Relationships within the aldehyde dehydrogenase extended family

One hundred-forty-five full-length aldehyde dehydrogenase-related sequences were aligned to determine relationships within the aldehyde dehydrogenase (ALDH) extended family. The alignment reveals only four invariant residues: two glycines, a phenylalanine involved in NAD binding, and a glutamic acid that coordinates the nicotinamide ribose in certain E-NAD binary complex c rystal structures, but which may also serve as a general base for the catal ytic reaction. The cysteine that provides the catalytic thiol and its close st neighbor in space, an asparagine residue, are conserved in all ALDHs wit h demonstrated dehydrogenase activity. Sixteen residues are conserved in at least 95% of the sequences; 12 of these cluster into seven sequence motifs conserved in almost ail ALDHs. These motifs cluster around the active site of the enzyme. Phylogenetic analysis of these ALDHs indicates at least 13 ALDH families, most of which have previously been identified but not groupe d separately by alignment. ALDHs cluster into two main trunks of the phylog enetic tree. The largest, the "Class 3" trunk, contains mostly substrate-sp ecific ALDH families, as well as the class 3 ALDH family itself The other t runk, the "Class 1/2" trunk, contains mostly variable substrate ALDH famili es, including the class 1 and 2 ALDH families. Divergence of the substrate- specific ALDHs occurred earlier than the division between ALDHs with broad substrate specificities. A site on the World Wide Web has also been devoted to this alignment project.