Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The aldehyde dehydrogenases (ALDHs) are a superfamily of multimeric enzymes which catalyse the oxidation of a broad range of aldehydes into their corresponding carboxylic acids with the reduction of their cofactor, NAD or NADP, into NADH or NADPH. At present, the only known structures concern NAD-dependent ALDHs. Three structures are available in the Protein Data Bank: two are tetrameric and the other is a dimer. We solved by molecular replacement the first structure of an NADP-dependent ALDH isolated from Streptococcus mutans, in its apo form and holo form in complex with NADP, at 1.8 and 2.6 A resolution, respectively. Although the protein sequence shares only approximately 30 % identity with the other solved tetrameric ALDHs, the structures are very similar. However, a large local conformational change in the region surrounding the 2' phosphate group of the adenosine moiety is observed when the enzyme binds NADP, in contrast to the NAD-dependent ALDHs. Structure and sequence analyses reveal several properties. A small number of residues seem to determine the oligomeric state. Likewise, the nature (charge and volume) of the residue at position 180 (Thr in ALDH from S. mutans) determines the cofactor specificity in comparison with the structures of NAD-dependent ALDHs. The presence of a hydrogen bond network around the cofactor not only allows it to bind to the enzyme but also directs the side-chains in a correct orientation for the catalytic reaction to take place. Moreover, a specific part of this network appears to be important in substrate binding. Since the enzyme oxidises the same substrate, glyceraldehyde-3-phosphate (G3P), as NAD-dependent phosphorylating glyceraldehyde-3-phosphate dehydrogenases (GAPDH), the active site of GAPDH was compared with that of the S. mutans ALDH. It was found that Arg103, Arg283 and Asp440 might be key residues for substrate binding.
J Mol Biol 1999 Jul 02
PMID:Apo and holo crystal structures of an NADP-dependent aldehyde dehydrogenase from Streptococcus mutans. 1038 64

The NADP-dependent non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase from Streptococcus mutans (abbreviated Sm-ALDH) belongs to the aldehyde dehydrogenase (ALDH) family. Its catalytic mechanism proceeds via two steps, acylation and deacylation. Its high catalytic efficiency at neutral pH implies prerequisites relative to the chemical mechanism. First, the catalytic Cys284 should be accessible and in a thiolate form at physiological pH to attack efficiently the aldehydic group of the glyceraldehyde-3-phosphate (G3P). Second, the hydride transfer from the hemithioacetal intermediate toward the nicotinamide ring of NADP should be efficient. Third, the nucleophilic character of the water molecule involved in the deacylation should be strongly increased. Moreover, the different complexes formed during the catalytic process should be stabilised. The crystal structures presented here (an apoenzyme named Apo2 with two sulphate ions bound to the catalytic site, the C284S mutant holoenzyme and the ternary complex composed of the C284S holoenzyme and G3P) together with biochemical results and previously published apo and holo crystal structures (named Apo1 and Holo1, respectively) contribute to the understanding of the ALDH catalytic mechanism. Comparison of Apo1 and Holo1 crystal structures shows a Cys284 side-chain rotation of 110 degrees, upon cofactor binding, which is probably responsible for its pK(a) decrease. In the Apo2 structure, an oxygen atom of a sulphate anion interacts by hydrogen bonds with the NH2 group of a conserved asparagine residue (Asn154 in Sm-ALDH) and the Cys284 NH group. In the ternary complex, the oxygen atom of the aldehydic carbonyl group of the substrate interacts with the Ser284 NH group and the Asn154 NH2 group. A substrate isotope effect on acylation is observed for both the wild-type and the N154A and N154T mutants. The rate of the acylation step strongly decreases for the mutants and becomes limiting. All these results suggest the involvement of Asn154 in an oxyanion hole in order to stabilise the tetrahedral intermediate and likely the other intermediates of the reaction. In the ternary complex, the cofactor conformation is shifted in comparison with its conformation in the C284S holoenzyme structure, likely resulting from its peculiar binding mode to the Rossmann fold (i.e. non-perpendicular to the plane of the beta-sheet). This change is likely favoured by a characteristic loop of the Rossmann fold, longer in ALDHs than in other dehydrogenases, whose orientation could be constrained by a conserved proline residue. In the ternary and C284S holenzyme structures, as well as in the Apo2 structure, the Glu250 side-chain is situated less than 4 A from Cys284 or Ser284 instead of 7 A in the crystal structure of the wild-type holoenzyme. It is now positioned in a hydrophobic environment. This supports the pK(a) assignment of 7.6 to Glu250 as recently proposed from enzymatic studies.
J Mol Biol 2000 Jun 30
PMID:Structural and biochemical investigations of the catalytic mechanism of an NADP-dependent aldehyde dehydrogenase from Streptococcus mutans. 1086 5

4-Hydroxy-2-nonenal (HNE) is a highly reactive lipid aldehyde byproduct of the peroxidation of cellular membranes. The structure of HNE features three functional groups, a C1 aldehyde, a C2==C3 double bond, and a C4- hydroxyl group, each of which may contribute to the toxicity of the compound. In addition, the length of the aliphatic chain may influence toxic potency by altering lipophilicity. Using analogous compounds that lacked one or more of the structural moieties, the role of each of these structural motifs in the cytotoxicity of HNE was examined in a mouse alveolar macrophage cell line (RAW 264.7) by a cell survival and growth assay. The importance of these functional groups in the potency of HNE for induction of apoptosis was also examined. The rank order of effects on toxicity was C1---aldehyde >/= C2==C3 double bond >> C4---hydroxyl, with parallel results in both the survival/growth inhibition and apoptosis induction assays. The chain length also influenced toxicity in a series of alpha,beta-unsaturated alkenyl aldehydes, with increasing chain length yielding increasing toxicity. To confirm the importance of the aldehyde moiety, and to examine the role of metabolic detoxification in cellular defenses against HNE toxicity, a RAW 264.7 cell line overexpressing human aldehyde dehydrogenase-3 (hALDH3) was generated. This cell line exhibited nearly complete protection against HNE-protein adduct formation as well as HNE-induced apoptosis. These results illustrate the comparative significance of key structural features of HNE in relation to its potent toxicity and induction of apoptosis.
Mol Pharmacol 2000 Oct
PMID:Structure-activity relationships for growth inhibition and induction of apoptosis by 4-hydroxy-2-nonenal in raw 264.7 cells. 1099 49

There has been considerable recent debate concerning the distances over which levels of allelic association useful for genomic quantitative trait locus (QTL) scans can be detected. We have examined simple sequence repeat (SSR) polymorphisms and two single nucleotide polymorphisms (SNPs) in the region flanking the aldehyde dehydrogenase 2 locus, ALDH2, in populations of Japanese alcoholics and controls. These groups differ significantly in the allele frequencies for the functional SNP in exon XII of this gene located on chromosome 12. The results obtained with SSR markers complement recent investigations with SNPs over similar distances at the TCR alpha/delta locus. Significant allelic association with this marker could be detected for SSRs over distances up to 400 kb and over 37 kb for the SNP thereby extending the distance over which LD at this locus could be detected by an order of magnitude. Furthermore, as a proof of principle, we show that comparisons of allele frequency differences for the SSR markers in the case (alcoholics) and control populations would have detected the ALDH2 marker as a putative QTL. Extending the tests to include alleles at two or three flanking loci suggests that the power to detect QTLs through association can be enhanced significantly.
Hum Mol Genet 2000 Dec 12
PMID:Allele association studies with SSR and SNP markers at known physical distances within a 1 Mb region embracing the ALDH2 locus in the Japanese, demonstrates linkage disequilibrium extending up to 400 kb. 1111 43

Disulfiram, an aldehyde dehydrogenase inhibitor, interferes with normal song maturation when applied to brain nucleus HVC of male zebra finches. We present here evidence from Western blots and enzymatic assays showing that known disulfiram targets other than retinaldehyde-specific aldehyde dehydrogenase (zRalDH) are absent in HVC. These findings are consistent with the conclusion that disulfiram disrupts song maturation by interfering with retinoic acid production.
Brain Res Mol Brain Res 2001 Mar 05
PMID:Molecular targets of disulfiram action on song maturation in zebra finches. 1124 27

Glycinebetaine is an important osmoprotectant in bacteria, plants, and animals, but only little information is available on the synthesis of glycinebetaine in tree plants. Among four mangrove species, glycinebetaine could be detected only in Avicennia marina. Pinitol was the main osmoprotectant in the other three species. The level of glycinebetaine in A. marina increased under high salinity. Betaine-aldehyde dehydrogenase (BADH) was detected in all four species, but choline monooxygenase could not be detected. A cDNA library was constructed from the leaves of A. marina. Two kinds of BADH cDNAs were isolated, one homologous to the spinach chloroplast BADH, and the other with unique residues SKL at the end of C-terminus. The BADH transcription levels of the former were higher than those of the latter. The levels of the former BADH increased at high salinity whereas those of the latter were independent of salinity. BADHs were expressed in Escherichia coli and purified. Two kinds of A. marina BADHs exhibited similar kinetic and stability properties, but were significantly different from those of spinach BADH. A. marina BADHs efficiently catalyzed the oxidation of betainealdehyde, but not the oxidation of omega-aminoaldehydes and were more stable at high temperature than the spinach BADH.
Plant Mol Biol 2001 Feb
PMID:Molecular cloning and functional characterization of two kinds of betaine-aldehyde dehydrogenase in betaine-accumulating mangrove Avicennia marina (Forsk.) Vierh. 1129 80

This article reviews our knowledge of the ethanol utilization pathway (alc system) in the hyphal fungus Aspergillus nidulans. We discuss the progress made over the past decade in elucidating the two regulatory circuits controlling ethanol catabolism at the level of transcription, specific induction, and carbon catabolite repression, and show how their interplay modulates the utilization of nutrient carbon sources. The mechanisms featuring in this regulation are presented and their modes of action are discussed: First, AlcR, the transcriptional activator, which demonstrates quite remarkable structural features and an original mode of action; second, the physiological inducer acetaldehyde, whose intracellular accumulation induces the alc genes and thereby a catabolic flux while avoiding intoxification; third, CreA, the transcriptional repressor mediating carbon catabolite repression in A. nidulans, which acts in different ways on the various alc genes; Fourth, the promoters of the structural genes for alcohol dehydrogenase (alcA) and aldehyde dehydrogenase (aldA) and the regulatory alcR gene, which exhibit exceptional strength compared to other genes of the respective classes. alc gene expression depends on the number and localization of regulatory cis-acting elements and on the particular interaction between the two regulator proteins, AlcR and CreA, binding to them. All these characteristics make the ethanol regulon a suitable system for induced expression of heterologous protein in filamentous fungi.
Prog Nucleic Acid Res Mol Biol 2001
PMID:Ethanol catabolism in Aspergillus nidulans: a model system for studying gene regulation. 1155 Jul 94

Allyl alcohol hepatotoxicity is mediated by an alcohol dehydrogenase-derived biotranformation product, acrolein. This highly reactive alpha,beta-unsaturated aldehyde readily alkylates model proteins in vitro, forming, among other products, Michael addition adducts that possess a free carbonyl group. Whether such damage accompanies acrolein-mediated toxicity in cells is unknown. In this work we established that allyl alcohol toxicity in mouse hepatocytes involves extensive carbonylation of a wide range of proteins, and that the severity of such damage to a subset of 18-50 kDa proteins closely correlated with the degree of cell death. In addition to abolishing cytotoxicity and glutathione depletion, the alcohol dehydrogenase inhibitor 4-methyl pyrazole strongly attenuated protein carbonylation. Conversely, cyanamide, an aldehyde dehydrogenase inhibitor, enhanced cytotoxicity and protein carbonylation. Since protein carbonylation clearly preceded the loss of membrane integrity, it may be associated with the toxic process leading to cell death.
J Biochem Mol Toxicol 2001
PMID:Extensive protein carbonylation precedes acrolein-mediated cell death in mouse hepatocytes. 1183 30

Cytoplasmic male sterility is a maternally transmitted inability to produce viable pollen. Male sterility occurs in Texas (T) cytoplasm maize as a consequence of the premature degeneration of the tapetal cell layer during microspore development. This sterility can be overcome by the combined action of two nuclear restorer genes, rf1 and rf2a. The rf2a gene encodes a mitochondrial aldehyde dehydrogenase (ALDH) that is capable of oxidizing a variety of aldehydes. Six additional ALDH genes were cloned from maize and Arabidopsis. In vivo complementation assays and in vitro enzyme analyses demonstrated that all six genes encode functional ALDHs. Some of these ALDHs are predicted to accumulate in the mitochondria, others in the cytosol. The intron/exon boundaries of these genes are highly conserved across maize and Arabidopsis and between mitochondrial and cytosolic ALDHs. Although animal, fungal, and plant genomes each encode both mitochondrial and cytosolic ALDHs, it appears that either the gene duplications that generated the mitochondrial and the cytosolic ALDHs occurred independently within each lineage or that homogenizing gene conversion-like events have occurred independently within each lineage. All studied plant genomes contain two confirmed or predicted mitochondrial ALDHs. It appears that these mitochondrial ALDH genes arose via independent duplications after the divergence of monocots and dicots or that independent gene conversion-like events have homogenized the mitochondrial ALDH genes in the monocot and dicot lineages. A computation approach was used to identify amino acid residues likely to be responsible for functional differences between mitochondrial and cytosolic ALDHs.
Plant Mol Biol
PMID:Characterization of the aldehyde dehydrogenase gene families of Zea mays and Arabidopsis. 1199 48

Membrane-associated cytotoxicity induced by hydrophobic bile salts is a major contributing factor leading to liver diseases. Administration of ursodeoxycholate reduces serum liver enzymes in chronic liver diseases but the nature of this effect is still unclear. Using alcohol metabolising enzymes as cellular markers, the hepatotoxic properties of hydrophobic bile salts and the putative hepatoprotective effect of ursodeoxycholate was examined. Two animal models of biliary retention, bile duct obstruction and choledochocaval fistula was used to investigate the effect of taurocholate on the hepatic alcohol metabolizing enzymes: cytosolic alcohol dehydrogenase, microsomal ethanol oxidizing system, catalase and aldehyde dehydrogenase before and after the infusion of taurocholic acid or tauroursodeoxycholic acid for two days period. Bile duct obstruction was found to be similar to or slightly exceeds choledochocaval fistula in the degree of retention. Following the taurocholic acid infusion, the serum alcohol dehydrogenase activity as well as microsomal ethanol oxidizing system and aldehyde dehydrogenase were greatly increased but the level of cytosolic alcohol dehydrogenase and catalase activities was found to be lower in either or both models in comparison with the control animals. However, the tauroursodeoxycholic acid infusion did not induce any significant changes in the levels of all the alcohol metabolizing enzyme activities in either or both models. These findings suggest that hydrophobic taurocholic acid (7alpha) affects the plasmalemma to allow leakage of cytosolic alcohol dehydrogenase into the blood circulation, stimulates the biosynthesis of microsomal ethanol oxidizing system and aldehyde dehydrogenase, and suppresses the biosynthesis of alcohol dehydrogenase and catalase. But in contrast, the hydrophilic tauroursodeoxycholic acid (7beta) provided hepatoprotective effect.
Exp Mol Med 2002 May 31
PMID:Effects of high taurocholate load on activities of hepatic alcohol metabolizing enzymes. 1208 87


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