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Nat Chem Biol. 2017 Sep;13(9):975-981. doi: 10.1038/nchembio.2434. Epub 2017 Jul 17.

Structures of carboxylic acid reductase reveal domain dynamics underlying catalysis.

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Manchester Institute of Biotechnology, School of Chemistry, University of Manchester, Manchester, UK.
Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, University of Manchester, Manchester, UK.
Diamond Light Source, Harwell Science and Innovation Campus, Didcot, UK.


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.

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