Molecular modelling of human gastric alcohol dehydrogenase (class IV) and substrate docking: differences towards the classical liver enzyme (class I).
A three-dimensional model of the human class IV alcohol dehydrogenase has been calculated based upon the X-ray structure of the class I enzyme. As judged from the model, the substrate-binding site is wider than in class I, compatible with the differences in substrate specificities and the large difference in Km value for ethanol. Substrate docking performed for the class I structure and the class IV model show all-trans-retinol and 11-cis-retinol to bind better to the class IV enzyme. The calculations also indicate that 16-hydroxyhexadecanoic acid binds in a different manner for the two enzyme classes. A simulation of coenzyme-binding indicates that the adenine ring of the coenzyme might be differently bound in class IV than in class I, decreasing the interactions with Asp-223 which is compatible with the higher k(cat) values for class IV.
Moreno
A
A
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Farrés
J
J
Parés
X
X
Jörnvall
H
H
Persson
B
B
D000426:Alcohol Dehydrogenase / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*; D000595:Amino Acid Sequence; D001665:Binding Sites; D003067:Coenzymes / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008958:Models, Molecular; D011487:Protein Conformation; D013270:Stomach / Q000201:enzymology*; D013379:Substrate Specificity
D003067:Coenzymes; D000426:Alcohol Dehydrogenase