University of Oulu

Zavarise, A., Sridhar, S., Kiema, T.-R., Wierenga, R.K. and Widersten, M. (2023), Structures of lactaldehyde reductase, FucO, link enzyme activity to hydrogen bond networks and conformational dynamics. FEBS J, 290: 465-481.

Structures of lactaldehyde reductase, FucO, link enzyme activity to hydrogen bond networks and conformational dynamics

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Author: Zavarise, Alberto1; Sridhar, Shruthi1,2; Kiema, Tiila-Riikka2;
Organizations: 1Department of Chemistry – BMC, Uppsala University, Sweden
2Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.4 MB)
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Language: English
Published: John Wiley & Sons, 2023
Publish Date: 2023-08-25


A group-III iron containing 1,2-propanediol oxidoreductase, FucO, (also known as lactaldehyde reductase) from Escherichia coli was examined regarding its structure–dynamics–function relationships in the catalysis of the NADH-dependent reduction of (2S)-lactaldehyde. Crystal structures of FucO variants in the presence or absence of cofactors have been determined, illustrating large domain movements between the apo and holo enzyme structures. Different structures of FucO variants co-crystallized with NAD⁺ or NADH together with substrate further suggest dynamic properties of the nicotinamide moiety of the coenzyme that are important for the reaction mechanism. Modelling of the native substrate (2S)-lactaldehyde into the active site can explain the stereoselectivity exhibited by the enzyme, with a critical hydrogen bond interaction between the (2S)-hydroxyl and the side-chain of N151, as well as the previously experimentally demonstrated pro-(R) selectivity in hydride transfer from NADH to the aldehydic carbon. Furthermore, the deuterium kinetic isotope effect of hydride transfer suggests that reduction chemistry is the main rate-limiting step for turnover which is not the case in FucO catalysed alcohol oxidation. We further propose that a water molecule in the active site — hydrogen bonded to a conserved histidine (H267) and the 2′-hydroxyl of the coenzyme ribose — functions as a catalytic proton donor in the protonation of the product alcohol. A hydrogen bond network of water molecules and the side-chains of amino acid residues D360 and H267 links bulk solvent to this proposed catalytic water molecule.

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Series: FEBS journal
ISSN: 1742-464X
ISSN-E: 1742-4658
ISSN-L: 1742-464X
Volume: 290
Issue: 2
Pages: 465 - 481
DOI: 10.1111/febs.16603
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: This work was kindly supported by Foundation Olle Engkvist Byggmästare (MW, #194-0638).
Copyright information: © 2022 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.