Aldehydes, Aldehyde Metabolism, and the ALDH2 Consortium.
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ABSTRACT:
SUBMITTER: Rwere F
PROVIDER: S-EPMC9221099 | biostudies-literature | 2022 May
REPOSITORIES: biostudies-literature
Publications
Aldehydes, Aldehyde Metabolism, and the ALDH2 Consortium.
Rwere Freeborn F Yu Xuan X Chen Che-Hong CH Gross Eric R ER
Biomolecules 20220530 6
The discovery of aldehydes dates back to 1774 when Carl Wilhelm Scheele synthesized acetaldehyde [...]. ...[more]
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Project description:Correcting a genetic mutation that leads to a loss of function has been a challenge. One such mutation is in aldehyde dehydrogenase 2 (ALDH2), denoted ALDH2*2. This mutation is present in ∼ 0.6 billion East Asians and results in accumulation of toxic acetaldehyde after consumption of ethanol. To temporarily increase metabolism of acetaldehyde in vivo, we describe an approach in which a pharmacologic agent recruited another ALDH to metabolize acetaldehyde. We focused on ALDH3A1, which is enriched in the upper aerodigestive track, and identified Alda-89 as a small molecule that enables ALDH3A1 to metabolize acetaldehyde. When given together with the ALDH2-specific activator, Alda-1, Alda-89 reduced acetaldehyde-induced behavioral impairment by causing a rapid reduction in blood ethanol and acetaldehyde levels after acute ethanol intoxication in both wild-type and ALDH2-deficient, ALDH2*1/*2, heterozygotic knock-in mice. The use of a pharmacologic agent to recruit an enzyme to metabolize a substrate that it usually does not metabolize may represent a novel means to temporarily increase elimination of toxic agents in vivo.
| S-EPMC4364197 | biostudies-literature
Project description:AimsThe present study was designed to examine the mechanism involved in mitochondrial aldehyde dehydrogenase (ALDH2)-induced cardioprotection against ischaemia/reperfusion (I/R) injury with a focus on autophagy.MethodsWild-type (WT), ALDH2 overexpression, and knockout (KO) mice (n = 4-6 for each index measured) were subjected to I/R, and myocardial function was assessed using echocardiographic, Langendroff, and edge-detection systems. Western blotting was used to evaluate AMP-dependent protein kinase (AMPK), Akt, autophagy, and the AMPK/Akt upstream signalling LKB1 and PTEN.ResultsALDH2 overexpression and KO significantly attenuated and accentuated, respectively, infarct size, factional shortening, and recovery of post-ischaemic left ventricular function following I/R as well as hypoxia/reoxygenation-induced cardiomyocyte contractile dysfunction. Autophagy was induced during ischaemia and remained elevated during reperfusion. ALDH2 significantly promoted autophagy during ischaemia, which was accompanied by AMPK activation and mammalian target of rapamycin (mTOR) inhibition. On the contrary, ALDH2 overtly inhibited autophagy during reperfusion accompanied by the activation of Akt and mTOR. Inhibition and induction of autophagy mitigated ALDH2-induced protection against cell death in hypoxia and reoxygenation, respectively. In addition, levels of the endogenous toxic aldehyde 4-hydroxy-2-nonenal (4-HNE) were elevated by ischaemia and reperfusion, which was abrogated by ALDH2. Furthermore, ALDH2 ablated 4-HNE-induced cardiomyocyte dysfunction and protein damage, whereas 4-HNE directly decreased pan and phosphorylated LKB1 and PTEN expression.ConclusionOur data suggest a myocardial protective effect of ALDH2 against I/R injury possibly through detoxification of toxic aldehyde and a differential regulation of autophagy through AMPK- and Akt-mTOR signalling during ischaemia and reperfusion, respectively.
| S-EPMC3076664 | biostudies-literature
Project description:Aldehyde-deformylating oxygenase (ADO) catalyzes O2-dependent release of the terminal carbon of a biological substrate, octadecanal, to yield formate and heptadecane in a reaction that requires external reducing equivalents. We show here that ADO also catalyzes incorporation of an oxygen atom from O2 into the alkane product to yield alcohol and aldehyde products. Oxygenation of the alkane product is much more pronounced with C9-10 aldehyde substrates, so that use of nonanal as the substrate yields similar amounts of octane, octanal, and octanol products. When using doubly-labeled [1,2-13C]-octanal as the substrate, the heptane, heptanal and heptanol products each contained a single 13C-label in the C-1 carbons atoms. The only one-carbon product identified was formate. [18O]-O2 incorporation studies demonstrated formation of [18O]-alcohol product, but rapid solvent exchange prevented similar determination for the aldehyde product. Addition of [1-13C]-nonanol with decanal as the substrate at the outset of the reaction resulted in formation of [1-13C]-nonanal. No 13C-product was formed in the absence of decanal. ADO contains an oxygen-bridged dinuclear iron cluster. The observation of alcohol and aldehyde products derived from the initially formed alkane product suggests a reactive species similar to that formed by methane monooxygenase (MMO) and other members of the bacterial multicomponent monooxygenase family. Accordingly, characterization by EPR and Mössbauer spectroscopies shows that the electronic structure of the ADO cluster is similar, but not identical, to that of MMO hydroxylase component. In particular, the two irons of ADO reside in nearly identical environments in both the oxidized and fully reduced states, whereas those of MMOH show distinct differences. These favorable characteristics of the iron sites allow a comprehensive determination of the spin Hamiltonian parameters describing the electronic state of the diferrous cluster for the first time for any biological system. The nature of the diiron cluster and the newly recognized products from ADO catalysis hold implications for the mechanism of C-C bond cleavage.
| S-EPMC3903409 | biostudies-literature
Project description:A number of studies have explored the association of the aldehyde dehydrogenases-2 (ALDH2) Glu487Lys polymorphism and risk of colorectal cancer; however, the results are inconsistent. We performed this meta-analysis to clarify this issue using all the available evidence. Relevant studies were retrieved by searching PubMed. Eleven case-control studies were included in the meta-analysis, representing 2909 cases and 4903 controls. The pooled results based on all included studies showed a decreased colorectal cancer risk in the analysis of the GA genotype vs. the GG genotype (OR = 0.81, 95%CI = 0.68-0.98, p = 0.03) and in the dominant genetic model analysis (OR = 0.81, 95%CI = 0.67-0.98, p = 0.03). However, there was no statistical difference in the AA vs. GG analysis (OR = 0.74, 95%CI = 0.52-1.06,p = 0.11) and the recessive genetic model analysis (OR = 0.86, 95%CI = 0.69-1.07, p = 0.17). Cumulative meta-analysis based on publication time confirmed these findings. Patients with colorectal cancer had a higher frequency of the GG genotype (OR = 1.10, 95% CI = 1.02-1.20, p = 0.02) and a lower frequency of the GA genotype (OR = 0.89, 95%CI = 0.81-0.98, p = 0.02) comparing with control population. Our results suggested that the ALDH2 Glu487Lys polymorphism may be associated with a decreased risk of colorectal cancer.
| S-EPMC3928247 | biostudies-literature
Project description:The biosynthesis of long-chain aliphatic hydrocarbons, which are derived from fatty acids, is widespread in Nature. The last step in this pathway involves the decarbonylation of fatty aldehydes to the corresponding alkanes or alkenes. In cyanobacteria, this is catalyzed by an aldehyde deformylating oxygenase. We have investigated the mechanism of this enzyme using substrates bearing an oxirane ring adjacent to the aldehyde carbon. The enzyme catalyzed the deformylation of these substrates to produce the corresponding oxiranes. Performing the reaction in D2O allowed the facial selectivity of proton addition to be examined by (1)H NMR spectroscopy. The proton is delivered with equal probability to either face of the oxirane ring, indicating the formation of an oxiranyl radical intermediate that is free to rotate during the reaction. Unexpectedly, the enzyme also catalyzes a side reaction in which oxiranyl-aldehydes undergo tandem deformylation to furnish alkanes two carbons shorter. We present evidence that this involves the rearrangement of the intermediate oxiranyl radical formed in the first step, resulting in aldehyde that is further deformylated in a second step. These observations provide support for a radical mechanism for deformylation and, furthermore, allow the lifetime of the radical intermediate to be estimated based on prior measurements of rate constants for the rearrangement of oxiranyl radicals.
| S-EPMC3944378 | biostudies-literature
Project description:BackgroundAldehyde dehydrogenase 2 (ALDH2) catalyzes the detoxification of aliphatic aldehydes, including acetaldehyde. About 45% of Han Chinese (East Asians), accounting for 8% of humans, carry a single point mutation in ALDH2*2 (E504K) that leads to accumulation of toxic reactive aldehydes.MethodsSequencing of a small Mexican cohort and a search in the ExAC genomic database for additional ALDH2 variants common in various ethnic groups was set to identify missense variants. These were evaluated in vitro, and in cultured cells expressing these new and common variants.FindingsIn a cohort of Hispanic donors, we identified 2 novel mutations in ALDH2. Using the ExAC genomic database, we found these identified variants and at least three other ALDH2 variants with a single point mutation among Latino, African, South Asian, and Finnish ethnic groups, at a frequency of >5/1000. Although located in different parts of the ALDH2 molecule, these common ALDH2 mutants exhibited a significant reduction in activity compared with the wild type enzyme in vitro and in 3T3 cells overexpressing each of the variants, and a greater ethanol-induced toxicity. As Alda-1, previously identified activator, did not activate some of the new mutant ALDH2 enzymes, we continued the screen and identified Alda-64, which is effective in correcting the loss of activity in most of these new and common ALDH2 variants.InterpretationSince ~80% of the world population consumes ethanol and since acetaldehyde accumulation contributes to a variety of diseases, the identification of additional inactivating variants of ALDH2 in different ethnic groups may help develop new 'precision medicine' for carriers of these inactive ALDH2.
| S-EPMC7218264 | biostudies-literature
Project description:Human alcohol-consumption behavior is partly genetically encoded. The alcohol consumption of 987 residents in Keelung, Taiwan, was evaluated by using the Alcohol Use Disorder Identification Test (AUDIT). We assessed ~750,000 genomic variants of 71 residents who drank hazardously (AUDIT score ≥ 8) and 126 residents who did not drink in their daily lives (AUDIT score = 0), using high-density single nucleotide polymorphism (SNP) arrays. The rs671 G > A manifests the highest significance of the association with drinking behavior (Fisher's exact P = 8.75 × 10-9). It is a pleiotropic, non-synonymous variant in the aldehyde dehydrogenase 2 (ALDH2) gene. The minor allele "A", commonly known as ALDH2*2, is associated with non-drinkers. Intriguingly, identity-by-descent haplotypes encompassing genomic regions with a median length of 1.6 (0.6-2.0) million nucleotide bases were found in all study participants with either heterozygous or homozygous ALDH2*2 (n = 81 and 13, respectively). We also analyzed a public-domain dataset with genome-wide genotypes of 2000 participants in Guangzhou, a coastal city in Southern China. Among them, 175 participants have homozygous ALDH2*2 genotype, and again, long ALDH2*2-carrying haplotypes were found in all 175 participants without exceptions. The median length of the ALDH2*2-carrying haplotype is 1.7 (0.5-2.8) million nucleotide bases. The haplotype lengths in the Keelung and Guangzhou cohorts combined indicate that the origin of the ALDH2*2 allele dates back to 7935 (7014-9381) years ago. In conclusion, the rs671 G > A is the leading genomic variant associated with the long-term drinking behavior among residents of Keelung, Taiwan. The ALDH2*2 allele has been in Asian populations since prehistoric times.
| S-EPMC8465343 | biostudies-literature
Project description:BackgroundThe association of the aldehyde dehydrogenases-2 (ALDH2) Glu504Lys polymorphism and hypertension in Asians has been investigated. This meta-analysis aims to comprehensively assess the influence of this polymorphism on the hypertension risk.MethodAn electronic literature search was conducted using the following database: PubMed, Embase and China National Knowledge Infrastructure (CNKI) till to Mar 25th, 2015. The strength of the association between statins and fractures risk was calculated with the OR and respective 95% CIs. The random effect model was used.ResultsNine studies evaluating the relationship between ALDH2 Glu504Lys polymorphism and hypertension risk in Asians were selected in this meta-analysis. A total of 12161 subjects were included. The data showed that ALDH2 Glu504Lys polymorphism could increase the risk of hypertension of Asians (OR = 1.31; 95% CI, 1.18-1.47; P < 0.00001). In the subgroup analysis of race, both Japanese and Chinese with ALDH2 Glu504Lys polymorphism showed increased hypertension risk (OR = 1.23; 95% CI, 1.09-1.38; P = 0.0006 and OR = 1.46; 95% CI, 1.21-1.77; P = 0.0001), respectively. In the subgroup analysis of gender, males with this polymorphism showed increased hypertension risk (OR = 1.59; 95% CI, 1.40-1.80; P < 0.00001). However, females did not showed this result (OR = 0.94; 95% CI, 0.69-1.30; P = 0.71). When considered alcohol consumption, we found that drinkers and non-drinkers all had increased hypertension risk, if they carried this polymorphism.ConclusionThis meta-analysis suggested that ALDH2 Glu504Lys polymorphism was a risk factor of hypertension in Asians.
| S-EPMC4565253 | biostudies-literature
Project description:BackgroundAldehyde dehydrogenases (ALDHs) play a major role in detoxification of aldehydes. High expression of ALDHs is a marker for stem cells of many organs including the lungs. A common polymorphism in ALDH2 gene (ALDH2*2) results in inactivation of the enzyme and is associated with alcohol flushing syndrome and increased risk for cardiovascular and Alzheimer's diseases and some cancers. The effect of this ALDH2 polymorphism on the lung and its stem cells has not been thoroughly examined.MethodsWe examined the association between the ALDH2*2 allele and lung function parameters in a population of healthy individuals. We also examined its association with the incidence of asthma and COPD in patient cohorts. We used the in vitro colony forming assay to detect the effect of the polymorphism on lung epithelial stem cells from both primary human surgical samples and Aldh2*2 transgenic (Tg) and Aldh2 -/- mice. Response to acute and chronic lung injuries was compared between wild type (WT), Aldh2*2 Tg and Aldh2 -/- mice.ResultsIn humans, the ALDH2*2 allele was associated with lower FEV1/FVC in the general population, but not with the development of asthma or COPD. Both the bronchial and lung epithelium carrying the ALDH2*2 allele showed a tendency for lower colony forming efficiency (CFE) compared to ALDH2 allele. In mice, the tracheal epithelial thickness, nuclear density, and number of basal stem cells were significantly lower in Aldh2 -/- and Aldh2*2 Tg adult mice than in WT. Electron microscopy showed significantly increased number of morphologically abnormal mitochondria in the trachea of Aldh2 -/- mice. Aldh2 -/- tracheal and lung cells showed higher ROS levels and fewer functional mitochondria than those from WT mice. No significant differences were detected when tracheal and lung epithelial stem cells were examined for their in vitro CFE. When exposed to chronic cigarette smoke, Aldh2*2 Tg mice were resistant to emphysema development, whereas influenza infection caused more epithelial damage in Aldh2 -/- mice than in WT mice.ConclusionsALDH2 polymorphism has several subtle effects on the lungs, some of which are similar to changes observed during normal aging, suggesting a "premature lung aging" effect.
| S-EPMC5399815 | biostudies-literature
Project description:Chronic alcohol intake leads to insulin resistance and alcoholic cardiomyopathy, which appears to be a result of the complex interaction between genes and environment. This study was designed to examine the impact of aldehyde dehydrogenase-2 (ALDH2) transgenic overexpression on alcohol-induced insulin resistance and myocardial injury. ALDH2 transgenic mice were produced using chicken beta-actin promoter. Wild-type FVB and ALDH2 mice were fed a 4% alcohol or control diet for 12 weeks. Cell shortening was evaluated using an edge-detection system. Western blot analysis was used to assess insulin signaling at the levels of receptor, IRS, Akt, GSK-3beta, the transcription factors Foxo3a, c-Jun amino-terminal kinase (JNK) and c-Jun. Chronic alcohol intake led to glucose intolerance, reduced glucose uptake, cardiac hypertrophy and reduced cell shortening, the effects of which were alleviated by ALDH2. ALDH2 significantly attenuated alcohol-induced decrease in the insulin-stimulated tyrosine phosphorylation and increase in serine phosphorylation of IRS. Phosphorylation of Akt, GSK-3beta and Foxo3a was reduced following alcohol intake, the effect of which was abrogated by ALDH2. Levels of JNK, c-Jun and their phosphorylation were elevated following chronic alcohol intake, which were obliterated by ALDH2. Transfection of H9C2 myoblast cells with Foxo3a adenovirus mimicked acetaldehyde-induced JNK activation and glucose uptake defect whereas the dominant negative Foxo3a ablated acetaldehyde-elicited insulin insensitivity. In addition, ALDH2 reversed alcohol-induced myocardial ER stress. These data revealed that ALDH2 overexpression antagonizes chronic alcohol intake-induced cardiac insulin insensitivity and contractile defect, possibly via improvement of insulin signaling at the levels of insulin receptor, IRS, Akt, Foxo3a and JNK.
| S-EPMC2703697 | biostudies-literature