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Acetaldehyde dehydrogenase
(acetylating)

AcetaldehydeDehydrogenase-1NVM.png

Crystallographic texture of the acetaldehyde dehydrogenase from Pseudomonas sp.[1]

Identifiers

EC figure

1.2.1.10

CAS number

9028-91-5

Databases

IntEnz

IntEnz view

BRENDA

BRENDA entry

ExPASy

NiceZyme view

KEGG

KEGG entry

MetaCyc

metabolic pathway

PRIAM

profile

PDB structures

RCSB PDB PDBe PDBsum

Gene Ontology

AmiGO / EGO

Search

PMC

articles

PubMed

articles

NCBI

proteins

Acetaldehyde dehydrogenases (EC 1.2.1.10) are dehydrogenase enzymes that catalyze the conversion of acetaldehyde into acetic stinging. The oxidation of acetaldehyde to acetate be possible to be summarized as follows:
acetaldehyde + NAD+ + H2O → acetate + NADH + 2H+
In humans, there are three known genes which encode this enzymatic exercise, ALDH1A1, ALDH2, and the more lately discovered ALDH1B1 (also known as ALDH5). These enzymes are members of the larger rank of aldehyde dehydrogenases.
The CAS numerate for this type of the enzyme is [9028-91-5].

Contents

1 Structure

2 Evolution

3 Role in metabolism of highly rectified spirit

4 Role in fat metabolism

5 See too

6 References

7 External links

Structure[bring out]

Cysteine-302 is one of three consecutive Cys residues and is crucial to the enzyme’s catalytic occupation. The residue is alkylated by iodoacetamide in the two the cytosolic and mitochondrial isozymes, through modifications to Cys-302 indicative of catalytic agility with other residues. Furthermore, the preceding sequence Gln-Gly-Gln-Cys is conserved in one as well as the other isozymes for both human and horse, which is consistent with Cys-302 root crucial to catalytic function.[2]
As discovered through site-directed mutagenesis, glutamate-268 is a elucidation component of liver acetaldehyde dehydrogenase and is furthermore critical to catalytic activity. Since nimbleness in mutants could not be restored ~ the agency of addition of general bases, it’s suggested that the remainder functions as a general base beneficial to activation of the essential Cys-302 excess.[3]
In bacteria, acylating acetaldehyde dehydrogenase forms a bifunctional heterodimer with metal-dependent 4-hydroxy-2-ketovalerate aldolase. Utilized in the bacterial debasement of toxic aromatic compounds, the enzyme’s crystal conformation indicates that intermediates are shuttled speedily between active sites through a hydrophobic intermediary groove, providing an unreactive environment in that to move the reactive acetaldehyde intervening from the aldolase active site to the acetaldehyde dehydrogenase effectual site. Such communication between proteins allows on this account that the efficient transfer substrates from united active site to the next.[1]

Evolution[prepare for the press]

Although the two isozymes (ALDH1 and ALDH2) work not share a common subunit, the homology between the human ALDH1 and ALDH2 proteins is 66% at the coding nucleotide suit and 69% at the amino sharp level, which is found to be lower than the 91% homology between human ALDH1 and horse ALDH1. Such a verdict is consistent with evidence suggesting the seasonable evoluationary divergence between cytosolic and mitochondrial isozymes, taken in the character of seen in the 50% homology betwixt pig mitochondrial and cytosolic asparatate aminotransferases.[4]

Role in metabolism of alcohol[edit]

In the liver, the enzyme pure spirit dehydrogenase oxidizes ethanol into acetaldehyde, which is then further converted into the harmless acetic acid (vinegar) by acetaldehyde dehydrogenase. Acetaldehyde is greater amount of toxic than alcohol[citation needed] and is amenable for many hangover symptoms[citation needed].
About 50% of family of Northeast Asian descent have a ruling mutation in their acetaldehyde dehydrogenase gene,[5] fabrication this enzyme less effective. A similar mutation is found in about 5–10% of fair-haired blue-eyed people of Northern European going down.[6] In these people, acetaldehyde accumulates in relation to drinking alcohol, leading to symptoms of acetaldehyde poisoning, including the characteristic flushing of the skin and increased intent and respiration rates.[6] Other symptoms have power to include severe abdominal and urinary part cramping, hot and cold flashes, improvident sweating, and profound malaise.[6] Individuals through deficient acetaldehyde dehydrogenase activity are alienated less likely to become alcoholics, ~-end seem to be at a greater risk of liver damage, alcohol-induced asthma, and contracting cancers of the oro-pharynx and gullet due to acetaldehyde overexposure.[6]

Acetaldehyde dehydrogenase recoil diagram

ALDH2, which has a humble KM for acetaldhehydes than ALDH1 and acts predominantly in the mitochondrial matrix, is the main enzyme in acetaldehyde metabolism and has three genotypes. A uncorrupt point mutation (G → A) at exon 12 of the ALDH2 gene causes a re-establishment of glutamine with lysine at surplus 487, resulting in the ALDH2K enzyme.[7] ALDH2K has ~y increased KM for NAD+, rendering it practically inactive at cellular concentrations of NAD+.[5] Since ALDH2 is a randomized tetramer, the hetero-mutated genotype is reduced to merely 6% activity compared to wild representation, while homo-mutated genotypes have in effect zero enzyme activity.[8] The ALDH2-insufficient subunit is dominant in hybridization through a wild type subunit, resulting in inactivation of the isozyme through interfering with catalytic activity and increasing turnover.[9] ALDH2 genetic modification has been closely correlated with alcohol dependence, with heterozygotes at a reduced jeopard compared to wild type homozygotes and individual homozygotes in quest of the ALDH2-deficient at a same low risk for alcoholism.[10]
The put ~s into disulfiram (Antabuse) prevents the oxidation of acetaldehyde to acetic pricking and is used in the handling of alcoholism. ALDH1 is strongly inhibited through disulfiram, while ALDH2 is resistant to its validity. The cysteine residue at 302 in ALDH1 and 200 in ALDH2 is implicated being of the kind which a disulfiram binding site on the enzyme and serves while a disfulfiram sensitive thiol site.[11]Covalent bandage of disulfiram to the thiol blocks the band of one of the cysteine residues through iodoacetamide, thereby inactivating the enzyme and significantly dark catalytic activity. Activity can be recovered through treatment with 2-mercaptoethanol, although not by glutathione.[12]
Metronidazole (Flagyl), which is used to deal with certain parasitic infections as well being of the cl~s who pseudomembranous colitis, causes similar effects to disulfiram. Coprine (that is an amino acid found in undeniable coprinoid mushrooms) metabolizes in vivo to 1-aminocyclopropanol what one. causes similar effects as well.

Role in heavy metabolism[edit]

ALDH1 is involved in the metabolism of Vitamin A. Animal models move that absence of the gene is associated through protection against visceral adiposity (PMC2233696).

See furthermore[edit]

Alcohol flush reaction

Oxidoreductase

References[bring out]

^ a b PDB 1NVM; Manjasetty BA, Powlowski J, Vrielink A (June 2003). “Crystal arrangement of parts of a bifunctional aldolase-dehydrogenase: sequestering a reactive and evaporable intermediate”. Proc. Natl. Acad. Sci. U.S.A. 100 (12): 6992–6997. doi:10.1073/pnas.1236794100. PMC 165818. PMID 12764229. 

^ Hempel J, Kaiser R, Jornvall H. (1985). “Mitochondrial aldehyde dehydrogenase from human liver”. Eur. J. Biochem. 153 (1): 13–28. doi:10.1111/j.1432-1033.1985.tb09260.x. PMID 4065146. 

^ Wang X, Weiner H. (1995). “Involvement of glutamate 268 in the vigorous site of human liver mitochondrial (class 2) aldehyde dehydrogenase as probed ~ the agency of site-directed mutagenesis”. Biochemistry 34 (JAN 10): 237–243. doi:10.1021/bi00001a028. PMID 7819202. 

^ Hsu L.C., Tani K, Fujiyoshi T, Kurachi K, Yoshida A. (1985). “Cloning of cDNAs beneficial to human aldehyde dehydrogenases 1 and 2”. Porc. Natl. Acad. Sci. USA 82 (JUNE): 3771–3775. doi:10.1073/pnas.82.11.3771. PMC 397869. PMID 2987944. 

^ a b Xiao Q, Weiner H, Crabb DW (1996). “The mutation in the mitochondrial aldehyde dehydrogenase (ALDH2) gene accountable for alcohol-induced flushing increases turnover of the enzyme tetramers in a ascendant fashion”. J. Clin. Invest. 98 (9): 2027–2032. doi:10.1172/JCI119007. PMC 507646. PMID 8903321. 

^ a b c d 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 diversity with self report alcohol reactions, destruction and dependence: an integrated analysis”, Human Molecular Genetics, 18(3):580-93.

^ Crabb D, Xiao Q. (2006). “Studies in c~tinuance the Enzymology of Aldehyde Dehydrogenase-2 in Genetically Modified HeLa Cells”. Alcoholism: Clinical and Experimental Research 22 (4): 780–781. doi:10.1111/j.1530-0277.1998.tb03867.x. PMID 9660300. 

^ Lu Y, Morimoto K. (2009). “Is regular alcohol drinking associated with reduced electrophoretic DNA migration in peripheral kindred leukocytes from ALDH2-deficient male Japanese?”. Mutagenesis. 24 (4): 303–308. doi:10.1093/mutage/gep008. PMID 19286920. 

^ Macgregor S, Lind P, Bucholz K, Hansell N, Madden P, Richter M, Montgomery G, Martin N, Heath A, Whitfield J. (2009). “Associations of ADH and ALDH2 gene diversity with self report alcohol reactions, expenditure and dependence: an integrated analysis”. Human Molecular Genetics 18 (3): 580–593. doi:10.1093/hmg/ddn372. PMC 2722191. PMID 18996923. 

^ Lind PA, Eriksson CJ, Wilhelmsen KC. (2008). “The role of aldehyde dehydrogenase-1 (ALDH1A1) polymorphisms in detrimental alcohol consumption in a Finnish inhabitants”. Human Genomics 3 (1): 24–35. PMID 19129088. 

^ Hempel J, Bahr-Lindstrom, Jornvall Hans. (1985). “Aldehyde dehydrogenase from human liver”. European Journal of Biochemistry 141 (1): 21–35. doi:10.1111/j.1432-1033.1984.tb08150.x. PMID 6723659. 

^ Vallari RC, Pietruszko R. (1982). “Human aldehyde dehydrogenase: mechanical construction of inhibition of disulfiram”. Science 216 (4546): 637–639. doi:10.1126/science.7071604. PMID 7071604. 

External links[conduct ]

acetaldehyde dehydrogenase at the US National Library of Medicine Medical Subject Headings (MeSH)

v

t

e

Aldehyde/oxo oxidoreductases (EC 1.2)

1.2.1: NAD or NADP

Aldehyde dehydrogenase: Acetaldehyde dehydrogenase

ALDH2

Long-fetter-aldehyde dehydrogenase

Glyceraldehyde 3-phosphate dehydrogenase

1.2.2: cytochrome

Formate dehydrogenase (cytochrome)

1.2.3: oxygen

Aldehyde oxidase

1.2.4: disulfide

Oxoglutarate dehydrogenase

Pyruvate dehydrogenase

Branched-fasten with a ~ alpha-keto acid dehydrogenase complex

BCKDHA

BCKDHB

DBT

DLD

1.2.7: iron-sulfur protein

Pyruvate synthase

B

enzm

1.1

2

3

4

5

6

7

8

10

11

13

14

15-18

2.1

2

3

4

5

6

7

2.7.10

11-12

8

3.1

3.1.3.48

2

3

4

3.4.21

22

23

24

5

6

7

4.1

2

3

4

5

6

5.1

2

3

4

99

6.1-3

4

5-6

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