Showing papers on "Aldehyde dehydrogenase published in 2001"
TL;DR: The finding that T cytoplasm plants that are homozygous for the rf2-R213 allele are male sterile but accumulate normal amounts of RF2 protein that lacks normal mitochondrial ALDH activity provides strong evidence that rf1-encoded mtALDH activity is required to restore male fertility to T cy toplasm maize.
Abstract: Some plant cytoplasms express novel mitochondrial genes that cause male sterility. Nuclear genes that disrupt the accumulation of the corresponding mitochondrial gene products can restore fertility to such plants. The Texas (T) cytoplasm mitochondrial genome of maize expresses a novel protein, URF13, which is necessary for T cytoplasm–induced male sterility. Working in concert, functional alleles of two nuclear genes, rf1 and rf2, can restore fertility to T cytoplasm plants. Rf1 alleles, but not Rf2 alleles, reduce the accumulation of URF13. Hence, Rf2 differs from typical nuclear restorers in that it does not alter the accumulation of the mitochondrial protein necessary for T cytoplasm–induced male sterility. This study established that the rf2 gene encodes a soluble protein that accumulates in the mitochondrial matrix. Three independent lines of evidence establish that the RF2 protein is an aldehyde dehydrogenase (ALDH). The finding that T cytoplasm plants that are homozygous for the rf2-R213 allele are male sterile but accumulate normal amounts of RF2 protein that lacks normal mitochondrial (mt) ALDH activity provides strong evidence that rf2-encoded mtALDH activity is required to restore male fertility to T cytoplasm maize. Detailed genetic analyses have established that the rf2 gene also is required for anther development in normal cytoplasm maize. Hence, it appears that the rf2 gene was recruited recently to function as a nuclear restorer. ALDHs typically have very broad substrate specificities. Indeed, the RF2 protein is capable of oxidizing at least three aldehydes. Hence, the specific metabolic pathway(s) within which the rf2-encoded mtALDH acts remains to be discovered.
227 citations
TL;DR: This review summarizes recent developments in the investigation of the following influences on alcohol elimination rate: gender, body composition and lean body mass, liver volume, food and food composition, ethnicity, and genetic polymorphisms in alcohol metabolizing enzymes as well as in the promoter regions of the genes for these enzymes.
214 citations
TL;DR: Apoptosis of alveolar epithelial cells may be one of the mechanisms of lung injury induced by cigarette smoking, and this cytotoxic effect might be due to an interaction between aldehydes and oxidants present in CSE or formed in C SE-exposed cells.
Abstract: Injury of the alveolar epithelium by cigarette smoke is presumed to be an important process in the pathogenesis of smoking-related pulmonary diseases We investigated the cytotoxic effects of cigarette smoke extract (CSE) on an alveolar type II cell-derived cell line (A549) CSE caused apoptosis at concentrations of 5% or less and necrosis at 10% or more When CSE was exposed to air before application to A549 cells, the cytotoxic effects were attenuated CSE caused cell death without direct contact with the cells Acrolein and hydrogen peroxide, two major volatile factors in cigarette smoke, caused cell death in a similar manner Aldehyde dehydrogenase, a scavenger of aldehydes, and N-acetylcysteine, a scavenger of oxidants and aldehydes, completely inhibited CSE-induced apoptosis CSE and acrolein increased intracellular oxidant activity In conclusion, apoptosis of alveolar epithelial cells may be one of the mechanisms of lung injury induced by cigarette smoking This cytotoxic effect might be due to an interaction between aldehydes and oxidants present in CSE or formed in CSE-exposed cells
208 citations
TL;DR: Recent advances in the understanding of the functional polymorphisms of ADH, ALDH and CYP2E1 and their metabolic, physiologic and clinical correlations are presented.
157 citations
TL;DR: In this article, the C. plantagineum gene Cp-ALDH constitutes a novel class of plant ALDHs and was identified with homology to class 3 variable substrate aldehyde dehydrogenases (ALDHs).
Abstract: Summary
In order to identify genes that are critical for the ABA-dependent stress response in the resurrection plant Craterostigma plantagineum, a gene was isolated with homology to class 3 variable substrate aldehyde dehydrogenases (ALDH). The C. plantagineum gene Cp-ALDH constitutes a novel class of plant ALDHs. In a search for corresponding genes from Arabidopsis thaliana, Ath-ALDH3 and Ath-ALDH4 were isolated, showing 70% and 80% similarity to Cp-ALDH. Phylogenetically, the Cp- and Ath-ALDH3 and -ALDH4 proteins are closely related to aldehyde dehydrogenases from bacteria and mammalian species and are separated from known plant ALDHs and betaine-aldehyde dehydrogenases (BADH). Cp-ALDH transcript and polypeptide are up-regulated in vegetative tissues and callus in response to dehydration or ABA-treatment. Ath-ALDH3 expression was induced in response to dehydration and ABA treatment, while Ath-ALDH4 is constitutively expressed at a low level. Recombinant Cp-ALDH protein oxidizes nonanal, propionaldehyde and acetaldehyde, with Km values of 2.2 µm, 0.27 mm and 3.23 mm, respectively, in an NAD-dependent manner. Immunogold electron microscopy shows that Cp-ALDH is localized in plastids.
124 citations
TL;DR: The observation that the ALDH2*2 gene protects against the development of alcoholism is confirmed, however, theDevelopment of cirrhosis in Korean alcoholic patients was not associated with polymorphisms of ethanol-metabolizing enzymes.
Abstract: Alcohol is oxidized to acetaldehyde by alcohol dehydrogenase (ADH) and cytochrome P-4502E1 (CYP2E1), and then to acetate by aldehyde dehydrogenase (ALDH). Polymorphisms of these ethanol-metabolizing enzymes may be associated with inter-individual difference in alcohol metabolism and susceptibility to alcoholic liver disease. We determined genotype and allele frequencies of ALDH2, CYP2E1, ADH2, and ADH3 in male Korean patients with alcoholic cirrhosis (n=56), alcoholics without evidence of liver disease (n=52), and nondrinkers (n=64) by using PCR or PCR-directed mutagenesis followed by restriction enzyme digestion. The prevalences of heterozygous ALDH2*1/*2 plus homozygous ALDH2*2/*2 in patients with alcoholic cirrhosis (7.1%) and alcoholics without evidence of liver disease (3.8%) were significantly lower than that in nondrinkers (45.3%). The c2 allele frequencies of the CYP2E1 in alcoholic cirrhosis, alcoholics without evidence of liver disease, and nondrinkers were 0.21, 0.20, and 0.20, respectively. Allele frequencies of ADH2*2 in the three groups were 0.78, 0.74, and 0.77 and those of ADH3*1 were 0.94, 0.98, and 0.95. Therefore, we confirmed the observation that the ALDH2*2 gene protects against the development of alcoholism. However, the development of cirrhosis in Korean alcoholic patients was not associated with polymorphisms of ethanol-metabolizing enzymes.
98 citations
TL;DR: The results suggest that in brain regions involved in AD, neurons and glia utilize different mechanisms to detoxify HNE, and that increased ALDH activity is a protective response of cerebral cortex to AD.
Abstract: A reactive intermediate generated by lipid peroxidation, 4-hydroxy-2-nonenal (HNE), has received considerable attention as a potential effector of oxidative damage and Aβ peptide-mediated neurotoxicity in Alzheimer disease (AD). However, little is known about aldo-keto oxidoreductases, a group of enzymes that constitute a major detoxifying pathway for HNE and related reactive aldehydes in human brain. We have determined the regional, cellular, and class distribution in human brain of the 4 major aldo-keto oxidoreductases that detoxify HNE: aldehyde dehydrogenase (ALDH); aldose reductase; aldehyde reductase; and alcohol dehydrogenase (ADH). Of these 4 enzymes, only ALDH and aldose reductase were expressed in cerebral cortex, hippocampus, basal ganglia, and midbrain; all 4 enzymes were present in cerebellum. In cerebrum and hippocampus, aldose reductase was localized to pyramidal neurons and mitochondrial class 2 ALDH was localized to glia and senile plaques. ALDH, but not aldose reductase, activity was significantly increased in temporal cortex from patients with AD compared to age-matched controls. These results suggest that in brain regions involved in AD, neurons and glia utilize different mechanisms to detoxify HNE, and that increased ALDH activity is a protective response of cerebral cortex to AD.
85 citations
TL;DR: Protein levels of both enzymes were increased in several brain regions because of enzyme induction by elevated carbonyls in DS and AD, supporting the involvement of oxidative stress and contributing to the understanding of carbonyl handling in brain of both neurodegenerative disorders.
Abstract: Oxidative stress is considered to be crucial in the pathogenesis of Alzheimer’s disease-like neurodegeneration. An elevation of carbonyl compounds that are biomarkers of and leading to oxidative stress has been demonstrated in Down Syndrome (DS) and Alzheimer’s Disease (AD) brains and seems to be the result of a multifactorial process. Carbonyls, which are cytotoxic metabolic intermediates, are detoxified by either oxidation catalyzed by aldehyde dehydrogenase (ALDH), or by reduction to their corresponding alcohols by carbonyl reductase (CBR) and/or alcohol dehydrogenase (ADH). We quantified protein levels of CBR and its agonist/antagonist ADH using 2D gel electrophoresis with subsequent MALDI-identification and specific software in several brain regions of DS as well as AD patients and compared them to levels of CBR and ADH in brains of controls. Protein levels of both enzymes were increased in several brain regions because of enzyme induction by elevated carbonyls in DS and AD. Increased CBR in DS (trisomy 21) may be due to a gene dosage effect as the gene encoding CBR has been mapped to chromosome 21. These findings may confirm the proposed increase of reactive carbonyls in the brain thus supporting the involvement of oxidative stress and contribute to the understanding of carbonyl handling in brain of both neurodegenerative disorders.
85 citations
TL;DR: It is shown that agmatine, a metabolite of arginine, inhibits iNOS mediated nitric oxide generation in cytokine stimulated cell culture preparations, and this effect was not cell type specific.
Abstract: The induction of inducible nitric oxide synthase (iNOS) serves an important immuno-protective function in inflammatory states, but ungoverned nitric oxide (NO) generation can contribute to a number of pathologic consequences. Delineation of the mechanisms that can downregulate iNOS-generated NO in inflammation could have therapeutic relevance. Here we show that agmatine, a metabolite of arginine, inhibits iNOS mediated nitric oxide generation in cytokine stimulated cell culture preparations. This effect was not cell type specific. Increased diamine oxidase (DAO) and decreased aldehyde dehydrogenase (AldDH) activities are also representative of inflammatory settings. Increasing the conversion of agmatine to an aldehyde form by addition of purified DAO or suppression of aldehyde breakdown by inhibition of AldDH activity increases the inhibitory effects of agmatine in an additive fashion. Inhibitors of DAO, but not monoamine oxidase (MAO), decreased the inhibitory effects of agmatine, as did the addition of AldDH or reacting aldehydes with phenylhydrazine. We examined rats given lipopolysaccharide (LPS) to evaluate the potential effects of agmatine in vivo. Endotoxic rats administered agmatine prevented the decreases in blood pressure and renal function normally associated with sepsis. Agmatine treatment also increased the survival of LPS treated mice. Our data demonstrate the capacity of agmatine aldehyde to suppress iNOS mediated NO generation, and indicate a protective function of agmatine in a model of endotoxic shock. How agmatine may aid in coordinating the early NO phase and the later repair phase responses in models of inflammation is discussed.
84 citations
TL;DR: A complete list of all ALDH sequences known to date is presented here along with the evolution analysis of the eukaryotic ALDHs.
82 citations
TL;DR: Findings indicated that N-dealkylation may be an important step in DSF metabolism, and that the inhibition of ALDH occurred by carbamoylation caused by one of the DSF metabolites, most likely S-methyl-N,N-diethylthiocarbamoyl sulfoxide (MeDTC-SO).
TL;DR: To identify tumour-related enzyme alterations, 2D-gels are used to analyse the proteome from dissected malignant and benign kidney areas from patients with clear-cell-type renal carcinoma to identify proteins diminished in tumour.
Abstract: To identify tumour-related enzyme alterations we have used 2D-gels to analyse the proteome from dissected malignant and benign kidney areas from patients with clear-cell-type renal carcinoma The expression of 12 proteins was diminished in tumour Four proteins were characterized by mass spectrometry and were identified as enoyl-CoA hydratase, α-glycerol-3-phosphate dehydrogenase, aldehyde dehydrogenase 1 and aminoacylase-I
TL;DR: It is demonstrated that expression of class 3 ALDH, but not class 1 AL DH, can be an important determinant of cellular resistance to toxicity mediated by aldehydes of intermediate chain length that are produced during lipid peroxidation.
Journal Article•
TL;DR: In this article, aldehyde dehydrogenase 6 (ALDH6) was identified as the enzyme responsible for the loss of RA synthesis ability in cancer cells and the relationship of this process to malignant transformation.
Abstract: Retinoic acid (RA) is the form of vitamin A that controls differentiation and proliferation of epithelia. Our previous work established that normal breast epithelia synthesize RA from retinol, an ability retained by three immortalized but nontumorigenic cell lines but lost in five of six breast cell lines. In this work, we characterize the cause of this defect in one of the lines, the MCF-7 line. We have determined that the immortalized but nontumorigenic cell line, MTSV1.7, capable of synthesizing RA from both retinol and retinal, contains a retinaldehyde dehydrogenase activity for the second step in RA biosynthesis. We have identified it, after isolation, as a previously described enzyme, aldehyde dehydrogenase 6 (ALDH6). Immunohistochemical analysis of normal human breast with antibodies to ALDH6 showed expression of this enzyme in the glandular epithelia colocalized with cellular RA-binding protein type II, a possible marker for certain cells able to synthesize RA. ALDH6 was not present in MCF-7 cells, and these cells were unable to oxidize retinal to RA in culture. When MCF-7 cells were then transfected with ALDH6, they (re)gained the ability to oxidize retinal to RA as well as some ability to synthesize RA when provided with retinol. This suggests that loss of ALDH6 expression is the defect in RA biosynthesis in these cells. Identification of ALDH6 as the retinaldehyde dehydrogenase present in normal human breast epithelia provides the first tool necessary for studying the loss of RA synthetic ability in cancer cells and the relationship of this process to malignant transformation.
TL;DR: It is shown unambiguously that acetaldehyde is the sole physiological inducer of ethanol catabolism, and it is hypothesized that the intracellular acetaldehyde concentration is the critical factor governing the induction of the alc gene system.
TL;DR: The identification of the major metabolic pathways and products of [(3)H]-HNE in rat aortic smooth muscle cells in culture is reported and these metabolic pathways may be the key regulators of the vascular effects of HNE and oxidized LDL.
TL;DR: Experimental data show that disulfiram affects the level of brain biogenic amines at dose levels higher than those inhibiting the activity of aldehyde dehydrogenase, and in clinical practice 'disulfIRam reaction' could still be achieved with a low dosage regimen not producing neurotoxicity.
Abstract: Disulfiram is used in the treatment of chronic alcoholism, because of the unpleasant symptoms it provokes after ethanol intake. The underlying mechanism is believed to be the accumulation of acetaldehyde in the blood, due to inhibition of the liver aldehyde dehydrogenases. In addition, it is known that disulfiram also has some neurotoxic properties. The aim of our study was to investigate the relationship between the pharmacological and neurotoxicological properties of disulfiram with respect to the doses applied. Increasing doses of disulfiram (25, 50, 75, 100 and 150 mg/kg) were administered intraperitoneally to Wistar rats and the hepatic enzyme activities of alcohol and aldehyde dehydrogenases were measured. Also, in two brain subregions (midbrain and hypothalamus) the levels of noradrenaline, dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid were determined. The higher dose of disulfiram (150 mg/kg) produced lethal effects in all treated animals. Aldehyde dehydrogenase activities were inhibited by disulfiram in a dose-dependent way, while alcohol dehydrogenase was not affected at all. Concerning the levels of brain biogenic amines, disulfiram produced a significant reduction in noradrenaline and an increase in dopamine levels in both structures of the brain, in a dose-dependent way. However, the lowest dose applied (25 mg/kg) had no effects on brain catecholamines. It is known that high doses of disulfiram may cause severe encephalopathy and peripheral neuropathy in humans, which could be attributed to the impairment of the metabolism of brain biogenic amines, due to inhibition of dopamine-beta-hydroxylase. Our experimental data show that disulfiram affects the level of brain biogenic amines at dose levels higher than those inhibiting the activity of aldehyde dehydrogenase. Therefore, in clinical practice 'disulfiram reaction' could still be achieved with a low dosage regimen not producing neurotoxicity
TL;DR: The in vitro interactions of DSF, as well as a principal metabolite S-methyl-N,N-diethylthiocarbamoyl sulfoxide (MeDTC-SO), with both recombinant rat liver mitochondrial monomeric ALDH (rmALDH) and homotetrameric rmALDH are described.
TL;DR: It is shown that EhADH2 enzyme is required for E. histolytica growth and survival and that the C-terminal ADH domain of the enzyme functions as a separate entity, however, ALDH activity requires residues in both the N- and C-Terminal halves of the molecule.
TL;DR: The data suggest that reactive gliosis, as a response to injury, may affect GHB neuromodulatory pathways in neurodegenerative disease and elevate aldehyde detoxification pathways.
TL;DR: The metabolic ability of Kupffer cells to detoxify 4-HNE through oxidative (aldehyde dehydrogenase; ALDH), reductive (alcohol dehydrogen enzyme; ADH), and conjugative (glutathione S-transferase; GST) pathways was characterized and suggested that Kupfer cells are potentially vulnerable to the increased concentrations of 4- HNE occurring during oxidative stress.
TL;DR: The deprotected compound inhibited (KI 95 microM) aspartate semi-aldehyde dehydrogenase, a key enzyme involved in bacterial amino acid and peptidoglycan biosynthesis.
TL;DR: Using subcellular localization studies, it is shown that peroxisomes contain pristanal dehydrogenase activity which leads to conclude that the complete phytanic acid alpha-oxidation pathway is localized in peroxISomes.
TL;DR: Findings indicated that N-dealkylation may be an important step in DSF metabolism, and that the inhibition of ALDH occurred by carbamoylation caused by one of the DSF metabolites, most likely S-methyl-N,N-diethylthiocarbamoyl sulfoxide (MeDTC-SO).
TL;DR: These results identify alcohol oxidase as a novel pathogenicity factor and are discussed in relation to peroxisomal metabolism of fungal pathogens during growth in planta.
Abstract: Cladosporium fulvum is a mitosporic ascomycete pathogen of tomato. A study of fungal genes expressed during carbon starvation in vitro identified several genes that were up regulated during growth in planta. These included genes predicted to encode acetaldehyde dehydrogenase (Aldh1) and alcohol oxidase (Aox1). An Aldh1 deletion mutant was constructed. This mutant lacked all detectable ALDH activity, had lost the ability to grow with ethanol as a carbon source, but was unaffected in pathogenicity. Aox1 expression was induced by carbon starvation and during the later stages of infection. The alcohol oxidase enzyme activity has broadly similar properties (Km values, substrate specificity, pH, and heat stability) to yeast enzymes. Antibodies raised to Hansenula polymorpha alcohol oxi-dase (AOX) detected antigens in Western blots of starved C. fulvum mycelium and infected plant material. Antigen reacting with the antibodies was localized to organelles resembling peroxisomes in starved mycelium and infected plants. Disruption mutants of Aox1 lacked detectable AOX activity and had markedly reduced pathogenicity as assayed by two different measures of fungal growth. These results identify alcohol oxidase as a novel pathogenicity factor and are discussed in relation to peroxisomal metabolism of fungal pathogens during growth in planta.
01 Jun 2001
TL;DR: The liver and other major tissues of guinea-pigs had no immunologically detectable level of a putative GSTA4-4 orthologue, which exists as a minor GST protein in rat, mouse and human livers and exhibits extremely high catalytic activity towards HNE.
Abstract: In guinea-pig liver cytosol, racemic 4-hydroxy-2(E)-nonenal (HNE), a reactive and highly toxic product released from biomembranes by lipid peroxidation, was detoxified (S)-preferentially by GSH conjugation mediated by glutathione S-transferases (GSTs) and (R)-preferentially by NAD(+)-dependent oxidation mediated by aldehyde dehydrogenase (ALDH). The GST-mediated detoxification of the HNE enantiomers proceeded at much higher rates than that mediated by ALDH in guinea-pig liver cytosol. All the major guinea-pig GSTs, A1-1, M1-1, M1-2 and M1-3*, isolated from guinea-pig liver cytosol also catalysed the (S)-preferential conjugation of the HNE enantiomers. The liver and other major tissues of guinea-pigs had no immunologically detectable level of a putative GSTA4-4 orthologue, which exists as a minor GST protein in rat, mouse and human livers and exhibits extremely high catalytic activity towards HNE. All the hepatic rat GSTs, A1-1(2), A1-3, A4-4, M1-1, M1-2 and M2-2, also catalysed the (S)-preferential conjugation of HNE enantiomers.
TL;DR: Tight inhibition by zinc and activation of glycerol phosphate dehydrogenase by Thionein, a biological chelating agent, provide further support that modulation of zinc binding by metallothionein and thionein is a physiological mechanism of enzyme regulation.
TL;DR: Two studies provide a proof of principle that specific inhibition of gene expression can be used to mimic the protective effects afforded by the ALDH2–2 phenotype and lead to an aversion to ethanol.
Abstract: A mutation in the gene encoding for the liver mitochondrial aldehyde dehydrogenase ( ALDH2‐2 ), present in some Asian populations, lowers or abolishes the activity of this enzyme and results in elevations in blood acetaldehyde upon ethanol consumption, a phenotype that greatly protects against alcohol abuse and alcoholism. We have determined whether the administration of antisense phosphorothioate oligonucleotides (ASOs) can mimic the low-activity ALDH2‐2 Asian phenotype. Rat hepatoma cells incubated for 24 h with an antisense oligonucleotide (ASO-9) showed reductions in ALDH2 mRNA levels of 85% and ALDH2 (half-life of 22 h) activity of 55% equivalent to a � 90% inhibition in ALDH2 synthesis. Glutamate dehydrogenase mRNA and activity remained unchanged. Base mismatches in the oligonucleotide rendered ASO-9 virtually inactive, confirming an antisense effect. Administration of ASO-9 (20 mg/kg/day for 4 d) to rats resulted in a 50% reduction in liver ALDH2 mRNA, a 40% inhibition in ALDH2 activity, and a fourfold ( P � 0.001) increase in circulating plasma acetaldehyde levels after ethanol (1 g/kg) administration. Administration of ASO-9 to rats by osmotic pumps led to an aversion ( � 61%, P � 0.02) to ethanol. These studies provide a proof of principle that specific inhibition of gene expression can be used to mimic the protective effects afforded by the ALDH2‐2 phenotype.
TL;DR: Biochemical studies indicate that these two enzymes comprise a bifunctional heterodimer (DmpFG, molecular mass 71 kDa) and suggest that the product of the aldolase reaction is transferred to the dehydrogenase active site via a channeling mechanism.
Abstract: The final two steps of the meta-cleavage pathway for catechol degradation in Pseudomonas sp. strain CF600 involve the conversion of 4-hydroxy-2-ketovalerate to pyruvate and acetyl coenzyme A by the enzymes 4-hydroxy-2-ketovalerate aldolase and NAD+-dependent acylating aldehyde dehydrogenase. Biochemical studies indicate that these two enzymes comprise a bifunctional heterodimer (DmpFG, molecular mass 71 kDa) and suggest that the product of the aldolase reaction is transferred to the dehydrogenase active site via a channeling mechanism. Crystals of the DmpFG complex grow in multiple fan-like clusters of thin plates by the hanging-drop method and are improved by streak-seeding. The crystals belong to the orthorhombic space group P212121, with unit-cell parameters a = 102.0, b = 140.7, c = 191.3 A, and diffract to 2.1 A resolution. The asymmetric unit contains four DmpFG heterodimers. Heavy-atom derivative screening identified three isomorphous derivatives.