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High-titer production of lathyrane diterpenoids from sugar by engineered Saccharomyces cerevisiae

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  • Jeff Wong
  • Tristan de Rond
  • Leo d'Espaux
  • Cas van der Horst
  • Ishaan Dev
  • Leonardo Rios-Solis
  • James Kirby
  • Henrik Scheller
  • Jay Keasling

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Original languageEnglish
Article number45
Pages (from-to)142-148
Number of pages7
JournalMetabolic engineering
Volume45
Issue number 1096-7176
Early online date14 Dec 2017
DOIs
Publication statusPublished - Jan 2018

Abstract

Euphorbiaceae are an important source of medically important diterpenoids, such as the anticancer drug ingenol-3-angelate and the antiretroviral drug prostratin. However, extraction from the genetically intractable natural producers is often limited by the small quantities produced, while the organic synthesis of terpene-derived drugs is challenging and similarly low-yielding. While transplanting the biosynthetic pathway into a heterologous host has proven successful for some drugs, it has been largely unsuccessful for diterpenoids due to their elaborate biosynthetic pathways and lack of genetic resources and tools for gene discovery. We engineered casbene precursor production in S. cerevisiae, verified the ability of six Euphorbia lathyris and Jatropha curcas cytochrome P450s to oxidize casbene, and optimized the expression of these P450s and an alcohol dehydrogenase to generate jolkinol C, achieving ~800mg/L of jolkinol C and over 1g/L total oxidized casbanes in millititer plates, the highest titer of oxidized diterpenes in yeast reported to date. This strain enables the semisynthesis of biologically active jolkinol C derivatives and will be an important tool in the elucidation of the biosynthetic pathways for ingenanes, tiglianes, and lathyranes. These findings demonstrate the ability of S. cerevisiae to produce oxidized drug precursors in quantities that are sufficient for drug development and pathway discovery.

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