Abstract
The metabolism of alcohol in the mammalian liver involves two enzymes: (i) alcohol dehydrogenase, which converts an alcohol to its corresponding aldehyde product through a readily reversible reaction, and (ii) aldehyde dehydrogenase, which catalyzes the oxidation of the aldehyde to a carboxylic acid through an essentially irreversible step. For both enzymes the reaction proceeds at the level of a ternary complex formed by the enzyme, the nicotinamide adenine dinucleotide coenzyme, and the substrate. In the case of alcohol dehydrogenase, the ternary complex is formed with coordination of the alcohol or the aldehyde to the active site Zn2+, and no covalent interaction occurs between the substrate and the protein. In this complex, hydride transfer proceeds directly between the substrate and the nicotinamide ring of the coenzyme that is responsible for chemical conversion of alcohol to aldehyde (Morris et al, 1980; Pettersson, 1987). In aldehyde dehydrogenase, hydride transfer from the aldehyde to the coenzyme results in formation of an acylenzyme intermediate in which a thiol group of a cysteinyl residue serves as a nucleophile (Tu and Weiner, 1988). It is likely that the conformations of the bound substrate for both enzymes are critically important in directing the path of the reaction. However, hitherto there has been relatively little structural data of sufficient resolution and accuracy to define catalytically competent conformations in alcohol dehydrogenase (Cedergren-Zeppezauer et al., 1982; Eklund et al, 1982), and at present X-ray crystallographic studies of aldehyde dehydrogenase are only at a preliminary stage (Rone et al, 1991; Hurley et al., 1993). Incisive progress towards understanding the molecular basis of the catalytic action of both enzymes would be obtained through high resolution studies of the structural relationships of active site residues with bound substrates in catalytically competent conformations.
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Boisvert, W.E. et al. (1993). Kinetically Specific Spin-Label Substrates of Liver Alcohol Dehydrogenase and of Liver Aldehyde Dehydrogenase. In: Weiner, H., Crabb, D.W., Flynn, T.G. (eds) Enzymology and Molecular Biology of Carbonyl Metabolism 4. Advances in Experimental Medicine and Biology, vol 328. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2904-0_53
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DOI: https://doi.org/10.1007/978-1-4615-2904-0_53
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