The three class I alcohol dehydrogenases (ADHs) in humans comprise homo- and heterodimers of three subunits (alpha, beta, and gamma) with greater than 90% sequence identity. These are encoded by distinct genes (ADH1, ADH2, and ADH3, respectively) and are all expressed in the liver. In baboons, only the beta ADH subunit is expressed in liver. A second class I ADH is expressed in the kidney; we isolated, cloned, and sequenced the cDNA corresponding to this ADH and conclude that it is of the gamma ADH lineage. We also amplified and sequenced the 5' noncoding regions of all three class I baboon ADH genes and the rhesus monkey ADH1 gene and compared their nucleotide sequences with the corresponding human sequences. There is clear evidence that the evolution of these genes has been reticulate. At least three gene conversion events, affecting the coding and 3' noncoding regions of the genes, are inferred from compatibility and partition matrices and phylogenetic analysis of the sequences. Our estimation of the evolutionary history of these genes provides a framework for the investigation of relative substitution rates and functional variation among the sequences. Relative-rate tests, designed to account for the reticulate evolution of these genes, indicate no difference in substitution rate either between genes encoding different subunits or between human and Old World monkey lineages. The human and baboon gamma ADH sequences do not show clear differences at functionally important sites within the coding region, but they do differ at a number of sites in regions previously proposed to be regulatory sites for transcriptional control. This variation may explain the different patterns of gene expression in humans and baboons.
A partial human stomach alcohol dehydrogenase (ADH) encoding cDNA has been isolated, cloned, and sequenced, which contains 222 nucleotides encoding amino acid residues 227-299 of the ADH subunit. The amino acid sequence deduced from this cDNA was highly homologous with the rat stomach class IV ADH sequence recently reported (81.1% sequence identity). Homology with other human ADH classes was also observed: class I, 58.1% sequence identity; class II, 39.2% sequence identity; class III, 55.4% sequence identity; and class V, 50.0% sequence identity. These results support a proposal that the isolated cDNA encodes a partial sequence for human stomach class IV ADH. This sequence retains val294 for all other human ADH classes reported, as compared with an ala294 at this position reported for rat class IV ADH. This ala residue may contribute to the very high Km values with ethanol for the latter enzyme. In addition, three substitutions are reported for key residues in the coenzyme binding site: 251, gln/ser; 260, gly/asn; and 261, gly/asn, which may contribute to the weak coenzyme binding properties reported for human class IV ADH.
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