Structure-function relationships in Drosophila melanogaster alcohol dehydrogenase allozymes ADH(S), ADH(F) and ADH(UF), and distantly related forms

Drosophila melanogaster alcohol dehydrogenase (ADH), a paradigm for gene-en zyme molecular evolution and natural selection studies, presents three main alleloforms (ADH(S), ADH(F) and ADH(UF)) differing by one or two substitut ions that render different biochemical properties to the allelozymes. A thr ee-dimensional molecular model of the three allozymes was built by homology modeling using as a template the available crystal structure of the orthol ogous D. lebanonensis ADH, which shares a sequence identity of 82.2%. Compa rison between D. lebanonensis and D. melanogaster structures showed that th ere is almost no amino-acid change near the substrate or coenzyme binding s ites and that the hydrophobic active site cavity is strictly conserved. Nev ertheless, substitutions are not distributed at random in nonconstricted po sitions, or located in external loops, but they appear clustered mainly in secondary structure elements. From comparisons between D. melanogaster allo zymes and with D. simulans, a very closely related species, a model based o n changes in the electrostatic potential distribution is presented to expla in their differential behavior. The depth of knowledge on Drosophila ADH ge netics and kinetics, together with the recently obtained structural informa tion, could provide a better understanding of the mechanisms underlying mol ecular evolution and population genetics.