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Here we report a systematic approach to sequentially identify the rate-limiting steps and improve the biosynthesis of the cannabinoid precursor olivetolic acid (OLA) in\n                    <jats:italic>Yarrowia lipolytica<\/jats:italic>\n                    . We find that\n                    <jats:italic>Pseudomonas sp<\/jats:italic>\n                    LvaE encoding a short-chain acyl-CoA synthetase can efficiently convert hexanoic acid to hexanoyl-CoA. The co-expression of the acetyl-CoA carboxylase, the pyruvate dehydrogenase bypass, the NADPH-generating malic enzyme, as well as the activation of peroxisomal \u03b2-oxidation pathway and ATP export pathway are effective strategies to redirect carbon flux toward OLA synthesis. Implementation of these strategies led to an 83-fold increase in OLA titer, reaching 9.18\u2009mg\/L of OLA in shake flask culture. This work may serve as a baseline for engineering cannabinoids biosynthesis in oleaginous yeast species.\n                  <\/jats:p>","DOI":"10.1038\/s42003-022-04202-1","type":"journal-article","created":{"date-parts":[[2022,11,12]],"date-time":"2022-11-12T11:02:28Z","timestamp":1668250948000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Biosynthesis of cannabinoid precursor olivetolic acid in genetically engineered Yarrowia lipolytica"],"prefix":"10.1038","volume":"5","author":[{"given":"Jingbo","family":"Ma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0999-8546","authenticated-orcid":false,"given":"Peng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,12]]},"reference":[{"key":"4202_CR1","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1111\/j.1365-2826.2008.01671.x","volume":"20","author":"K Mackie","year":"2008","unstructured":"Mackie, K. 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