Orthogonal monoterpenoid biosynthesis in yeast constructed on an isomeric substrate

Codruta Ignea, Morten H. Raadam, Mohammed S. Motawia, Antonios M. Makris, Claudia E. Vickers and Sotirios C. Kampranis ()
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Codruta Ignea: University of Copenhagen
Morten H. Raadam: University of Copenhagen
Mohammed S. Motawia: University of Copenhagen
Antonios M. Makris: Institute of Applied Biosciences – Centre for Research and Technology Hellas (INAB-CERTH)
Claudia E. Vickers: University of Queensland
Sotirios C. Kampranis: University of Copenhagen

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11290-x

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