Construction of a synthetic metabolic pathway for biosynthesis of the non-natural methionine precursor 2,4-dihydroxybutyric acid

Thomas Walther, Christopher M. Topham, Romain Irague, Clément Auriol, Audrey Baylac, Hélène Cordier, Clémentine Dressaire, Luce Lozano-Huguet, Nathalie Tarrat, Nelly Martineau, Marion Stodel, Yannick Malbert, Marc Maestracci, Robert Huet, Isabelle André, Magali Remaud-Siméon and Jean Marie François ()
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Thomas Walther: LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France
Christopher M. Topham: LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France
Romain Irague: LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France
Clément Auriol: LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France
Audrey Baylac: LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France
Hélène Cordier: TWB
Clémentine Dressaire: LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France
Luce Lozano-Huguet: LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France
Nathalie Tarrat: LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France
Nelly Martineau: LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France
Marion Stodel: LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France
Yannick Malbert: LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France
Marc Maestracci: Adisseo SA, Antony Parc II
Robert Huet: Adisseo SA, Antony Parc II
Isabelle André: LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France
Magali Remaud-Siméon: LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France
Jean Marie François: LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract 2,4-Dihydroxybutyric acid (DHB) is a molecule with considerable potential as a versatile chemical synthon. Notably, it may serve as a precursor for chemical synthesis of the methionine analogue 2-hydroxy-4-(methylthio)butyrate, thus, targeting a considerable market in animal nutrition. However, no natural metabolic pathway exists for the biosynthesis of DHB. Here we have therefore conceived a three-step metabolic pathway for the synthesis of DHB starting from the natural metabolite malate. The pathway employs previously unreported malate kinase, malate semialdehyde dehydrogenase and malate semialdehyde reductase activities. The kinase and semialdehyde dehydrogenase activities were obtained by rational design based on structural and mechanistic knowledge of candidate enzymes acting on sterically cognate substrates. Malate semialdehyde reductase activity was identified from an initial screening of several natural enzymes, and was further improved by rational design. The pathway was expressed in a minimally engineered Escherichia coli strain and produces 1.8 g l−1 DHB with a molar yield of 0.15.

Date: 2017
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DOI: 10.1038/ncomms15828

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