Orthogonal monoterpenoid biosynthesis in yeast constructed on an isomeric substrate
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Raadam, Morten H
Motawia, Mohammed S
Makris, Antonios M
Vickers, Claudia E
Kampranis, Sotirios C
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Abstract
Synthetic biology efforts for the production of valuable chemicals are frequently hindered by the structure and regulation of the native metabolic pathways of the chassis. This is particularly evident in the case of monoterpenoid production in Saccharomyces cerevisiae, where the canonical terpene precursor geranyl diphosphate is tightly coupled to the biosynthesis of isoprenoid compounds essential for yeast viability. Here, we establish a synthetic orthogonal monoterpenoid pathway based on an alternative precursor, neryl diphosphate. We identify structural determinants of isomeric substrate selectivity in monoterpene synthases and engineer five different enzymes to accept the alternative substrate with improved efficiency and specificity. We combine the engineered enzymes with dynamic regulation of metabolic flux to harness the potential of the orthogonal substrate and improve the production of industrially-relevant monoterpenes by several-fold compared to the canonical pathway. This approach highlights the introduction of synthetic metabolism as an effective strategy for high-value compound production.
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Nature Communications
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10
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© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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Biochemistry and cell biology
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
DYNAMIC PATHWAY REGULATION
FUNCTIONAL EXPRESSION
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Ignea, C; Raadam, MH; Motawia, MS; Makris, AM; Vickers, CE; Kampranis, SC, Orthogonal monoterpenoid biosynthesis in yeast constructed on an isomeric substrate, Nature Communications, 2019, 10, pp. 3799