Ternary complexes of liver alcohol dehydrogenase |
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| Institution: | 1. Department of Biomedical Engineering, School of Engineering, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Lane, Gulou District, Nanjing 210009, China;2. Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, China;1. Amrita Centre for Industrial Research & Innovation, Amrita School of Engineering, Amrita Vishwa Vidyapeetham, Ettimadai, Coimbatore 641112, India;2. Department of Applied Chemistry, National Chiao Tung University, 1001 Ta Hsueh Road, Hsinchu, 300, Taiwan;3. Department of Chemical Engineering and Materials Science, Amrita School of Engineering, Amrita Vishwa Vidyapeetham, Ettimadai, Coimbatore 641112, India;1. College of Science, University of Shanghai for Science and Technology, Shanghai 200093, China;2. Zhangjiang Institute, China State Institute of Pharmaceutical Industry, 1599 Zhangheng Road, Shanghai 201203, China;3. College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing 400715, China;1. Univ. Artois, EA 7394, Institut Charles VIOLLETTE, Lens, F-62300, France;2. PFINV, F-62200, Boulogne-sur-Mer, France;3. ISA Lille, EA 7394, Institut Charles VIOLLETTE, Lille, F-59000, France;4. Ulco, EA 7394, Institut Charles VIOLLETTE, Boulogne sur Mer, F-62200, France;5. Univ. Lille, EA 7394, Institut Charles VIOLLETTE, Lille, F-59000, France;6. ADRIANOR, Tilloy Les Mofflaines, F-62217, France;1. Institute of Fluorescent Probes for Biological Imaging, School of Chemistry and Chemical Engineering, School of Materials Science and Engineering, University of Jinan, Jinan, Shandong 250022, PR China;2. Guangxi Key Laboratory of Electrochemical Energy Materials, Institute of Optical Materials and Chemical Biology, School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi 530004, PR China;1. Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, China;2. Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding 071002, China |
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| Abstract: | Liver alcohol dehydrogenase (LADH; E.C. 1.1.1.1) provides an excellent system for probing the role of binding interactions with NAD+ and alcohols as well as with NADH and the corresponding aldehydes. The enzyme catalyzes the transfer of hydride ion from an alcohol substrate to the NAD+ cofactor, yielding the corresponding aldehyde and the reduced cofactor, NADH. The enzyme is also an excellent catalyst for the reverse reaction. X-ray crystallography has shown that the NAD+ binds in an extended conformation with a distance of 15 Å between the buried reacting carbon of the nicotinamide ring and the adenine ring near the surface of the horse liver enzyme. A major criticism of X-ray crystallographic studies of enzymes is that they do not provide dynamic information. Such data provide time-averaged and space-averaged models. Significantly, entries in the protein data bank contain both coordinates as well as temperature factors. However, enzyme function involves both dynamics and motion. The motions can be as large as a domain closure such as observed with liver alcohol dehydrogenase or as small as the vibrations of certain atoms in the active site where reactions take place. Ternary complexes produced during the reaction of the enzyme binary entity, E-NAD+, with retinol (vitamin A alcohol) lead to retinal (vitamin A aldehyde) release and the enzyme binary entity E-NADH. Retinal is further metabolized via the E-NAD+-retinal ternary complex to retinoic acid (vitamin A acid). To unravel the mechanistic aspects of these transformations, the kinetics and energetics of interconversion between various ternary complexes are characterized. Proton transfers along hydrogen bond bridges and NADH hydride transfers along hydrophobic entities are considered in some detail. Secondary kinetic isotope effects with retinol are not particularly large with the wild-type form of alcohol dehydrogenase from horse liver. We analyze alcohol dehydrogenase catalysis through a re-examination of the reaction coordinates. The ground states of the binary and ternary complexes are shown to be related to the corresponding transition states through topology and free energy acting along the reaction path. |
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