Site-directed mutagenesis and enzyme properties of mammalian alcohol dehydrogenases correlated with their tissue distribution

Abstract

Site-directed mutagenesis of mammalian alcohol dehydrogenases has helped to explain functional differences between enzymes within the protein family and traced these characteristics to specific amino acid residues. A threonine/serine exchange at position 48 in the human beta/gamma subunits can explain sensitivity to testosterone inhibition, as well as steroid dehydrogenase activity. It is possible to correlate the glutathione-dependent formaldehyde dehydrogenase activity of class III alcohol dehydrogenase with an arginine at position 115. Tissue distribution analysis of the three initially established classes of mammalian alcohol dehydrogenase show pronouncedly different patterns. Class I alcohol dehydrogenase is widespread but varies between the tissues, and exists in small amounts in the brain. The occurrence of class II is limited in contrast to the class III enzyme which is abundant in all tissues examined. The latter probably reflects the need for scavenging of formaldehyde in cytoprotection. Additional enzyme forms of mammalian alcohol dehydrogenase have been detected and have to be investigated further, together with the enzymes characterized earlier, regarding their physiological role in alcohol metabolism.