Alcohol dehydrogenase 2 is a major hepatic enzyme for human retinol metabolism

• Published in: Cellular and molecular life sciences : CMLS 2007-02, Vol.64 (4), p.498-505
• Main Authors: Hellgren, M, Strömberg, P, Gallego, O, Martras, S, Farrés, J, Persson, B, Parés, X, Höög, J. -O
• Format: Article
• Language: English
• Subjects: Alcohol dehydrogenase; Alcohol Dehydrogenase - chemistry; Alcohol Dehydrogenase - metabolism; Amino Acid Sequence; Animals; Binding Sites; computer modeling; Dehydrogenase; Enzymes; Humans; kinetic constant; Kinetics; Liquid chromatography; Liver; Liver - enzymology; Medicin och hälsovetenskap; Metabolism; Mice; Models, Molecular; Molecular Sequence Data; NATURAL SCIENCES; NATURVETENSKAP; Protein Structure, Secondary; Rats; retinaldehyde; retinol; Rodents; Sequence Alignment; substrate docking; vitamin A; Vitamin A - metabolism
• ISSN: 1420-682X; 1420-9071; 1420-9071
• DOI: 10.1007/s00018-007-6449-8

The metabolism of all-trans- and 9-cis-retinol/ retinaldehyde has been investigated with focus on the activities of human, mouse and rat alcohol dehydrogenase 2 (ADH2), an intriguing enzyme with apparently different functions in human and rodents. Kinetic constants were determined with an HPLC method and a structural approach was implemented by in silico substrate dockings. For human ADH2, the determined Km values ranged from 0.05 to 0.3 μM and kcat values from 2.3 to 17.6 min-¹, while the catalytic efficiency for 9-cis-retinol showed the highest value for any substrate. In contrast, poor activities were detected for the rodent enzymes. A mouse ADH2 mutant (ADH2Pro47His) was studied that resembles the human ADH2 setup. This mutation increased the retinoid activity up to 100-fold. The Km values of human ADH2 are the lowest among all known human retinol dehydrogenases, which clearly support a role in hepatic retinol oxidation at physiological concentrations.