Research Article

Cellular and Molecular Life Sciences

, 64:498

First online:

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

  • M. HellgrenAffiliated withDepartment of Medical Biochemistry and Biophysics, Karolinska Institutet
  • , P. StrömbergAffiliated withDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetAstraZeneca R&D
  • , O. GallegoAffiliated withDepartment of Biochemistry and Molecular Biology, Universitat Autònoma de BarcelonaEMBL
  • , S. MartrasAffiliated withDepartment of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona
  • , J. FarrésAffiliated withDepartment of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona
  • , B. PerssonAffiliated withIFM Bioinformatics, Linköping UniversityDepartment of Cell and Molecular Biology, Karolinska Institutet
  • , X. ParésAffiliated withDepartment of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona
  • , J. -O. HöögAffiliated withDepartment of Medical Biochemistry and Biophysics, Karolinska Institutet Email author 

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Abstract.

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.

Keywords.

Alcohol dehydrogenase computer modeling kinetic constant retinaldehyde retinol substrate docking