Nature Chemical Biology
Nature Chemical Biology
4 years ago

Structures of carboxylic acid reductase reveal domain dynamics underlying catalysis

Structures of carboxylic acid reductase reveal domain dynamics underlying catalysis
Michael P Lockhart-Cairns, Sasha R Derrington, Daniela Quaglia, Deepankar Gahloth, Nicholas J Turner, Mark S Dunstan, Andrew M Hill, Evaldas Klumbys, David Leys, Nigel S Scrutton
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.

Publisher URL: http://dx.doi.org/10.1038/nchembio.2434

DOI: 10.1038/nchembio.2434

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