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Structures of carboxylic acid reductase reveal domain dynamics underlying catalysis

Gahloth, Deepankar; Dunstan, Mark S.; Quaglia, Daniela; Klumbys, Evaldas; Lockhart-Cairns, Michael P.; Hill, Andrew M.; Derrington, Sasha R.; Scrutton, Nigel S.; Turner, Nicholas J.; Leys, David

Structures of carboxylic acid reductase reveal domain dynamics underlying catalysis Thumbnail


Authors

Deepankar Gahloth

Mark S. Dunstan

Daniela Quaglia

Evaldas Klumbys

Michael P. Lockhart-Cairns

Andrew M. Hill

Sasha R. Derrington

Nigel S. Scrutton

Nicholas J. Turner

David Leys



Abstract

Carboxylic acid reductase (CAR) catalyzes the ATP- and NADPH-dependent reduction of carboxylic acids to the corresponding aldehydes. The enzyme is related to the nonribosomal peptide synthetases, consisting of an adenylation domain fused via a peptidyl carrier protein (PCP) to a reductase termination domain. Crystal structures of the CAR adenylation-PCP didomain demonstrate that large-scale domain motions occur between the adenylation and thiolation states. Crystal structures of the PCP-reductase didomain reveal that phosphopantetheine binding alters the orientation of a key Asp, resulting in a productive orientation of the bound nicotinamide. This ensures that further reduction of the aldehyde product does not occur. Combining crystallography with small-angle X-ray scattering (SAXS), we propose that molecular interactions between initiation and termination domains are limited to competing PCP docking sites. This theory is supported by the fact that (R)-pantetheine can support CAR activity for mixtures of the isolated domains. Our model suggests directions for further development of CAR as a biocatalyst.

Citation

Gahloth, D., Dunstan, M. S., Quaglia, D., Klumbys, E., Lockhart-Cairns, M. P., Hill, A. M., Derrington, S. R., Scrutton, N. S., Turner, N. J., & Leys, D. (2017). Structures of carboxylic acid reductase reveal domain dynamics underlying catalysis. Nature Chemical Biology, 13(9), 975-981. https://doi.org/10.1038/nchembio.2434

Journal Article Type Article
Acceptance Date Jun 8, 2017
Online Publication Date Jul 17, 2017
Publication Date Sep 1, 2017
Deposit Date Jun 18, 2020
Publicly Available Date Jul 7, 2020
Journal Nature Chemical Biology
Print ISSN 1552-4450
Electronic ISSN 1552-4469
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 13
Issue 9
Pages 975-981
DOI https://doi.org/10.1038/nchembio.2434
Public URL https://nottingham-repository.worktribe.com/output/4672184
Publisher URL https://www.nature.com/articles/nchembio.2434

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