Abstract:
:Liver alcohol dehydrogenase (E.C.1.1.1.1) is an NAD(+)/NADH dependent enzyme with a broad substrate specificity being active on an assortment of primary and secondary alcohols. It catalyzes the reversible oxidation of a wide variety of alcohols to the corresponding aldehydes and ketones as well as the oxidation of certain aldehydes to their related carboxylic acids. Although the bioinorganic and bioorganic aspects of the enzymatic mechanism, as well as the structures of various ternary complexes, have been extensively studied, the kinetic significance of certain intermediates has not been fully evaluated. Nevertheless, the availability of computer-assisted programs for kinetic simulation and molecular modeling make it possible to describe the biochemical mechanism more completely. Although the true physiological substrates of this zinc metalloenzyme are unknown, alcohol dehydrogenase effectively catalyzes not only the interconversion of all-trans-retinol and all-trans-retinal but also the oxidation of all-trans-retinal to the corresponding retinoic acid. Retinal and related vitamin A derivatives play fundamental roles in many physiological processes, most notably the vision process. Furthermore, retinoic acid is used in dermatology as well as in the prevention and treatment of different types of cancer. The enzyme-NAD(+)-retinol complex has an apparent pK(a) value of 7.2 and loses a proton rapidly. Proton inventory modeling suggests that the transition state for the hydride transfer step has a partial negative charge on the oxygen of retinoxide. Spectral evidence for an intermediate such as E-NAD(+)-retinoxide was obtained with enzyme that has cobalt(II) substituted for the active site zinc(II). Biophysical considerations of water in these biological processes coupled with the inverse solvent isotope effect lead to the conclusion that the zinc-bound alkoxide makes a strong hydrogen bond with the hydroxyl group of Ser48 and is thus activated for hydride transfer. Moderate pressure accelerates enzyme action indicative of a negative volume of activation. The data with retinol is discussed in terms of enzyme stability, mechanism, adaptation to extreme conditions, as well as water affinities of substrates and inhibitors. Our data concern all-trans, 9-cis, 11-cis, and 13-cis retinols as well as the corresponding retinals. In all cases the enzyme utilizes an approximately ordered mechanism for retinol-retinal interconversion and for retinal-retinoic acid transformation.
journal_name
Chem Biol Interactjournal_title
Chemico-biological interactionsauthors
Pocker Ydoi
10.1016/s0009-2797(00)00263-5subject
Has Abstractpub_date
2001-01-30 00:00:00pages
383-93issue
1-3eissn
0009-2797issn
1872-7786pii
S0009279700002635journal_volume
130-132pub_type
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
pub_type: 杂志文章,评审
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
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