Engineering acetyl-CoA supply and ERG9 repression to enhance mevalonate production in Saccharomyces cerevisiae.

TitleEngineering acetyl-CoA supply and ERG9 repression to enhance mevalonate production in Saccharomyces cerevisiae.
Publication TypeJournal Article
Year of Publication2021
AuthorsWegner, SA, Chen, J-M, Ip, SS, Zhang, Y, Dugar, D, Avalos, JL
JournalJ Ind Microbiol Biotechnol
Date Published2021 Dec 23
KeywordsAcetate-CoA Ligase, Acetyl Coenzyme A, Enterococcus faecalis, Metabolic Engineering, Mevalonic Acid, Microorganisms, Genetically-Modified, Saccharomyces cerevisiae, Salmonella enterica

<p>Mevalonate is a key precursor in isoprenoid biosynthesis and a promising commodity chemical. Although mevalonate is a native metabolite in Saccharomyces cerevisiae, its production is challenged by the relatively low flux toward acetyl-CoA in this yeast. In this study we explore different approaches to increase acetyl-CoA supply in S. cerevisiae to boost mevalonate production. Stable integration of a feedback-insensitive acetyl-CoA synthetase (Se-acsL641P) from Salmonella enterica and the mevalonate pathway from Enterococcus faecalis results in the production of 1,390 ± 10 mg/l of mevalonate from glucose. While bifid shunt enzymes failed to improve titers in high-producing strains, inhibition of squalene synthase (ERG9) results in a significant enhancement. Finally, increasing coenzyme A (CoA) biosynthesis by overexpression of pantothenate kinase (CAB1) and pantothenate supplementation further increased production to 3,830 ± 120 mg/l. Using strains that combine these strategies in lab-scale bioreactors results in the production of 13.3 ± 0.5 g/l, which is ∼360-fold higher than previously reported mevalonate titers in yeast. This study demonstrates the feasibility of engineering S. cerevisiae for high-level mevalonate production.</p>

Alternate JournalJ Ind Microbiol Biotechnol
PubMed ID34351398
PubMed Central IDPMC8788843
Grant List / / Alfred P. Sloan Foundation /
CBET-1751840 / / National Science Foundation /