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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.

Author information

1
Manchester Institute of Biotechnology, School of Chemistry, University of Manchester, Manchester, UK.
2
Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, University of Manchester, Manchester, UK.
3
Diamond Light Source, Harwell Science and Innovation Campus, Didcot, UK.

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.

PMID:
28719588
PMCID:
PMC5563451
DOI:
10.1038/nchembio.2434
[Indexed for MEDLINE]
Free PMC Article

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