Twelve aldehyde dehydrogenase (ALDH) genes have been identified in humans. These genes, located on different chromosomes, encode a group of enzymes which oxidizes varieties of aliphatic and aromatic aldehydes. Metabolic disorders and clinical problems associated with mutations of ALDH1, ALDH2, ALDH4, ALDH10 and succinic semialdehyde (SSDH) genes have been emerged. Comparison of the human ALDHs indicates a wide range of divergency (Ͼ 80ϪϽ 15% identity at the protein sequence level) among them. However, several protein regions, some of which are implicated in functional activities, are conserved in the family members.The phylogenic tree constructed of 56 ALDH sequences of humans, animals, fungi, protozoa and eubacteria, suggests that the present-day human ALDH genes were derived from four ancestral genes that existed prior to the divergence of Eubacteria and Eukaryotes. The neighbor-joining tree derived from 12 human ALDHs and antiquitin indicates that diversification within the ALDH1/2/5/6 gene cluster occurred during the Neoproterozoic period (about 800 million years ago). Duplication in the ALDH 3/10/7/8 gene cluster occurred in Phanerozoic period (about 300 million years ago). Separations of ALDH3/ALDH10 and that of ALDH7/ALDH8 had occurred during the period of appearance and radiation of mammalian species.Keywords : gene family ; genomic organization; genetic disease; genetic variant; detoxification; evolution ; phylogenetic tree. This paper reviews the functional and structural diversity and Aldehyde dehydrogenases [aldehyde: NAD(P) ϩ oxidoreductase] are a group of enzymes catalyzing the conversion of alde-evolution of the human ALDH gene family.There is no uniform nomenclature system for human and hydes to the corresponding acids by means of an NAD(P) ϩ -dependent virtually irreversible reaction. ALDHs are widely dis-animal ALDH genes and enzymes. Therefore, commonly used abbreviated human gene symbols (GBD symbols) are used for tributed from bacteria to humans.Mammalian ALDH activity was first observed in ox liver genes (in italic) and enzymes (in non-italic) in the present review. GenBank identification numbers are also given. nearly 50 years ago [1] and thereafter several types of ALDH were distinguished based on their physico-chemical characteristics, enzymological properties, subcellular localization, and tissue distribution [2Ϫ4]. Two ALDH genes were cloned and char-Members of ALDH families acterized in 1985 [5]. At the present time, ten non-allelic genes Twelve known human ALDH genes and corresponding enhave been identified in the human ALDH family. In addition, zymes are listed in Proteins (enzyme subunits) encoded by these genes consist probably exist in other mammals. Protein sequences, genes and/ of about 500 amino acid residues. Catalytically active forms of or cDNAs for more than 50 animals, fungi, and bacterial ALDHs the enzymes are homodimers (ALDH3, ALDH4), homotetrahave been reported. mers (ALDH1, ALDH2, ALDH9, MMSDD) or unknown.

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The major cytosolic aldehyde dehydrogenase isozyme (ALDH1) exhibits strong activity for oxidation of retinal to retinoic acid, while the major mitochondrial ALDH2 and the stomach cytosolic ALDH3 have no such activity. The K(m) of ALDH1 for retinal is about 0.06 μmol/l at pH 7.5, and the catalytic efficiency (Vmax/Km) for retinal is about 600 times higher than that for acetaldehyde. Thus, ALDH1 can efficiently produce retinoic acid from retinal in tissues with low retinal concentrations (<0.1 μmol/l). The gene for ALDH1 has hormone response elements. These findings suggest that the major physiological substrate of human ALDH1 is retinal, and that its primary biological role is generation of retinoic acid resulting in modulation of cell differentiation including hormone-mediated development.

Partial cDNA clones encoding human cytosolic aldehyde dehydrogenase (ALDH1) and mitochondrial aldehyde dehydrogenase (ALDH2) were isolated from a human liver cDNA library constructed in phage Agtll. The expression library was screened by using rabbit antibodies against ALDH1 and ALDH2. Positive clones thus obtained were subsequently screened with mixed synthetic oligonudeotides compatible with peptide sequences of ALDH1 and ALDH2. One of the positive clones for ALDH1 contained an insertion of 1.6 kilobase pairs (kbp). The insert encoded 340 amino acid residues and had a 3' noncoding region of 538 bp and a poly(A) segment. The amino acid sequence deduced from the cDNA sequence coincided with the reported amino acid sequence of human ALDH1 [Hempel, J., von Bahr-Lindstrom, H. & Jornvall, H. (1984) Eur. J. Biochem. 141, 21-35], except that valine at position 161 in the previous amino acid sequence study was found to be isoleucine in the deduced sequence. Since the amino acid sequence of ALDH2 was unknown, 33 tryptic peptides of human ALDH2 were isolated and sequenced. Based on the amino acid sequence data thus obtained, a mixed oligonucleotide probe was prepared. Two positive clones, AALDH2-21 and AALDH2-36, contained the same insert of 1.2 kbp. Another done, AALDH2-22, contained an insert of 1.3 kbp. These two inserts contained an overlap region of 0.9 kbp. The combined cDNA contained a sequence that encodes 399 amino acid residues, a chain-termination codon, a 3' untranslated region of 403 bp, and a poly(A) segment. The deduced amino acid sequence was compatible with the amino acid sequences of the tryptic peptides. The degree of homology between human ALDH1 and ALDH2 is 66% for the coding regions of their cDNAs and 69% at the protein level. No significant homology was found in their 3' untranslated regions.Liver aldehyde dehydrogenase (ALDH; aldehyde:NAD+ oxidoreductase, EC 1.2.1.3) is considered to play a major role in alcohol metabolism. Two major and several minor isozymes exist in the livers of mammals, including man.

F1F0-ATP synthases utilize protein conformational changes induced by a transmembrane proton gradient to synthesize ATP. The allosteric cooperativity of these multisubunit enzymes presumably requires numerous protein-protein interactions within the enzyme complex. To correlate known in vitro changes in subunit structure with in vivo allosteric interactions, we introduced the beta subunit of spinach chloroplast coupling factor 1 ATP into a bacterial F1 ATP synthase. A cloned atpB gene, encoding the complete chloroplast beta subunit, complemented a chromosomal deletion of the cognate uncD gene in Escherichia coli and was incorporated into a functional hybrid F1 ATP synthase. The cysteine residue at position 63 in chloroplast beta is known to be located at the interface between alpha and beta subunits and to be conformationally coupled, in vitro, to the nucleotide binding site > 40 A away. Enlarging the side chain of chloroplast coupling factor 1 beta residue 63 from Cys to Trp blocked ATP synthesis in vivo without significantly impairing ATPase activity or ADP binding in vitro. The in vivo coupling of nucleotide binding at catalytic sites to transmembrane proton movement may thus involve an interaction, via conformational changes, between the amino-terminal domains of the alpha and beta subunits.