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Revealing reaction intermediates in one-carbon elongation by thiamine diphosphate/CoA-dependent enzyme family

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Nattermann,  Maren
Cellular Operating Systems, Department of Biochemistry and Synthetic Metabolism, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

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Wichmann,  Philipp
Cellular Operating Systems, Department of Biochemistry and Synthetic Metabolism, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

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Marchal,  Daniel G.
Cellular Operating Systems, Department of Biochemistry and Synthetic Metabolism, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

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Erb,  Tobias J.       
Cellular Operating Systems, Department of Biochemistry and Synthetic Metabolism, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

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Citation

Kim, Y., Lee, S. H., Gade, P., Nattermann, M., Maltseva, N., Endres, M., et al. (2024). Revealing reaction intermediates in one-carbon elongation by thiamine diphosphate/CoA-dependent enzyme family. Communications Chemistry, 7(1). doi:10.1038/s42004-024-01242-y.


Cite as: https://hdl.handle.net/21.11116/0000-000F-9CB7-3
Abstract
2-Hydroxyacyl-CoA lyase/synthase (HACL/S) is a thiamine diphosphate (ThDP)-dependent versatile enzyme originally discovered in the mammalian α-oxidation pathway. HACL/S natively cleaves 2-hydroxyacyl-CoAs and, in its reverse direction, condenses formyl-CoA with aldehydes or ketones. The one-carbon elongation biochemistry based on HACL/S has enabled the use of molecules derived from greenhouse gases as biomanufacturing feedstocks. We investigated several HACL/S family members with high activity in the condensation of formyl-CoA and aldehydes, and distinct chain-length specificities and kinetic parameters. Our analysis revealed the structures of enzymes in complex with acyl-CoA substrates and products, several covalent intermediates, bound ThDP and ADP, as well as the C-terminal active site region. One of these observed states corresponds to the intermediary α–carbanion with hydroxymethyl-CoA covalently attached to ThDP. This research distinguishes HACL/S from related sub-families and identifies key residues involved in substrate binding and catalysis. These findings expand our knowledge of acyloin-condensation biochemistry and offer attractive prospects for biocatalysis using carbon elongation.