THE SHORT-CHAIN ALCOHOL-DEHYDROGENASE SUPERFAMILY - VARIATIONS ON A COMMON THEME

Multiple alignment of members of the short-chain alcohol dehydrogenase (SCAD) superfamily, according to the conserved domains A-F, has revea led a number of important relationships. It can be shown that the 17 b eta-hydroxysteroid dehydrogenase type 2 enzyme is more closely related to D-beta-hydroxybutyrate dehydrogenase than it is to 17 beta-hydroxy steroid dehydrogenase type 1. Carbonyl reductase, previously considere d to be a member of the aldo-keto reductase superfamily, displayed hig h homology in the conserved domains and is clearly part of the SCAD su perfamily despite the insertion of a large peptide between conserved d omains. Alignment of the product of the Leishmania methotrexate resist ance gene HMTX showed that an internal, highly conserved domain can be substituted by an unrelated sequence without loss of biological activ ity. Furthermore, comparisons of the chimeric trifunctional enzyme eno yl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase/3-hydroxyacyl-CoA epi merase with other family members suggests that the region between the conserved B and C domains is the last to diverge between closely relat ed enzymes and that the F domain appears to evolve with a different ev olutionary clock to the rest of the protein. Finally, a highly conserv ed pattern of serine and threonine residues in the active site of SCAD enzymes indicates that these residues may play an important role in c atalysis. These observations should facilitate alignment of future mem bers of the SCAD superfamily.