One application of synthetic biology is the redesign of existing biological systems to acquire new functions. In this context, expanding the chemical code underlying key biosynthetic pathways will lead to the synthesis of compounds with new structures and potentially new biological activities. Terpenoids are a large group of specialized metabolites with numerous applications. Yet, being synthesized from five-carbon units, they are restricted to distinct classes that differ by five carbon atoms (C10, C15, C20, etc.). To expand the diversity of terpenoid structures, we engineered yeast cells to synthesize a noncanonical building block with 11 carbons, and produced 40 C11 terpene scaffolds that can form the basis for an entire terpenoid class. By identifying a single-residue switch that converts C10 plant monoterpene synthases to C11-specific enzymes, we engineered dedicated synthases for C11 terpene production. This approach will enable the systematic expansion of the chemical space accessed by terpenoids.
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We would like to thank D. Cane and W. Chou (Brown University, USA) for providing the bacterial construct pET28a(+)/PlGPPMT, C.E. Vickers (University of Queensland, Australia) for providing construct pCEV-G2-Ph/ClLimS, F. Geu-Flores (University of Copenhagen, Denmark) for critical reading of the manuscript, and M. Raadam for technical assistance. We are grateful to D.I. Pattison and E. Lazaridi from the PLEN metabolomics platform for their support. This work was supported by the Greek General Secretariat of Research and Technology (GSRT) grant 11ΣΥΝ_3_770 (to A.M.M. and S.C.K.) and the Novo Nordisk Foundation grants NNF16OC0019554 (to C.I.) and NNF16OC0021760 (to S.C.K.).
The authors declare no competing interests.
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Ignea, C., Pontini, M., Motawia, M.S. et al. Synthesis of 11-carbon terpenoids in yeast using protein and metabolic engineering. Nat Chem Biol 14, 1090–1098 (2018). https://doi.org/10.1038/s41589-018-0166-5
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