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Edited by Jens Nielsen, BioInnovation Institute, Copenhagen, Denmark, and approved November 9, 2020 (received for review July 3, 2020)
Significance
Monoterpenoids, monoterpene indole alkaloids, and cannabinoids are highly valued for their fragrant and therapeutic properties, but sourcing them from nature or deriving them from petrochemicals is no longer sustainable. However, sustainable production of these compounds in engineered microorganisms is mostly hampered by the limited availability of the main building block in their biosynthesis, geranyl diphosphate. Here, we overcome this challenge by engineering yeast peroxisomes as geranyl diphosphate-synthesizing microfactories and unlock the potential of yeast to produce a wide range of high-value isoprenoids. Conceptually, in this work we develop peroxisomes as synthetic biology devices that can be used for the modular assembly and optimization of complex pathways, adding an extra level of hierarchical abstraction in the systematic engineering of cell factories.
Abstract
Current approaches for the production of high-value compounds in microorganisms mostly use the cytosol as a general reaction vessel. However, competing pathways and metabolic cross-talk frequently prevent efficient synthesis of target compounds in the cytosol. Eukaryotic cells control the complexity of their metabolism by harnessing organelles to insulate biochemical pathways. Inspired by this concept, herein we transform yeast peroxisomes into microfactories for geranyl diphosphate-derived compounds, focusing on monoterpenoids, monoterpene indole alkaloids, and cannabinoids. We introduce a complete mevalonate pathway in the peroxisome to convert acetyl-CoA to several commercially important monoterpenes and achieve up to 125-fold increase over cytosolic production. Furthermore, peroxisomal production improves subsequent decoration by cytochrome P450s, supporting efficient conversion of (S)-(-)-limonene to the menthol precursor trans-isopiperitenol. We also establish synthesis of 8-hydroxygeraniol, the precursor of monoterpene indole alkaloids, and cannabigerolic acid, the cannabinoid precursor. Our findings establish peroxisomal engineering as an efficient strategy for the production of isoprenoids.
Footnotes
↵1Present address: Department of Bioengineering, McGill University, Montreal, QC H3A 0E9, Canada.
- ↵2To whom correspondence may be addressed. Email: soka{at}plen.ku.dk.
Author contributions: S.D., C.I., and S.C.K. designed research; S.D., W.T.W., and Y.L. performed research; S.D., W.T.W., and S.C.K. analyzed data; and S.D. and S.C.K. wrote the paper.
Competing interest statement: S.D., W.T.W., C.I., and S.C.K. are coinventors in a patent application describing the production of geranyl diphosphate-derived compounds using the yeast peroxisomes.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2013968117/-/DCSupplemental.
Data Availability.
All study data are included in the article and supporting information.
Published under the PNAS license.
References
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Transforming yeast peroxisomes into microfactories for the efficient production of high-value isoprenoids
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- Applied Biological Sciences
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