Showing papers on "Aldehyde dehydrogenase published in 2003"
TL;DR: Increased activity of Ath-ALDH3 appears to constitute a detoxification mechanism that limits aldehyde accumulation and oxidative stress, thus revealing a novel pathway of detoxification in plants.
Abstract: In plants, oxidative stress is one of the major causes of damage as a result of various environmental stresses. Oxidative stress is primarily because of the excessive accumulation of reactive oxygen species (ROS). The amplification of ROS damage is further stimulated by the accumulation of toxic degradation products, i.e. aldehydes, arising from reactions of ROS with lipids and proteins. Previously, the isolation of dehydration-inducible genes encoding aldehyde dehydrogenases (ALDHs) was reported from the desiccation-tolerant plant Craterostigma plantagineum and Arabidopsis thaliana. ALDHs belong to a family of NAD(P) + -dependent enzymes with a broad substrate specificity that catalyze the oxidation of various toxic aldehydes to carboxylic acids. Analysis of transcript accumulation revealed that Ath-ALDH3 is induced in response to NaCI, heavy metals (Cu 2+ and Cd 2+ ), and chemicals that induce oxidative stress (methyl viologen (MV) and H 2 O 2 ). To investigate the physiological role and possible involvement of ALDHs in stress protection, we generated transgenic Arabidopsis plants overexpressing Ath-ALDH3. Transgenic lines show improved tolerance when exposed to dehydration, NaCI, heavy metals (Cu 2+ and Cd 2+ ), MV, and H 2 O 2 . Tolerance of transgenic plants is correlated with decreased accumulation of lipid peroxidation-derived reactive aldehydes (as measured by malondialdehyde) compared to wild-type plants. Increased activity of Ath-ALDH3 appears to constitute a detoxification mechanism that limits aldehyde accumulation and oxidative stress, thus revealing a novel pathway of detoxification in plants. We suggest that Ath-ALDH3 could be used to obtain plants with tolerance to diverse environmental stresses.
430 citations
TL;DR: A complete listing of all ALDH sequences known to date, along with the evolutionary analysis of the eukaryotic ALDHs are presented.
327 citations
TL;DR: Protein S-thiolation appears to serve an adaptive function during exposure to an oxidative stress by reprogramming metabolism and protecting protein synthesis against irreversible oxidation, and is proposed to result in glucose equivalents entering the pentose phosphate pathway for the generation of NADPH.
Abstract: The irreversible oxidation of cysteine residues can be prevented by protein S-thiolation, a process by which protein SH groups form mixed disulphides with low-molecular-mass thiols such as glutathione. We report here the target proteins which are modified in yeast cells in response to H2O2 .I n particular, a range of glycolytic and related enzymes (Tdh3, Eno2, Adh1, Tpi1, Ald6 and Fba1), as well as translation factors (Tef2, Tef5, Nip1 and Rps5) are identified. The oxidative stress conditions used to induce S-thiolation are shown to inhibit GAPDH (glyceraldehyde3-phosphate dehydrogenase), enolase and alcohol dehydrogenase activities, whereas they have no effect on aldolase, triose phosphate isomerase or aldehyde dehydrogenase activities. The inhibition of GAPDH, enolase and alcohol dehydrogenase is readily reversible once the oxidant is removed. In addition, we show that peroxide stress has little or no effect on glucose-6-phosphate dehydrogenaseor6-phosphogluconatedehydrogenase,theenzymes that catalyse NADPH production via the pentose phosphate pathway. Thus the inhibition of glycolytic flux is proposed to result in glucose equivalents entering the pentose phosphate pathway for the generation of NADPH. Radiolabelling is used to confirm that peroxide stress results in a rapid and reversible inhibition of protein synthesis. Furthermore, we show that glycolytic enzyme activities and protein synthesis are irreversibly inhibited in a mutant that lacks glutathione, and hence cannot modify proteins by S-thiolation. In summary, protein S-thiolation appears to serve an adaptive function during exposure to an oxidative stress by reprogramming metabolism and protecting protein synthesis against irreversible oxidation.
312 citations
TL;DR: The absence of a fully functional first category aldehyde dehydrogenase results in a gross pathological phenotype in the absence of any insult, whereas the lack of a functional second category aLDNase is ordinarily of no consequence with respect to gross phenotype, but is of consequence in that regard when the organism is subjected to a relevant insult.
Abstract: Aldehyde dehydrogenases catalyze the pyridine nucleotide-dependent oxidation of aldehydes to acids. Seventeen enzymes are currently viewed as belonging to the human aldehyde dehydrogenase superfamily. Summarized herein, insofar as the information is available, are the structural composition, physical properties, tissue distribution, subcellular location, substrate specificity, and cofactor preference of each member of this superfamily. Also summarized are the chromosomal locations and organization of the genes that encode these enzymes and the biological consequences when enzyme activity is lost or substantially diminished. Broadly, aldehyde dehydrogenases can be categorized as critical for normal development and/or physiological homeostasis (1) even when the organism is in a friendly environment or (2) only when the organism finds itself in a hostile environment. The primary, if not sole, evolved raison d'etre of first category aldehyde dehydrogenases appears to be to catalyze the biotransformation of a single endobiotic for which they are relatively specific and of which the resultant metabolite is essential to the organism. Most of the human aldehyde dehydrogenases for which the relevant information is available fall into this category. Second category aldehyde dehydrogenases are relatively substrate nonspecific and their evolved raison d'etre seems to be to protect the organism from potentially harmful xenobiotics, specifically aldehydes or xenobiotics that give rise to aldehydes, by catalyzing their detoxification. Thus, the lack of a fully functional first category aldehyde dehydrogenase results in a gross pathological phenotype in the absence of any insult, whereas the lack of a functional second category aldehyde dehydrogenase is ordinarily of no consequence with respect to gross phenotype, but is of consequence in that regard when the organism is subjected to a relevant insult. © 2003 Wiley Periodicals, Inc. J Biochem Mol Toxicol 17:7–23, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10057
261 citations
TL;DR: The possible role of ethanolic fermentation as a robust back-up energy production pathway under adverse conditions when mitochondrial function is disturbed is discussed.
Abstract: Ethanolic fermentation is classically associated with flooding tolerance when plant cells switch from respiration to anaerobic fermentation. However, recent studies have suggested that fermentation also has important functions in the presence of oxygen, mainly in germinating pollen and during abiotic stress. Pyruvate decarboxylase (PDC), which catalyzes the first step in this pathway, is thought to be the main regulatory enzyme. Here, we characterize the PDC gene family in Arabidopsis. PDC is encoded by four closely related genes. By using real-time quantitative polymerase chain reaction, we determined the expression levels of each individual gene in different tissues, under normal growth conditions, and when the plants were subjected to anoxia or other environmental stress conditions. We show that PDC1 is the only gene induced under oxygen limitation among the PDC1 gene family and that a pdc1 null mutant is comprised in anoxia tolerance but not other environmental stresses. We also characterize the expression of the aldehyde dehydrogenase (ALDH) gene family. None of the three genes is induced by anoxia but ALDH2B7 reacts strongly to ABA application and dehydration, suggesting that ALDH may play a role in aerobic detoxification of acetaldehyde. We discuss the possible role of ethanolic fermentation as a robust back-up energy production pathway under adverse conditions when mitochondrial function is disturbed.
175 citations
TL;DR: The data suggest that the presence of magnesium may lead to selection of particular conformations and speed isomerization of the reduced cofactor following hydride transfer and the role of magnesium in activating the human class 2 enzyme is clarified.
Abstract: Crystal structures of many enzymes in the aldehyde dehydrogenase superfamily determined in the presence of bound NAD(P)+ have exhibited conformational flexibility for the nicotinamide half of the cofactor. This has been hypothesized to be important in catalysis because one conformation would block the second half of the reaction, but no firm evidence has been put forth which shows whether the oxidized and reduced cofactors preferentially occupy the two observed conformations. We present here two structures of the wild type and two structures of a Cys302Ser mutant of human mitochondrial aldehyde dehydrogenase in binary complexes with NAD+ and NADH. These structures, including the Cys302Ser mutant in complex with NAD+ at 1.4 A resolution and the wild-type enzyme in complex with NADH at 1.9 A resolution, provide strong evidence that bound NAD+ prefers an extended conformation ideal for hydride transfer and bound NADH prefers a contracted conformation ideal for acyl−enzyme hydrolysis. Unique interactions betw...
164 citations
TL;DR: The metabolic function of ALDH3A1 is supported as a part of a corneal cellular defence mechanism against oxidative damage caused by aldehydic products of lipid peroxidation.
Abstract: ALDH3A1 (aldehyde dehydrogenase 3A1) is expressed at high concentrations in the mammalian cornea and it is believed that it protects this vital tissue and the rest of the eye against UV-light-induced damage. The precise biological function(s) and cellular distribution of ALDH3A1 in the corneal tissue remain to be elucidated. Among the hypotheses proposed for ALDH3A1 function in cornea is detoxification of aldehydes formed during UV-induced lipid peroxidation. To investigate in detail the biochemical properties and distribution of this protein in the human cornea, we expressed human ALDH3A1 in Sf9 insect cells using a baculovirus vector and raised monoclonal antibodies against ALDH3A1. Recombinant ALDH3A1 protein was purified to homogeneity with a single-step affinity chromatography method using 5'-AMP-Sepharose 4B. Human ALDH3A1 demonstrated high substrate specificity for medium-chain (6 carbons and more) saturated and unsaturated aldehydes, including 4-hydroxy-2-nonenal, which are generated by the peroxidation of cellular lipids. Short-chain aliphatic aldehydes, such as acetaldehyde, propionaldehyde and malondialdehyde, were found to be very poor substrates for human ALDH3A1. In addition, ALDH3A1 metabolized glyceraldehyde poorly and did not metabolize glucose 6-phosphate, 6-phosphoglucono-delta-lactone and 6-phosphogluconate at all, suggesting that this enzyme is not involved in either glycolysis or the pentose phosphate pathway. Immunohistochemistry in human corneas, using the monoclonal antibodies described herein, revealed ALDH3A1 expression in epithelial cells and stromal keratocytes, but not in endothelial cells. Overall, these cumulative findings support the metabolic function of ALDH3A1 as a part of a corneal cellular defence mechanism against oxidative damage caused by aldehydic products of lipid peroxidation. Both recombinant human ALDH3A1 and the highly specific monoclonal antibodies described in the present paper may prove to be useful in probing biological functions of this protein in ocular tissue.
156 citations
TL;DR: It is demonstrated that Raldh1 functions downstream of Adh1 in the oxidative metabolism of excess retinol and that toxicity correlates primarily with accumulatingretinol rather than retinaldehyde.
132 citations
TL;DR: Findings suggest that mitochondrial ALDH2 functions as a protector against oxidative stress.
Abstract: Mitochondrial aldehyde dehydrogenase 2 (ALDH2) plays a major role in acetaldehyde detoxification. The alcohol sensitivity is associated with a genetic deficiency of ALDH2. We have previously reported that this deficiency influences the risk for late-onset Alzheimer's disease. However, the biological effects of the deficiency on neuronal cells are poorly understood. Thus, we obtained ALDH2-deficient cell lines by introducing mouse mutant Aldh2 cDNA into PC12 cells. The mutant ALDH2 repressed mitochondrial ALDH activity in a dominant negative fashion, but not cytosolic activity. The resultant ALDH2-deficient transfectants were highly vulnerable to exogenous 4-hydroxy-2-nonenal, an aldehyde derivative generated by the reaction of superoxide with unsaturated fatty acid. In addition, the ALDH2-deficient transfectants were sensitive to oxidative insult induced by antimycin A, accompanied by an accumulation of proteins modified with 4-hydroxy-2-nonenal. Thus, these findings suggest that mitochondrial ALDH2 functions as a protector against oxidative stress.
127 citations
TL;DR: Ziprasidone (Geodon, Zeldox), a recently approved atypical antipsychotic agent for the treatment of schizophrenia, undergoes extensive metabolism in humans with very little of the dose excreted as unchanged drug.
Abstract: Ziprasidone (Geodon, Zeldox), a recently approved atypical antipsychotic agent for the treatment of schizophrenia, undergoes extensive metabolism in humans with very little (<5%) of the dose excreted as unchanged drug. Two enzyme systems have been implicated in ziprasidone metabolism: the cytosolic enzyme, aldehyde oxidase, catalyzes the predominant reductive pathway, and cytochrome P4503A4 (CYP3A4) is responsible for two alternative oxidation pathways. The involvement of two competing pathways in ziprasidone metabolism greatly reduces the potential for pharmacokinetic interactions between ziprasidone and other drugs. Because CYP3A4 only mediates one third of ziprasidone metabolism, the likelihood of interactions between ziprasidone and CYP3A4 inhibitors/ substrates is low. Furthermore, aldehyde oxidase activity does not appear to be altered when drugs or xenobiotics are coadministered. Aldehyde oxidase, a molybdenum-containing enzyme, catalyzes the oxidation of N-heterocyclic drugs such as famciclovir and zaleplon, in addition to reducing some agents such as zonisamide. Both reactions can occur simultaneously. Although in vitro inhibitors of aldehyde oxidase have been identified, there are no reported clinical interactions with aldehyde oxidase inhibitors or inducers. There is no evidence of genetic polymorphism in aldehyde oxidase, and thus it not surprising that ziprasidone exposure demonstrates unimodality in humans. Aldehyde oxidase is unrelated to the similarly named enzyme aldehyde dehydrogenase, which is predominantly responsible for the oxidation of acetaldehyde during ethanol metabolism. Consequently, it is unlikely that there would be any pharmacokinetic interaction between ethanol and ziprasidone.
121 citations
TL;DR: Data suggest that ALDH3A1 is a regulatory element of the cellular defense system that protects corneal epithelium against UV- and 4-HNE-induced oxidative damage.
TL;DR: Under several growth conditions, further addition of acetaldehyde or ethanol in flor yeasts induced the expression of some ALD genes and led to an increase in ALDH activity, which is consistent with their need to obtain energy from ethanol during biological ageing processes.
Abstract: One of the stress conditions that yeast may encounter is the presence of acetaldehyde. In a previous study we identified that, in response to this stress, several HSP genes are induced that are also involved in the response to other forms of stress. Aldehyde dehydrogenases (ALDH) play an important role in yeast acetaldehyde metabolism (e.g. when cells are growing in ethanol). In this work we analyse the expression of the genes encoding these enzymes (ALD) and also the corresponding enzymatic activities under several growth conditions. We investigate three kinds of yeast strains: laboratory strains, strains involved in the alcoholic fermentation stage of wine production and flor yeasts (responsible for the biological ageing of sherry wines). The latter are very important to consider because they grow in media containing high ethanol concentrations, and produce important amounts of acetaldehyde. Under several growth conditions, further addition of acetaldehyde or ethanol in flor yeasts induced the expression of some ALD genes and led to an increase in ALDH activity. This result is consistent with their need to obtain energy from ethanol during biological ageing processes. Our data also suggest that post-transcriptional and/or post-translational mechanisms are involved in regulating the activity of these enzymes. Finally, analyses indicate that the Msn2/4p and Hsf1p transcription factors are necessary for HSP26, ALD2/3 and ALD4 gene expression under acetaldehyde stress, while PKA represses the expression of these genes. Copyright © 2003 John Wiley & Sons, Ltd.
TL;DR: It is suggested that rice ALDH2a mRNA is accumulated in order to quickly metabolize acetaldehyde that is produced upon re‐aeration, suggesting that post‐hypoxic injuries in plants are primarily caused by bursts of reactive oxygen species and acetaldehyde.
TL;DR: AlDH may play a role in detoxifying acetaldehyde formed through alcoholic fermentation during anaerobic germination in anoxia-tolerant and intolerant plants.
Abstract: To compare the regulation of anaerobic metabolism during germination in anoxia-tolerant and intolerant plants, enzymes associated with anaerobic metabolism such as sucrose synthase, aldolase, enolase, pyruvate decarboxylase (PDC), alcohol dehydrogenase (ADH), and aldehyde dehydrogenase (ALDH) were assayed in two varieties of Echinochloa crus-galli, formosensis (tolerant) and praticola (intolerant). The initial and intervening enzymes of the pathway (sucrose synthase and aldolase) and enzymes in the last part of the pathway (PDC, ADH and ALDH) revealed similar changing patterns in activities during germination. This implies that each group of enzymes may be controlled by an identical regulatory mechanism. During anoxia, activities of all enzymes increased 1.5-30-fold in both varieties compared to their activities under aerobic conditions. Activities of sucrose synthase, enolase and ADH exhibited the same induction patterns under anoxia in formosensis and praticola. However, the activities of aldolase, ALDH and PDC were more strongly induced in formosensis under anoxia (1.2-2-fold) than in praticola. These enzymes were also assayed in F(3) families which varied in their anaerobic germinability. For PDC, activities under anoxia in anoxia-tolerant families were similar to those of an anoxia-intolerant family during the whole period although the family did not exhibit anaerobic germinability. This suggests that there is no correlation between PDC activity and anaerobic germinability. For ALDH, activities were more strongly induced under anoxia in anoxia-tolerant families than in anoxia-intolerant families, a trend also exhibited by the parents. This indicates that ALDH may play a role in detoxifying acetaldehyde formed through alcoholic fermentation during anaerobic germination.
TL;DR: Results indicate that spermidine and spermine increase the expression of phase 2 genes in cells grown in culture through activation of the Nrf2-ARE pathway by generating the sulfhydryl reactive aldehyde, acrolein.
TL;DR: Induction of tolerance to Glyceryl trinitrate was induced using both in vivo and in vitro protocols and immunoblot analysis indicated that the majority of vascular ALDH2 is present in the cytoplasm, suggesting that mitochondrial biotransformation of GTN by AL DH2 plays a minor role in the overall vascular biotranformation ofGTN by this enzyme.
Abstract: Glyceryl trinitrate (GTN) is used in the treatment of angina pectoris and cardiac failure, but the rapid onset of GTN tolerance limits its clinical utility. Research suggests that a principal cause of tolerance is inhibition of an enzyme responsible for the production of physiologically active concentrations of NO from GTN. This enzyme has not conclusively been identified. However, the mitochondrial aldehyde dehydrogenase (ALDH2) is inhibited in GTN-tolerant tissues and produces NO2- from GTN, which is proposed to be converted to NO within mitochondria. To investigate the role of this enzyme in GTN tolerance, cumulative GTN concentration-response curves were obtained for both GTN-tolerant and -nontolerant rat aortic rings treated with the ALDH inhibitor cyanamide or the ALDH substrate propionaldehyde. Tolerance to GTN was induced using both in vivo and in vitro protocols. The in vivo protocol resulted in almost complete inhibition of ALDH2 activity and GTN biotransformation in hepatic mitochondria, indicating that long-term GTN exposure results in inactivation of the enzyme. Treatment with cyanamide or propionaldehyde caused a dose-dependent increase in the EC50 value for GTN-induced relaxation of similar magnitude in both tolerant and nontolerant aorta, suggesting that although cyanamide and propionaldehyde inhibit GTN-induced vasodilation, these inhibitors do not affect the enzyme or system involved in tolerance development to GTN. Treatment with cyanamide or propionaldehyde did not significantly inhibit 1,1-diethyl-2-hydroxy-2-nitrosohydrazine-mediated vasodilation in tolerant or nontolerant aorta, indicating that these ALDH inhibitors do not affect the downstream effectors of NO-induced vasodilation. Immunoblot analysis indicated that the majority of vascular ALDH2 is present in the cytoplasm, suggesting that mitochondrial biotransformation of GTN by ALDH2 plays a minor role in the overall vascular biotransformation of GTN by this enzyme.
TL;DR: Evidence is presented that the closely related aldehyde dehydrogenase genes ALD2 and ALD3 are required for pantothenic acid biosynthesis via conversion of 3-aminopropanal to beta-alanine in vivo.
Abstract: The amino acid β-alanine is an intermediate in pantothenic acid (vitamin B 5 ) and coenzyme A (CoA) biosynthesis. In contrast to bacteria, yeast derive the β-alanine required for pantothenic acid production via polyamine metabolism, mediated by the four SPE genes and by the FAD-dependent amine oxidase encoded by FMS1 . Because amine oxidases generally produce aldehyde derivatives of amine compounds, we propose that an additional aldehyde-dehydrogenase-mediated step is required to make β-alanine from the precursor aldehyde, 3-aminopropanal. This study presents evidence that the closely related aldehyde dehydrogenase genes ALD2 and ALD3 are required for pantothenic acid biosynthesis via conversion of 3-aminopropanal to β-alanine in vivo . While deletion of the nuclear gene encoding the unrelated mitochondrial Ald5p resulted in an enhanced requirement for pantothenic acid pathway metabolites, we found no evidence to indicate that the Ald5p functions directly in the conversion of 3-aminopropanal to β-alanine. Thus, in Saccharomyces cerevisiae, ALD2 and ALD3 are specialized for β-alanine biosynthesis and are consequently involved in the cellular biosynthesis of coenzyme A.
TL;DR: The results of this study clearly show that there is a difference in enzymatic activity between male and female patients for those isoenzymes that actively participate in ethanol oxidation in the liver (class I and II ADH), although the main form of ADH in this organ is class III ADH.
Abstract: Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are most abundant in the liver, are the main enzymes involved in ethanol metabolism in humans. Gender-related differences in total liver ADH and ALDH activity among different animal species have been observed in many studies. We measured total ADH and ALDH activity, and the activity of class I-IV ADH in the livers of male and female patients. Total ADH and class I and II ADH activities were significantly higher in males than in females (P=0.0052, P=0.0074, P=0.020, respectively). Class III and IV ADH and total ALDH activities were not significantly different between the genders (P=0.2917, P=0.0590, P=0.2940, respectively). The results of our study clearly show that there is a difference in enzymatic activity between male and female patients for those isoenzymes that actively participate in ethanol oxidation in the liver (class I and II ADH), although the main form of ADH in this organ is class III ADH.
TL;DR: This study has demonstrated that cutaneous ADH and ALDH activities, located within defined subcellular compartments, play important roles in the activation and detoxification of CAlc and CAld in skin.
TL;DR: Both AL DH1A1*2 and ALDH1A 1*3 produce a trend in an African American population that may be indicative of an association with alcoholism; however, more samples are required to validate this observation.
Abstract: Human aldehyde dehydrogenase 1 (ALDH1A1) functions as an important enzyme in both the metabolism of acetaldehyde and the synthesis of retinoic acid (Elizondo et al., 2000; Ueshima et al., 1993). ALDH1A1 also has been implicated in several alcohol-related phenotypes, including alcoholism, alcohol-induced flushing, and alcohol sensitivity (Chan, 1986; Yoshida, 1992). Studies suggest that low ALDH1A1 activity may contribute to alcohol sensitivity and alcohol-induced flushing in Caucasians and some Asians (Ward et al., 1994; Yoshida et al., 1989). Adverse reactions resulting from reduced ALDH1A1 function may be influencing the predisposition for alcoholism in non-Asian populations (Eriksson, 2001). In fact, a study has identified a polymorphism in the coding region of ALDH1A1 that contributes to ethanol preference in high alcohol-preferring (HAP)/low alcohol-preferring (LAP) rats, suggesting that a functionally altered ALDH1A1 influences alcohol consumption in an animal model (Negoro et al., 1997; Nishiguchi et al., 2002). Due to its involvement in ethanol metabolism, ALDH1A1 is an interesting candidate for alcohol research.
Multiple aldehyde dehydrogenase isozymes have been characterized that exhibit similar functional properties implicated in ethanol detoxification, including ALDH1A1, ALDH1B1, ALDH2, and ALDH3A1 (Vasiliou and Pappa, 2000; Yoshida, 1992). The mitochondrial form of aldehyde dehydrogenase, or ALDH2, has been associated with a reduced incidence of alcoholism in certain Asian populations (Higuchi et al., 1995). In these populations, a functional polymorphism in ALDH2 leads to acetaldehyde accumulation, resulting in alcohol-induced flushing (Takeshita et al., 1994), but the underlying mechanism influencing alcoholic predisposition is still unknown (Li, 1997). The ALDH2 enzyme exhibits a higher affinity for acetaldehyde and primarily oxidizes acetaldehyde in humans (Klyosov et al., 1996); however, the functions of the ALDH isozymes in the central nervous system remain unclear (Stewart et al., 1996; Tank et al., 1986).
The promoter region contains regulatory binding sites that are involved in gene expression and tissue specificity (Mitchell and Tjian, 1989). Mutations in regulatory binding sites can substantially affect gene regulation, altering enzyme levels that can ultimately contribute to phenotypic variability throughout a population. Polymorphism in the ALDH1A1 promoter region could affect the steady-state levels of ALDH1A1 and alter acetaldehyde and retinoid metabolism. Thus far, variants of the regulatory region in the promoter of the ALDH1A1 gene have not yet been studied.
Although previous studies indicate that ALDH1A1 may contribute to alcoholism, alcohol sensitivity, and alcohol-induced flushing, no definitive evidence has been provided to adequately link ALDH1A1 to these phenotypes. The purpose of this study was to identify human ALDH1A1 promoter polymorphisms, to determine their functional significance, and to screen for associations between these polymorphisms and alcoholism.
TL;DR: The class-specific expression of ADH and ALDH enzymes, in the skin and liver and their variation between species, may have toxicological significance, with respect to the metabolism of endogenous and xenobiotic alcohols and aldehydes.
TL;DR: The hypothesis that aldehyde products of lipid peroxidation inhibit SSADH activity using the endogenous substrate, succinic semialdehyde (SSA), is tested and suggests that acrolein and HNE disrupt SSA metabolism and may have subsequent effects on CNS neurochemistry.
TL;DR: ALDH2 and CYP2E1 polymorphisms may modify the risk of development of HCC against the background of LC in the Japanese, andPolymorphism analysis of alcohol-metabolic enzymes using molecular techniques may be useful in the risk assessment of liver cancer in patients with hepatitis C virus infection.
Abstract: Background: Hepatocellular carcinoma (HCC) in persons with liver cirrhosis (LC) arises following hepatitis virus infection. Alcohol may accelerate the risk of development of LC and HCC. Cytochrome p450 2E1 (CYP2E1) oxidizes ethanol to form acetaldehyde and aldehyde dehydrogenase 2 (ALDH2) detoxifies acetaldehyde, which is carcinogenic in humans, and both alcohol-metabolizing enzymes show the genetic polymorphisms in a Japanese population. Methods: Using polymorphism analysis, we studied the frequency of ALDH2 functional deletion due to the G to A single-bp mutation in exon 12 and CYP2E1 polymorphism in the transcriptional region, both associated with higher levels of acetaldehyde, in 135 patients with LC and/or HCC, including 99 with HCC, and 135 non-cancer controls. The mRNA expression levels of CYP2E1 in the liver were also examined in 55 surgical specimens. Results: The allelic frequency of the homozygous ALDH2 2-2 genotype, coding for the enzyme deletion, was significantly higher compared to that of t...
TL;DR: The data indicate that oxidation of HNE to its corresponding acid is a major detoxification pathway of H NE in the CNS and that mitochondria play a role in this process.
Abstract: 4-hydroxy-trans-2-nonenal (HNE) is a neurotoxic product of lipid peroxidation whose levels are elevated in multiple neurodegenerative diseases and CNS trauma. The detoxification of HNE may take the route of glutathione conjugation to the C3 carbon and the oxidation or reduction of the C1 aldehyde. In this work, we examined whether the oxidation of HNE to its corresponding carboxylic acid, 4-hydroxy-trans-2-nonenoate (HNEAcid) was detoxifying event, if it occurred in rat cerebral cortex, and in which subcellular compartments. Our results show that HNEAcid did not form protein adducts and was non-toxic to Neuro 2A cells. HNEAcid formation occurred in rat cerebral cortex slices following exposure to HNE in a time-dependent and dose-dependent fashion. Homogenate studies indicated that HNEAcid formation was NAD+ dependent. Subcellular fractionation demonstrated that mitochondria had the highest specific activity for HNEAcid formation with a KM of 21 micro m HNE. These data indicate that oxidation of HNE to its corresponding acid is a major detoxification pathway of HNE in the CNS and that mitochondria play a role in this process.
TL;DR: It is suggested that the rice AL DH2a and ALDH2b genes are orthologues of maize mitochondrial ALDH genes, rf2b and rf1a, respectively.
01 Jan 2003
TL;DR: This review describes how ALDHs can be used to obtain more stress tolerant plants by overexpressing ALDH genes in two ways: to obtain increased accumulation of osmolytes and to detoxify aldehydes.
Abstract: Summary. The deleterious effect of osmotic stress is often caused by the accumulation of reactive molecules e.g. aldehydes. These molecules can cause lipid peroxidation and modifications of proteins and nucleic acids. Aldehydes can be converted to non-toxic carboxylic acids by different aldehyde dehydrogenases (ALDH). ALDHs occur in all organisms implicating their importance in general biological functions. Aldehydes do not only represent toxic molecules but they are also intermediate products in the synthesis of osmolytes which have been shown to be protective molecules in osmotic stress. For this reason a careful balance of aldehydes is required. Evidence emerges that ALDH enzymes are involved in maintaining this balance, and the investigation of the physiological role of plant-ALDHs begins to attract attention. This review tries to summarize the current knowledge of stressregulated ALDHs in plants. It describes how ALDHs can be used to obtain more stress tolerant plants by overexpressing ALDH genes. ALDH genes have been used in two ways: 1. to obtain increased accumulation of osmolytes e.g. glycine betaine, 2. to detoxify aldehydes.
TL;DR: The molecular cytotoxic mechanisms of dietary benzaldehydes towards hepatocytes and its modulation by metabolizing enzymes were compared and cyanamide was the most effective ALDH inhibitor for increasing cinnamaldehyde induced cytotoxicity.
Patent•
12 Sep 2003TL;DR: In this paper, a Coenzyme-A-dependent aldehyde dehydrogenase, acyl-CoA transferase, Acyl CoA synthetase, s-ketothiolase, acetoacetyl-coA reductase and/or PHA synthase are described.
Abstract: Organisms are provided containing genes encoding one or more enzymes, Coenzyme-A-dependent aldehyde dehydrogenase, acyl-CoA transferase, acyl-CoA synthetase, s-ketothiolase, acetoacetyl-CoA reductase and/or PHA synthase. In some cases one or more of these genes are native to the host organism and the remainder are heterologous genes provided by genetic engineering. These organisms produce poly (3-hydroxyalkanoate) homopolymers or co-polymers comprising 3-hydroxalkanoate monomers other than 3-hydroxybutryrate wherein these 3-hydroxyalkanoate units are derived from the enzyme-catalyzed conversion of alcohols to 3-hydroxyacyl-CoA monomers, where at least one step in the conversion pathway involves a Co-enzyme A-dependent aldehyde dehydrogenase activity. The PHA polymers are readily recovered and industrially useful as polymers for articles such as films, latexes, coatings, adhesives, fibers, binders, resins, and medical devices.
Patent•
DSM1
TL;DR: In this article, a process for the production of 2-keto-L-gulonic acid (2-KGA) from L-sorbosone is described.
Abstract: The present invention relates to a DNA which encodes aldehyde dehydrogenase (SNDH), an expression vector containing the DNA and recombinant organisms containing said DNA. Furthermore, the present invention concerns a process for producing recombinant aldehyde dehydrogenase protein and a process for producing L-ascorbic acid (vitamin C) and/or 2-keto-L-gulonic acid (2-KGA) from L-sorbosone by using the recombinant aldehyde dehydrogenase protein or recombinant organisms containing the expression vector. Also provided is a process for the production of 2-KGA with a microorganism in which the gene encoding said aldehyde dehydrogenase is disrupted.