Human liver alcohol dehydrogenase

Determination of the amino acid sequence of the β 1 subunit from the class I (pyrazole‐sensitive) human liver alcohol dehydrogenase isoenzyme β 1 β 1 revealed a 373‐residue structure differing at 48 positions (including a gap) from that of the subunit of the well studied horse liver alcohol dehydrogenase EE isoenzyme. The structure deduced is compatible with known differences in composition, ultraviolet absorbance, electrophoretic mobility and catalytic properties between the horse and human enzymes. All zinc‐liganding residues of the horse E subunit are strictly conserved in the human β 1 subunit, despite an earlier report of a mutation involving Cys‐46. This residue therefore remains conserved in all known alcohol dehydrogenase structures. However, the total cysteine content of the β 1 structure is raised from 14 in the subunit of the horse enzyme to 15 by a Tyr→Cys exchange. Most exchanges are on the surface of the molecule and of a well conserved nature. Substitutions close to the catalytic centre are of interest to explain the altered substrate specificity and different catalytic activity of the β 1 homodimer. Functionally, a Ser→ Thr exchange at position 48 appears to be of special importance, since Thr‐48 in β 1 instead of Ser‐48 in the horse enzyme can restrict available space. Four other substitutions also line the active‐site pocket, and appear to constitute partly compensated exchanges.