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Asymmetric assembly of aldose carbohydrates from formaldehyde and glycolaldehyde by tandem biocatalytic aldol reactions

Nature Chemistry volume 7, pages 724–729 (2015)Cite this article

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Abstract

The preparation of multifunctional chiral molecules can be greatly simplified by adopting a route via the sequential catalytic assembly of achiral building blocks. The catalytic aldol assembly of prebiotic compounds into stereodefined pentoses and hexoses is an as yet unmet challenge. Such a process would be of remarkable synthetic utility and highly significant with regard to the origin of life. Pursuing an expedient enzymatic approach, here we use engineered D-fructose-6-phosphate aldolase from Escherichia coli to prepare a series of three- to six-carbon aldoses by sequential one-pot additions of glycolaldehyde. Notably, the pertinent selection of the aldolase variant provides control of the sugar size. The stereochemical outcome of the addition was also altered to allow the synthesis of L-glucose and related derivatives. Such engineered biocatalysts may offer new routes for the straightforward synthesis of natural molecules and their analogues that circumvent the intricate enzymatic pathways forged by evolution.

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Figure 1: Bottom-up synthesis of hexoses from achiral starting materials via chemical or biocatalytic routes.
Figure 2: Time progression curves for the enzymatic synthesis of L-xylose (3b) and D-idose (3a).
Figure 3: Molecular models of FSA-bound intermediates during formation of D-idose (3a) catalysed by FSA A129T/A165G.

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Acknowledgements

This work was supported by Spanish MINECO grants CTQ2012-31605 and CTQ2012-32436, the Generalitat de Catalunya (2009 SGR 00281), ERA-IB MICINN, PIM2010EEI-00607 (EIB.10.012. MicroTechEnz-EIB, www.fkit.unizg.hr/miten) and COST Action CM1303 Systems Biocatalysis. A.S. acknowledges the CSIC for a JAE predoctoral contract programme.

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Author notes

  1. Anna Szekrenyi & Xavier Garrabou

    Present address: Present addresses: Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt, Alarich-Weiss-Strasse 4, 64287 Darmstadt, Germany (A.S.); Laboratory of Organic Chemistry, HCI F322, ETH Hönggerberg, 8093 Zurich, Switzerland (X.G.),

Authors and Affiliations

  1. Biotransformation and Bioactive Molecules Group, Instituto de Química Avanzada de Cataluña, IQAC-CSIC, Jordi Girona 18-26, Barcelona, 08034, Spain

    Anna Szekrenyi, Xavier Garrabou, Jesús Joglar, Jordi Bujons & Pere Clapés

  2. Depatment Química. Servei de Ressonància Magnètica Nuclear, Universitat Autònoma de Barcelona, Bellaterra, Spain

    Teodor Parella

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  1. Anna Szekrenyi
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Contributions

P.C. and X.G. designed the study. A.S. and X.G. performed mutagenesis, library screening, activity measurements and synthesis of the compounds. J.B. performed the molecular docking experiments and designed the mutations. T.P. performed and supervised the NMR experiments and structural assignation of compounds. J.J., J.B. and P.C. supervised the scientific work. All authors contributed to writing the paper.

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Correspondence to Pere Clapés.

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The authors declare no competing financial interests.

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Szekrenyi, A., Garrabou, X., Parella, T. et al. Asymmetric assembly of aldose carbohydrates from formaldehyde and glycolaldehyde by tandem biocatalytic aldol reactions. Nature Chem 7, 724–729 (2015). https://doi.org/10.1038/nchem.2321

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