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Orthogonal monoterpenoid biosynthesis in yeast constructed on an isomeric substrate
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Journal Article
Orthogonal monoterpenoid biosynthesis in yeast constructed on an isomeric substrate
2019
Overview
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.
Titers of monoterpenoids production in yeast are low due to the fact that the geranyl diphosphate (GPP)-based pathway can redirect metabolic fluxes to growth. Here, the authors build an orthogonal pathway by selecting the
cis
isomer of GPP as an alternative precursor and achieve high titer monoterpene production.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 82/29
/ 82/58
/ 82/80
/ 82/83
/ Biosynthetic Pathways - genetics
/ Chassis
/ Enzymes
/ Humanities and Social Sciences
/ Intramolecular Lyases - genetics
/ Intramolecular Lyases - metabolism
/ Polyisoprenyl Phosphates - metabolism
/ Saccharomyces cerevisiae - enzymology
/ Saccharomyces cerevisiae - genetics
/ Saccharomyces cerevisiae Proteins - genetics
/ Saccharomyces cerevisiae Proteins - metabolism
/ Science
/ Substrate Specificity - genetics
/ Yeast
