U.S. Department of Energy (DOE) [DE-SC0008084] Funding Source: U.S. Department of Energy (DOE)
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Benzylisoquinoline alkaloids (BIAs) are a diverse family of plant-specialized metabolites that include the pharmaceuticals codeine and morphine and their derivatives. Microbial synthesis of BIAs holds promise as an alternative to traditional crop-based manufacturing. Here we demonstrate the production of the key BIA intermediate (S)-reticuline from glucose in Saccharomyces cerevisiae. To aid in this effort, we developed an enzyme-coupled biosensor for the upstream intermediate L-3,4-dihydroxyphenylalanine (L-DOPA). Using this sensor, we identified an active tyrosine hydroxylase and improved its L-DOPA yields by 2.8-fold via PCR mutagenesis. Coexpression of DOPA decarboxylase enabled what is to our knowledge the first demonstration of dopamine production from glucose in yeast, with a 7.4-fold improvement in titer obtained for our best mutant enzyme. We extended this pathway to fully reconstitute the seven-enzyme pathway from L-tyrosine to (S)-reticuline. Future work to improve titers and connect these steps with downstream pathway branches, already demonstrated in S. cerevisiae, will enable low-cost production of many high-value BIAs.
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