期刊
NATURE CHEMICAL BIOLOGY
卷 13, 期 9, 页码 975-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.2434
关键词
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资金
- BBSRC [BB/K00199X/1]
- BBSRC/EPSRC SYNBIOCHEM Centre [BB/M017702/1]
- CoEBio3 Affiliates programme
- BBSRC [BB/K00199X/1, BB/M017702/1] Funding Source: UKRI
- EPSRC [EP/J020192/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/M017702/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/J020192/1] Funding Source: researchfish
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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