Acetaldehyde dehydrogenase

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Acetaldehyde dehydrogenase
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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:

Acetaldehyde + NAD+ +

NADH
+ H+

In humans, there are three known genes which encode this enzymatic activity,

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

isozymes for both human and horse, which is consistent with Cys-302 being crucial to catalytic function.[2]

As discovered by

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

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

mitochondrial isozymes, as seen in the 50% homology between pig mitochondrial and cytosolic aspartate aminotransferases.[4]

Role in metabolism of alcohol

In the

toxic than alcohol and is responsible for many hangover symptoms.[5]

About 50% of people of Northeast Asian descent have a dominant

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

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.

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

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

References

  1. ^
    PMID 12764229
    .
  2. PMID 4065146
    .
  3. PMID 7819202
    .
  4. PMID 2987944
    .
  5. PMID 15706734
    . Retrieved 26 Mar 2017.
  6. ^
    PMID 8903321
    .
  7. ^ 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 variation with self report alcohol reactions, consumption and dependence: an integrated analysis", Human Molecular Genetics, 18(3):580-93.
  8. PMID 9660300
    .
  9. PMID 19286920
    .
  10. PMID 18996923
    .
  11. PMID 19129088
    .
  12. PMID 6723659
    .
  13. PMID 7071604
    .

External links
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