THE FIRST STRUCTURE OF AN ALDEHYDE DEHYDROGENASE REVEALS NOVEL INTERACTIONS BETWEEN NAD AND THE ROSSMANN FOLD

The first structure of an aldehyde dehydrogenase (ALDH) is described a t 2.6 Angstrom resolution. Each subunit of the dimeric enzyme contains an NAD-binding domain, a catalytic domain and a bridging domain. At t he interface of these domains is a 15 Angstrom long funnel-shaped pass age with a 6 x 12 Angstrom opening leading to a putative catalytic poc ket. A new mode of NAD binding, which differs substantially from the c lassic beta-alpha-beta binding mode associated with the 'Rossmann fold ', is observed which we term the beta-alpha,beta mode. Sequence compar isons of the class 3 ALDH with other ALDHs indicate a similar polypept ide fold, novel NAD-binding mode and catalytic site for this family. A mechanism for enzymatic specificity and activity is postulated.