Global metabolic rewiring of the nonconventional yeast Ogataea polymorpha for biosynthesis of the sesquiterpenoid β-elemene

Bioproduction of natural products via microbial cell factories is a promising alternative to traditional plant extraction. Recently, nonconventional microorganisms have emerged as attractive chassis hosts for biomanufacturing. One such microorganism, Ogataea polymorpha is an industrial yeast used for protein expression with numerous advantages, such as thermal-tolerance, a wide substrate spectrum and high-density fermentation. Here, we systematically rewired the cellular metabolism of O. polymorpha to achieve high-level production of the sesquiterpenoid beta-elemene by optimizing the mevalonate pathway, enhancing the supply of NADPH and acetylCoA, and downregulating competitive pathways. The engineered strain produced 509 mg/L and 4.7 g/L of beta-elemene under batch and fed-batch fermentation, respectively. Therefore, this study identified the potential industrial application of O. polymorpha as a good microbial platform for producing sesquiterpenoids.

Automated summary

Bioproduction of natural products using microbial cell factories is a promising alternative to traditional plant extraction. In this study, the cellular metabolism of Ogataea polymorpha was rewired to achieve high-level production of the sesquiterpenoid beta-elemene. By optimizing the mevalonate pathway, enhancing the supply of NADPH and acetylCoA, and downregulating competitive pathways, the engineered strain produced significant amounts of beta-elemene. This research highlights the potential industrial application of O. polymorpha as a microbial platform for producing sesquiterpenoids.