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Clinics in Liver Disease Nov 2012This article describes the pathways and factors that modulate blood alcohol levels and metabolism and describes how the body disposes of alcohol. The various factors... (Review)
Review
This article describes the pathways and factors that modulate blood alcohol levels and metabolism and describes how the body disposes of alcohol. The various factors that play a role in the distribution of alcohol in the body, influence the absorption of alcohol, and contribute to first-pass metabolism of alcohol are described. Most alcohol is oxidized in the liver, and general principles and overall mechanisms for alcohol oxidation are summarized. The kinetics of alcohol elimination in-vivo and the various genetic and environmental factors that can modify the rate of alcohol metabolism are discussed.
Topics: Absorption; Acetaldehyde; Alcohol Dehydrogenase; Alcoholism; Cytochrome P-450 CYP2E1; Electron Transport; Ethanol; Female; Food-Drug Interactions; Humans; Kinetics; Liver; Male; NAD; Oxidation-Reduction; Tissue Distribution
PubMed: 23101976
DOI: 10.1016/j.cld.2012.08.002 -
Alcohol Research & Health : the Journal... 2006Alcohol is eliminated from the body by various metabolic mechanisms. The primary enzymes involved are aldehyde dehydrogenase (ALDH), alcohol dehydrogenase (ADH),... (Review)
Review
Alcohol is eliminated from the body by various metabolic mechanisms. The primary enzymes involved are aldehyde dehydrogenase (ALDH), alcohol dehydrogenase (ADH), cytochrome P450 (CYP2E1), and catalase. Variations in the genes for these enzymes have been found to influence alcohol consumption, alcohol-related tissue damage, and alcohol dependence. The consequences of alcohol metabolism include oxygen deficits (i.e., hypoxia) in the liver; interaction between alcohol metabolism byproducts and other cell components, resulting in the formation of harmful compounds (i.e., adducts); formation of highly reactive oxygen-containing molecules (i.e., reactive oxygen species [ROS]) that can damage other cell components; changes in the ratio of NADH to NAD+ (i.e., the cell's redox state); tissue damage; fetal damage; impairment of other metabolic processes; cancer; and medication interactions. Several issues related to alcohol metabolism require further research.
Topics: Alcohol Dehydrogenase; Alcohol Drinking; Aldehyde Dehydrogenase; Cytochrome P-450 CYP2E1; Ethanol; Humans
PubMed: 17718403
DOI: No ID Found -
Microbiology Spectrum Jun 2023Alcohol is an essential drug in human life with multiple medical functions, but excessive alcohol intake, even a single episode of binge drinking, can cause serious...
Alcohol is an essential drug in human life with multiple medical functions, but excessive alcohol intake, even a single episode of binge drinking, can cause serious damage. Reducing alcohol consumption or absorption is a direct way to alleviate the related harm. Alcohol is decomposed successively by alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) in the liver. Here, we produced a human ADH1B (hADH1B)-expressing probiotic, a recombinant Lactococcus lactis, that aimed to enhance alcohol degradation in the intestinal tract after oral administration. Our results showed that the oral hADH1B-expressing probiotic reduced alcohol absorption, prolonged the alcohol tolerance time, and shortened the recovery time after acute alcohol challenge. More importantly, the liver and intestine were protected from acute injury caused by alcohol challenge. Therefore, the engineered probiotic has the potential to protect organ damage from alcohol consumption. Furthermore, this engineered probiotic may have beneficial effects on alcohol-related diseases such as alcoholic fatty liver disease. Alcohol plays an important role in medical treatment, culture, and social interaction. However, excessive alcohol consumption or improper alcohol intake patterns can lead to serious damage to health. Aiming to reduce the harm of alcohol consumption, we designed a recombinant probiotic expressing hADH1B. Our results showed that this recombinant probiotic can reduce alcohol absorption and protect the body from alcohol damage, including hangover, liver, and intestinal damage. Reducing alcohol damage is helpful to the health of people with difficulty in abstinence. The engineered probiotic may provide new strategies for treatment and prevention of the negative effects of alcohol, and it also has the potential for widespread application.
Topics: Humans; Mice; Animals; Ethanol; Alcohol Drinking; Liver; Alcohol Dehydrogenase; Probiotics
PubMed: 37039510
DOI: 10.1128/spectrum.04294-22 -
Breast (Edinburgh, Scotland) Aug 2012
Topics: Alcohol Dehydrogenase; Breast Neoplasms; Female; Genotype; Humans; Polymorphism, Genetic
PubMed: 22381152
DOI: 10.1016/j.breast.2012.01.017 -
Archiwum Medycyny Sadowej I Kryminologii 2016Alcohol dependence is both a medical and socioeconomic problem. The disease is multifactorial, i.e. its development is attributable to gene-gene and gene-environment... (Review)
Review
Alcohol dependence is both a medical and socioeconomic problem. The disease is multifactorial, i.e. its development is attributable to gene-gene and gene-environment interactions. Multi-centre studies investigating the genetic background of alcoholism stress the role of genes encoding enzymes of the ethanol decomposition pathway in the human body, particularly alcohol dehydrogenase (ADH), in the development of alcohol dependence. Among five classes of alcohol dehydrogenases, class I and IV isoenzymes have been found to be associated with alcohol dependence. Class IV is of particular interest due to its occurrence in the upper gastrointestinal tract, mainly in the stomach. No activity of the enzyme has been demonstrated in the liver. Single nucleotide polymorphism (SNP) of the gene encoding ADH class IV (ADH7) affects its ethanol-oxidizing activity in the gastric lumen, thereby influencing the first-pass metabolism (FPM) of the substance. The findings published by various research centres have demonstrated that specific SNP changes in the ADH7 gene are of different significance for the risk of alcohol dependence according to the population studied.
Topics: Alcohol Dehydrogenase; Alcohol Drinking; Aldehyde Dehydrogenase; Humans; Polymorphism, Single Nucleotide; Risk Factors
PubMed: 28453170
DOI: 10.5114/amsik.2016.66401 -
Applied and Environmental Microbiology Dec 2022Alkanes produced by microorganisms are expected to be an alternative to fossil fuels as an energy source. Microbial synthesis of alkanes involves the formation of fatty...
Alkanes produced by microorganisms are expected to be an alternative to fossil fuels as an energy source. Microbial synthesis of alkanes involves the formation of fatty aldehydes via fatty acyl coenzyme A (acyl-CoA) intermediates derived from fatty acid metabolism, followed by aldehyde decarbonylation to generate alkanes. Advancements in metabolic engineering have enabled the construction of such pathways in various microorganisms, including Escherichia coli. However, endogenous aldehyde reductases in the host microorganisms are highly active in converting fatty aldehydes to fatty alcohols, limiting the substrate pool for alkane production. To reuse the alcohol by-product, a screening of fatty alcohol-assimilating microorganisms was conducted, and a bacterial strain, sp. strain 7-4, was found to convert 1-tetradecanol to tetradecanal. From this strain, an alcohol dehydrogenase, PsADH, was purified and found to be involved in 1-tetradecanol-oxidizing reaction. Subsequent heterologous expression of the gene in E. coli was conducted, and recombinant PsADH was purified for a series of biochemical characterizations, including cofactors, optimal reaction conditions, and kinetic parameters. Furthermore, direct alkane production from alcohol was achieved in E. coli by coexpressing PsADH with a cyanobacterial aldehyde-deformylating oxygenase and a reducing system, including ferredoxin and ferredoxin reductase, from Nostoc punctiforme PCC73102. The alcohol-aldehyde-alkane synthetic route established in this study will provide a new approach to utilizing fatty alcohols for the production of alkane biofuel. Alcohol dehydrogenases are a group of enzymes found in many organisms. Unfortunately, studies on these enzymes mainly focus on their activities toward short-chain alcohols. In this study, we discovered an alcohol dehydrogenase, PsADH, from the bacterium sp. 7-4, which can oxidize 1-tetradecanol to tetradecanal. The medium-chain aldehyde products generated by this enzyme can serve as the substrate of aldehyde-deformylating oxygenase to produce alkanes. The enzyme found in this study can be applied to the biosynthetic pathway involving the formation of medium-chain aldehydes to produce alkanes and other valuable compounds.
Topics: Escherichia coli; Alcohol Dehydrogenase; Ferredoxins; Aldehydes; Alcohols; Alkanes; Fatty Acids; Fatty Alcohols; Oxygenases
PubMed: 36416567
DOI: 10.1128/aem.01264-22 -
Alcoholism, Clinical and Experimental... Dec 2018Alcohol use disorders (AUDs) are complex traits, meaning that variations in many genes contribute to the risk, as does the environment. Although the total genetic... (Review)
Review
Alcohol use disorders (AUDs) are complex traits, meaning that variations in many genes contribute to the risk, as does the environment. Although the total genetic contribution to risk is substantial, most individual variations make only very small contributions. By far the strongest contributors are functional variations in 2 genes involved in alcohol (ethanol [EtOH]) metabolism. A functional variant in alcohol dehydrogenase 1B (ADH1B) is protective in people of European and Asian descent, and a different functional variant in the same gene is protective in those of African descent. A strongly protective variant in aldehyde dehydrogenase 2 (ALDH2) is essentially only found in Asians. This highlights the need to study a wide range of populations. The likely mechanism of protection against heavy drinking and AUDs in both cases is alteration in the rate of metabolism of EtOH that at least transiently elevates acetaldehyde. Other ADH and ALDH variants, including functional variations in ADH1C, have also been implicated in affecting drinking behavior and risk for alcoholism. The pattern of linkage disequilibrium in the ADH region and the differences among populations complicate analyses, particularly of regulatory variants. This critical review focuses upon the ADH and ALDH genes as they affect AUDs.
Topics: Alcohol Dehydrogenase; Alcoholism; Aldehyde Dehydrogenase, Mitochondrial; Humans; Linkage Disequilibrium
PubMed: 30320893
DOI: 10.1111/acer.13904 -
The Journal of Biological Chemistry Oct 2014The role of evolutionary pressure on the chemical step catalyzed by enzymes is somewhat enigmatic, in part because chemistry is not rate-limiting for many optimized... (Review)
Review
The role of evolutionary pressure on the chemical step catalyzed by enzymes is somewhat enigmatic, in part because chemistry is not rate-limiting for many optimized systems. Herein, we present studies that examine various aspects of the evolutionary relationship between protein dynamics and the chemical step in two paradigmatic enzyme families, dihydrofolate reductases and alcohol dehydrogenases. Molecular details of both convergent and divergent evolution are beginning to emerge. The findings suggest that protein dynamics across an entire enzyme can play a role in adaptation to differing physiological conditions. The growing tool kit of kinetics, kinetic isotope effects, molecular biology, biophysics, and bioinformatics provides means to link evolutionary changes in structure-dynamics function to the vibrational and conformational states of each protein.
Topics: Alcohol Dehydrogenase; Animals; Bacterial Proteins; Biocatalysis; Catalytic Domain; Evolution, Molecular; Humans; Kinetics; Models, Chemical; Tetrahydrofolate Dehydrogenase
PubMed: 25210031
DOI: 10.1074/jbc.R114.565515 -
American Journal of Medical Genetics.... Mar 2018The ADH1B (Alcohol Dehydrogenase 1B (class I), Beta Polypeptide) gene and its best-known functional alleles, Arg48His (rs1229984, ADH1B*2) and Arg370Cys (rs2066702,... (Review)
Review
The ADH1B (Alcohol Dehydrogenase 1B (class I), Beta Polypeptide) gene and its best-known functional alleles, Arg48His (rs1229984, ADH1B*2) and Arg370Cys (rs2066702, ADH1B*3), have been investigated in relation to many phenotypic traits; most frequently including alcohol metabolism and alcohol drinking behaviors, but also human evolution, liver function, cancer, and, recently, the comprehensive human phenome. To understand ADH1B functions and consequences, we provide here a bioinformatic analysis of its gene regulation and molecular functions, literature review of studies focused on this gene, and a discussion regarding future research perspectives. Certain ADH1B alleles have large effects on alcohol metabolism, and this relationship particularly encourages further investigations in relation to alcoholism and alcohol-associated cancer to understand better the mechanisms by which alcohol metabolism contributes to alcohol abuse and carcinogenesis. We also observed that ADH1B has complex mechanisms that regulate its expression across multiple human tissues, and these may be involved in cardiac and metabolic traits. Evolutionary data strongly suggest that the selection signatures at the ADH1B locus are primarily related to effects other than those on alcohol metabolism. This is also supported by the involvement of ADH1B in multiple molecular pathways and by the findings of our recent phenome-wide association study. Accordingly, future studies should also investigate other functions of ADH1B potentially relevant for the human phenome. © 2017 Wiley Periodicals, Inc.
Topics: Alcohol Dehydrogenase; Alcohol Drinking; Alcoholism; Alleles; Genotype; Humans; Neoplasms; Phenotype
PubMed: 28349588
DOI: 10.1002/ajmg.b.32523 -
Archives of Biochemistry and Biophysics Jan 2010As shown by X-ray crystallography, horse liver alcohol dehydrogenase undergoes a global conformational change upon binding of NAD(+) or NADH, involving a rotation of the... (Review)
Review
As shown by X-ray crystallography, horse liver alcohol dehydrogenase undergoes a global conformational change upon binding of NAD(+) or NADH, involving a rotation of the catalytic domain relative to the coenzyme binding domain and the closing up of the active site to produce a catalytically efficient enzyme. The conformational change requires a complete coenzyme and is affected by various chemical or mutational substitutions that can increase the catalytic turnover by altering the kinetics of the isomerization and rate of dissociation of coenzymes. The binding of NAD(+) is kinetically limited by a unimolecular isomerization (corresponding to the conformational change) that is controlled by deprotonation of the catalytic zinc-water to produce a negatively-charged zinc-hydroxide, which can attract the positively-charged nicotinamide ring. The deprotonation is facilitated by His-51 acting through a hydrogen-bonded network to relay the proton to solvent. Binding of NADH also involves a conformational change, but the rate is very fast. After the enzyme binds NAD(+) and closes up, the substrate displaces the hydroxide bound to the catalytic zinc; this exchange may involve a double displacement reaction where the carboxylate group of a glutamate residue first displaces the hydroxide (inverting the tetrahedral coordination of the zinc), and then the exogenous ligand displaces the glutamate. The resulting enzyme-NAD(+)-alcoholate complex is poised for hydrogen transfer, and small conformational fluctuations may bring the reactants together so that the hydride ion is transferred by quantum mechanical tunneling. In the process, the nicotinamide ring may become puckered, as seen in structures of complexes of the enzyme with NADH. The conformational changes of alcohol dehydrogenase demonstrate the importance of protein dynamics in catalysis.
Topics: Alcohol Dehydrogenase; Amino Acids; Biocatalysis; Crystallography, X-Ray; Hydrogen-Ion Concentration; Isomerism; Kinetics; Models, Molecular; NAD; Protein Binding; Protein Conformation
PubMed: 19583966
DOI: 10.1016/j.abb.2009.07.001