Total enzymatic synthesis of cis-α-irone from a simple carbon source

Xixian Chen (), Rehka T, Jérémy Esque, Congqiang Zhang, Sudha Shukal, Chin Chin Lim, Leonard Ong, Derek Smith and Isabelle André ()
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Xixian Chen: Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A*STAR), Singapore. 31 Biopolis Way, Level 6 Nanos building
Rehka T: Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A*STAR), Singapore. 31 Biopolis Way, Level 6 Nanos building
Jérémy Esque: Toulouse Biotechnology Institute, TBI, Université de Toulouse, CNRS, INRAE, INSA, Toulouse, France. 135
Congqiang Zhang: Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A*STAR), Singapore. 31 Biopolis Way, Level 6 Nanos building
Sudha Shukal: Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A*STAR), Singapore. 31 Biopolis Way, Level 6 Nanos building
Chin Chin Lim: Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A*STAR), Singapore. 31 Biopolis Way, Level 6 Nanos building
Leonard Ong: Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A*STAR), Singapore. 31 Biopolis Way, Level 6 Nanos building
Derek Smith: Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A*STAR), Singapore. 31 Biopolis Way, Level 6 Nanos building
Isabelle André: Toulouse Biotechnology Institute, TBI, Université de Toulouse, CNRS, INRAE, INSA, Toulouse, France. 135

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract Metabolic engineering has become an attractive method for the efficient production of natural products. However, one important pre-requisite is to establish the biosynthetic pathways. Many commercially interesting molecules cannot be biosynthesized as their native biochemical pathways are not fully elucidated. Cis-α-irone, a top-end perfumery molecule, is an example. Retrobiosynthetic pathway design by employing promiscuous enzymes provides an alternative solution to this challenge. In this work, we design a synthetic pathway to produce cis-α-irone with a promiscuous methyltransferase (pMT). Using structure-guided enzyme engineering strategies, we improve pMT activity and specificity towards cis-α-irone by >10,000-fold and >1000-fold, respectively. By incorporating the optimized methyltransferase into our engineered microbial cells, ~86 mg l−1 cis-α-irone is produced from glucose in a 5 l bioreactor. Our work illustrates that integrated retrobiosynthetic pathway design and enzyme engineering can offer opportunities to expand the scope of natural molecules that can be biosynthesized.

Date: 2022
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DOI: 10.1038/s41467-022-35232-2

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