Acetaldehyde dehydrogenase

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Acetaldehyde dehydrogenase
Pseudomonas aldolase-dehydrogenase assembly PDB 1NVM.png
Pseudomonas sp. aldolase-dehydrogenase heterotetramer assembly consisting of 4-hydroxy-2-ketovalerate aldolase (blue) and acetaldehyde dehydrogenase (red). PDB: 1NVM ​ [1]
Identifiers
EC no. 1.2.1.10
CAS no. 9028-91-5
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Acetaldehyde dehydrogenases (EC 1.2.1.10) are dehydrogenase enzymes which catalyze the conversion of acetaldehyde into acetyl-CoA. This can be summarized as follows:

Contents

Acetaldehyde + NAD+ + Coenzyme A ↔ Acetyl-CoA + NADH + H+

In humans, there are three known genes which encode this enzymatic activity, ALDH1A1, ALDH2, and the more recently discovered ALDH1B1 (also known as ALDH5). These enzymes are members of the larger class of aldehyde dehydrogenases.

The CAS number for this type of the enzyme is [9028-91-5].

Structure

Cysteine-302 is one of three consecutive Cys residues and is crucial to the enzyme's catalytic function. The residue is alkylated by iodoacetamide in both the cytosolic and mitochondrial isozymes, with modifications to Cys-302 indicative of catalytic activity with other residues. Furthermore, the preceding sequence Gln-Gly-Gln-Cys is conserved in both isozymes for both human and horse, which is consistent with Cys-302 being crucial to catalytic function. [2]

As discovered by site-directed mutagenesis, glutamate-268 is a key component of liver acetaldehyde dehydrogenase and is also critical to catalytic activity. Since activity in mutants could not be restored by addition of general bases, it's suggested that the residue functions as a general base for activation of the essential Cys-302 residue. [3]

In bacteria, acylating acetaldehyde dehydrogenase forms a bifunctional heterodimer with metal-dependent 4-hydroxy-2-ketovalerate aldolase. Utilized in the bacterial degradation of toxic aromatic compounds, the enzyme's crystal structure indicates that intermediates are shuttled directly between active sites through a hydrophobic intermediary channel, providing an unreactive environment in which to move the reactive acetaldehyde intermediate from the aldolase active site to the acetaldehyde dehydrogenase active site. Such communication between proteins allows for the efficient transfer substrates from one active site to the next. [1]

Evolution

Although the two isozymes (ALDH1 and ALDH2) do not share a common subunit, the homology between the human ALDH1 and ALDH2 proteins is 66% at the coding nucleotide level and 69% at the amino acid level, which is found to be lower than the 91% homology between human ALDH1 and horse ALDH1. Such a finding is consistent with evidence suggesting the early evolutionary divergence between cytosolic and mitochondrial isozymes, as seen in the 50% homology between pig mitochondrial and cytosolic aspartate aminotransferases. [4]

Role in metabolism of alcohol

In the liver, ethanol is converted into acetyl CoA by a two step process. In the first step, ethanol is converted to acetaldehyde by alcohol dehydrogenase. In the second step, the acetaldehyde is converted to acetyl CoA by acetaldehyde dehydrogenase. Acetaldehyde is more toxic than alcohol and is responsible for many hangover symptoms. [5]

About 50% of people of Northeast Asian descent have a dominant mutation in their acetaldehyde dehydrogenase gene, [6] making this enzyme less effective, which causes the alcohol flush reaction, also known as Asian flush syndrome. A similar mutation is found in about 5–10% of blond-haired blue-eyed people of Northern European descent. [7] In these people, acetaldehyde accumulates after drinking alcohol, leading to symptoms of acetaldehyde poisoning, including the characteristic flushing of the skin and increased heart and respiration rates. [7] Other symptoms can include severe abdominal and urinary tract cramping, hot and cold flashes, profuse sweating, and profound malaise. [7] Individuals with deficient acetaldehyde dehydrogenase activity are far less likely to become alcoholics, but seem to be at a greater risk of liver damage, alcohol-induced asthma, and contracting cancers of the oro-pharynx and esophagus due to acetaldehyde overexposure. [7]

Acetaldehyde dehydrogenase reaction diagram Acetaldehyde Dehydrogenase Reaction.png
Acetaldehyde dehydrogenase reaction diagram

This demonstrates that many of ethanol's toxic effects are mediated via the acetaldehyde metabolite and can therefore be mitigated by substances such as fomepizole which effectively reduces the conversion rate of ethanol to acetaldehyde in vivo.

ALDH2, which has a lower KM for acetaldehydes than ALDH1 and acts predominantly in the mitochondrial matrix, is the main enzyme in acetaldehyde metabolism and has three genotypes. A single point mutation (G → A) at exon 12 of the ALDH2 gene causes a replacement of glutamate with lysine at residue 487, resulting in the ALDH2K enzyme. [8] ALDH2K has an increased KM for NAD+, rendering it virtually inactive at cellular concentrations of NAD+. [6] Since ALDH2 is a randomized tetramer, the hetero-mutated genotype is reduced to only 6% activity compared to wild type, while homo-mutated genotypes have virtually zero enzyme activity. [9] The ALDH2-deficient subunit is dominant in hybridization with a wild type subunit, resulting in inactivation of the isozyme by interfering with catalytic activity and increasing turnover. [10] ALDH2 genetic variation has been closely correlated with alcohol dependence, with heterozygotes at a reduced risk compared to wild type homozygotes and individual homozygotes for the ALDH2-deficient at a very low risk for alcoholism. [11]

The drug disulfiram (Antabuse) prevents the oxidation of acetaldehyde to acetic acid and is used in the treatment of alcoholism. ALDH1 is strongly inhibited by disulfiram, while ALDH2 is resistant to its effect. The cysteine residue at 302 in ALDH1 and 200 in ALDH2 is implicated as a disulfiram binding site on the enzyme and serves as a disulfiram sensitive thiol site. [12] Covalent binding of disulfiram to the thiol blocks the binding of one of the cysteine residues with iodoacetamide, thereby inactivating the enzyme and significantly lowering catalytic activity. Activity can be recovered by treatment with 2-mercaptoethanol, although not with glutathione. [13]

Metronidazole (Flagyl), which is used to treat certain parasitic infections as well as pseudomembranous colitis, causes similar effects to disulfiram. Coprine (which is an amino acid found in certain coprinoid mushrooms) metabolizes in vivo to 1-aminocyclopropanol which causes similar effects as well.

Role in fat metabolism

ALDH1 is involved in the metabolism of Vitamin A. Animal models suggest that absence of the gene is associated with protection against visceral adiposity (PMC   2233696).

See also

Related Research Articles

A dehydrogenase is an enzyme belonging to the group of oxidoreductases that oxidizes a substrate by reducing an electron acceptor, usually NAD+/NADP+ or a flavin coenzyme such as FAD or FMN. Like all catalysts, they catalyze reverse as well as forward reactions, and in some cases this has physiological significance: for example, alcohol dehydrogenase catalyzes the oxidation of ethanol to acetaldehyde in animals, but in yeast it catalyzes the production of ethanol from acetaldehyde.

Acetaldehyde (IUPAC systematic name ethanal) is an organic chemical compound with the formula CH3CHO, sometimes abbreviated as MeCHO. It is a colorless liquid or gas, boiling near room temperature. It is one of the most important aldehydes, occurring widely in nature and being produced on a large scale in industry. Acetaldehyde occurs naturally in coffee, bread, and ripe fruit, and is produced by plants. It is also produced by the partial oxidation of ethanol by the liver enzyme alcohol dehydrogenase and is a contributing cause of hangover after alcohol consumption. Pathways of exposure include air, water, land, or groundwater, as well as drink and smoke. Consumption of disulfiram inhibits acetaldehyde dehydrogenase, the enzyme responsible for the metabolism of acetaldehyde, thereby causing it to build up in the body.

<span class="mw-page-title-main">Alcohol dehydrogenase</span> Group of dehydrogenase enzymes

Alcohol dehydrogenases (ADH) (EC 1.1.1.1) are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide (NAD+) to NADH. In humans and many other animals, they serve to break down alcohols that are otherwise toxic, and they also participate in the generation of useful aldehyde, ketone, or alcohol groups during the biosynthesis of various metabolites. In yeast, plants, and many bacteria, some alcohol dehydrogenases catalyze the opposite reaction as part of fermentation to ensure a constant supply of NAD+.

<span class="mw-page-title-main">Disulfiram</span> Chemical compound

Disulfiram is a medication used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol. Disulfiram works by inhibiting the enzyme aldehyde dehydrogenase, causing many of the effects of a hangover to be felt immediately following alcohol consumption. Disulfiram plus alcohol, even small amounts, produces flushing, throbbing in the head and neck, a throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, fast heart rate, low blood pressure, fainting, marked uneasiness, weakness, vertigo, blurred vision, and confusion. In severe reactions there may be respiratory depression, cardiovascular collapse, abnormal heart rhythms, heart attack, acute congestive heart failure, unconsciousness, convulsions, and death.

<span class="mw-page-title-main">Alcohol flush reaction</span> Effect of alcohol consumption on the human body

Alcohol flush reaction is a condition in which a person develops flushes or blotches associated with erythema on the face, neck, shoulders, and in some cases, the entire body after consuming alcoholic beverages. The reaction is the result of an accumulation of acetaldehyde, a metabolic byproduct of the catabolic metabolism of alcohol, and is caused by an aldehyde dehydrogenase 2 deficiency.

<span class="mw-page-title-main">Alcohol tolerance</span> Bodily responses to the functional effects of ethanol in alcoholic beverages

Alcohol tolerance refers to the bodily responses to the functional effects of ethanol in alcoholic beverages. This includes direct tolerance, speed of recovery from insobriety and resistance to the development of alcohol use disorder.

<span class="mw-page-title-main">Aldehyde dehydrogenase</span> Group of enzymes

Aldehyde dehydrogenases are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes to carboxylic acids. The oxygen comes from a water molecule. To date, nineteen ALDH genes have been identified within the human genome. These genes participate in a wide variety of biological processes including the detoxification of exogenously and endogenously generated aldehydes.

Ethanol, an alcohol found in nature and in alcoholic drinks, is metabolized through a complex catabolic metabolic pathway. In humans, several enzymes are involved in processing ethanol first into acetaldehyde and further into acetic acid and acetyl-CoA. Once acetyl-CoA is formed, it becomes a substrate for the citric acid cycle ultimately producing cellular energy and releasing water and carbon dioxide. Due to differences in enzyme presence and availability, human adults and fetuses process ethanol through different pathways. Gene variation in these enzymes can lead to variation in catalytic efficiency between individuals. The liver is the major organ that metabolizes ethanol due to its high concentration of these enzymes.

<span class="mw-page-title-main">ALDH2</span> Enzyme

Aldehyde dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ALDH2 gene located on chromosome 12. ALDH2 belongs to the aldehyde dehydrogenase family of enzymes. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. ALDH2 has a low Km for acetaldehyde, and is localized in mitochondrial matrix. The other liver isozyme, ALDH1, localizes to the cytosol.

<span class="mw-page-title-main">Retinal dehydrogenase</span>

In enzymology, a retinal dehydrogenase, also known as retinaldehyde dehydrogenase (RALDH), catalyzes the chemical reaction converting retinal to retinoic acid. This enzyme belongs to the family of oxidoreductases, specifically the class acting on aldehyde or oxo- donor groups with NAD+ or NADP+ as acceptor groups, the systematic name being retinal:NAD+ oxidoreductase. This enzyme participates in retinol metabolism. The general scheme for the reaction catalyzed by this enzyme is:

<span class="mw-page-title-main">ADH1B</span> Protein-coding gene in the species Homo sapiens

Alcohol dehydrogenase 1B is an enzyme that in humans is encoded by the ADH1B gene.

<span class="mw-page-title-main">ADH1C</span> Protein-coding gene in the species Homo sapiens

Alcohol dehydrogenase 1C is an enzyme that in humans is encoded by the ADH1C gene.

<span class="mw-page-title-main">ADH1A</span> Protein-coding gene in the species Homo sapiens

Alcohol dehydrogenase 1A is an enzyme that in humans is encoded by the ADH1A gene.

<span class="mw-page-title-main">Short-term effects of alcohol consumption</span> Overview of the short-term effects of the consumption of alcoholic beverages

The short-term effects of alcohol consumption range from a decrease in anxiety and motor skills and euphoria at lower doses to intoxication (drunkenness), to stupor, unconsciousness, anterograde amnesia, and central nervous system depression at higher doses. Cell membranes are highly permeable to alcohol, so once it is in the bloodstream, it can diffuse into nearly every cell in the body.

<span class="mw-page-title-main">Coprine</span> Chemical compound

Coprine is a mycotoxin. It was first isolated from common inkcap. It occurs in mushrooms in the genera Coprinopsis. When combined with alcohol, it causes "Coprinus syndrome". It inhibits the enzyme acetaldehyde dehydrogenase, which is involved in the metabolism of alcohol. This inhibition leads to a buildup of acetaldehyde, causing an alcohol flush reaction. Because of this, the mushroom is commonly referred to as Tippler's Bane.

<span class="mw-page-title-main">ALDH1A1</span> Protein-coding gene in the species Homo sapiens

Aldehyde dehydrogenase 1 family, member A1, also known as ALDH1A1 or retinaldehyde dehydrogenase 1 (RALDH1), is an enzyme that is encoded by the ALDH1A1 gene.

Pseudohypoxia refers to increased cytosolic ratio of free NADH/NAD+ ratio in cells, where NADH is overly increased and NAD+ is overly decreased. It can be caused by diabetic hyperglycemia and by excessive alcohol consumption. The insufficiency of available NAD+ produces symptoms similar to hypoxia (lack of oxygen), because NAD+ is primarily needed by the Krebs cycle for oxidative phosphorylation, and to a lesser extent is needed in anaerobic glycolysis. Oxidative phosphorylation and glyocolysis are vital as these metabolic pathways produce ATP, which is the molecule that releases energy necessary for cells to function.

<span class="mw-page-title-main">Alcohol intolerance</span> Medical condition

Alcohol intolerance is due to a genetic polymorphism of the aldehyde dehydrogenase enzyme, which is responsible for the metabolism of acetaldehyde. This polymorphism is most often reported in patients of East Asian descent. Alcohol intolerance may also be an associated side effect of certain drugs such as disulfiram, metronidazole, or nilutamide. Skin flushing and nasal congestion are the most common symptoms of intolerance after alcohol ingestion. It may also be characterized as intolerance causing hangover symptoms similar to the "disulfiram-like reaction" of aldehyde dehydrogenase deficiency or chronic fatigue syndrome. Severe pain after drinking alcohol may indicate a more serious underlying condition.

<span class="mw-page-title-main">Alda-1</span> Organic compound

Alda-1 is an organic compound that enhances the enzymatic activity of human ALDH2. Alda-1 has been proposed as a potential treatment for the alcohol flush reaction experienced by people with genetically deficient ALDH2.

<span class="mw-page-title-main">Disulfiram-alcohol reaction</span> Medical condition

Disulfiram-alcohol reaction (DAR) is the effect of the interaction in the human body of alcohol drunk with disulfiram or some mushrooms. The DAR is key to disulfiram therapy that is widely used for alcohol-aversive treatment and management of other addictions. Once disulfiram-treated patients take alcohol, even in small doses, they experience strong unpleasant sensations.

References

  1. 1 2 PDB: 1NVM ​; Manjasetty BA, Powlowski J, Vrielink A (Jun 2003). "Crystal structure of a bifunctional aldolase-dehydrogenase: sequestering a reactive and volatile intermediate". Proceedings of the National Academy of Sciences of the United States of America. 100 (12): 6992–7. Bibcode:2003PNAS..100.6992M. doi: 10.1073/pnas.1236794100 . PMC   165818 . PMID   12764229.
  2. ↑ Hempel J, Kaiser R, Jörnvall H (Nov 1985). "Mitochondrial aldehyde dehydrogenase from human liver. Primary structure, differences in relation to the cytosolic enzyme, and functional correlations". European Journal of Biochemistry. 153 (1): 13–28. doi: 10.1111/j.1432-1033.1985.tb09260.x . PMID   4065146.
  3. ↑ Wang X, Weiner H (Jan 1995). "Involvement of glutamate 268 in the active site of human liver mitochondrial (class 2) aldehyde dehydrogenase as probed by site-directed mutagenesis". Biochemistry. 34 (1): 237–43. doi:10.1021/bi00001a028. PMID   7819202.
  4. ↑ Hsu LC, Tani K, Fujiyoshi T, Kurachi K, Yoshida A (Jun 1985). "Cloning of cDNAs for human aldehyde dehydrogenases 1 and 2". Proceedings of the National Academy of Sciences of the United States of America. 82 (11): 3771–5. Bibcode:1985PNAS...82.3771H. doi: 10.1073/pnas.82.11.3771 . PMC   397869 . PMID   2987944.
  5. ↑ Swift R, Davidson D (1998). "Alcohol Hangover: Mechanisms and Mediators" (PDF). Alcohol Health and Research World. 22 (1): 54–60. PMC   6761819 . PMID   15706734 . Retrieved 26 Mar 2017.
  6. 1 2 Xiao Q, Weiner H, Crabb DW (Nov 1996). "The mutation in the mitochondrial aldehyde dehydrogenase (ALDH2) gene responsible for alcohol-induced flushing increases turnover of the enzyme tetramers in a dominant fashion". The Journal of Clinical Investigation. 98 (9): 2027–32. doi:10.1172/JCI119007. PMC   507646 . PMID   8903321.
  7. 1 2 3 4 Macgregor S., Lind P. A., Bucholz K. K., Hansell N. K., Madden P. A. F., Richter M. M., Montgomery G. W., Martin N. G., Heath A. C., Whitfield J. B. (2008.) "Associations of ADH and ALDH2 gene variation with self report alcohol reactions, consumption and dependence: an integrated analysis", Human Molecular Genetics, 18(3):580-93.
  8. ↑ Crabb D, Xiao Q (Jun 1998). "Studies on the enzymology of aldehyde dehydrogenase-2 in genetically modified HeLa cells". Alcoholism: Clinical and Experimental Research. 22 (4): 780–1. doi:10.1111/j.1530-0277.1998.tb03867.x. PMID   9660300.
  9. ↑ Lu Y, Morimoto K (Jul 2009). "Is habitual alcohol drinking associated with reduced electrophoretic DNA migration in peripheral blood leukocytes from ALDH2-deficient male Japanese?". Mutagenesis. 24 (4): 303–8. doi: 10.1093/mutage/gep008 . PMID   19286920.
  10. ↑ Macgregor S, Lind PA, Bucholz KK, Hansell NK, Madden PA, Richter MM, Montgomery GW, Martin NG, Heath AC, Whitfield JB (Feb 2009). "Associations of ADH and ALDH2 gene variation with self report alcohol reactions, consumption and dependence: an integrated analysis". Human Molecular Genetics. 18 (3): 580–93. doi:10.1093/hmg/ddn372. PMC   2722191 . PMID   18996923.
  11. ↑ Lind PA, Eriksson CJ, Wilhelmsen KC (Sep 2008). "The role of aldehyde dehydrogenase-1 (ALDH1A1) polymorphisms in harmful alcohol consumption in a Finnish population". Human Genomics. 3 (1): 24–35. doi: 10.1186/1479-7364-3-1-24 . PMC   3525184 . PMID   19129088.
  12. ↑ Hempel J, von Bahr-Lindström H, Jörnvall H (May 1984). "Aldehyde dehydrogenase from human liver. Primary structure of the cytoplasmic isoenzyme". European Journal of Biochemistry. 141 (1): 21–35. doi: 10.1111/j.1432-1033.1984.tb08150.x . PMID   6723659.
  13. ↑ Vallari RC, Pietruszko R (May 1982). "Human aldehyde dehydrogenase: mechanism of inhibition of disulfiram". Science. 216 (4546): 637–9. Bibcode:1982Sci...216..637V. doi:10.1126/science.7071604. PMID   7071604.
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