Structural and functional similarities within the coenzyme binding domains of dehydrogenases

Three-dimensional homologies have been studied by comparing the structures of the coenzyme binding domains and the bound coenzyme molecules in liver alcohol dehydrogenase, lactic dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase. These domains were superposed pairwise and distances between equivalent Cα-atoms as well as between equivalent atoms of the coenzyme molecules were compared. Striking structural similarities were found in the polypeptide folds of those residues that comprise the six strands of parallel pleated-sheet, as well as those that form the helices and loops in the central regions of the domains. These more preserved areas are involved in coenzyme binding. The structures of the coenzyme molecules and their mode of binding to these regions are also very similar. The three-dimensional homologies have been used to align and compare the corresponding amino acid sequences of these three dehydrogenases. Only four invariant residues, Gly 199, Gly 204, Asp 223 and Gly 270 (corresponding to liver alcohol dehydrogenase), were found among the 94 positions compared. The extensive three-dimensional homologies observed here are discussed in terms of a divergent evolutionary process from a common ancestral gene. The apparent lack of sequence homology is thought to be related to the time involved since the divergence. We also suggest that sophisticated enzymes have evolved by fusion of primordial genes coding for smaller, monofunctional units.