Aldehyde Dehydrogenase

The major metabolic consequence of ethanol metabolism is the production of the highly reactive molecule acetaldehyde, which can form adducts on proteins in the liver, causing damage and inflammation that can ultimately lead to necrosis (7). As the efficiency of ALDH to oxidize acetaldehyde to acetate is greater than the efficiency of ADH to produce acetaldehyde, the levels of acetaldehyde in the liver and circulating in the blood are generally kept low. With chronic alcohol consumption, however, the efficiency of ALDH is impaired and aldehyde oxidation is decreased, leading to higher levels of circulating acetaldehyde and thus an increase in acetaldehyde adducts. This build-up of acetaldehyde adducts with thiol and amino groups in proteins can inhibit the function of these proteins as well as cause an inflammatory immune response. Accumulated acetaldehyde also acts as an inhibitor of ADH, which will impede the effective elimination of alcohol from the body (3).

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Figure 13: The mechanism of aldehyde dehydrogenase via a tetrahedral thiohemiacetal intermediate. The active residues, Cys302 and Glu268, catalyze the reaction (11).

There are 19 isozymes of aldehyde dehydrogenase, with ALDH2 specific to acetaldehyde oxidation. The catalytic reaction occurs in five steps: first Cys-302 is activated by a water-mediated proton abstraction by Glu-268, then the thiolate group of Cys-302 attacks the electrophilic aldehyde which forms a tetrahedral thiohemiacetal intermediate and a hydride transfer to the NAD+ ring, resulting in a thioester intermediate which is hydrolyzed, followed by the dissociation of NADH and regeneration of the enzyme due to NAD+ binding (11).

ALDH2 Active Site

Figure 14: The active site of aldehyde dehydrogenase. The residues in blue (Glu399 and Lys192) help coordinate the NAD into the active site, while the red residues catalyze the reaction with acetaldehyde (pdb file: 1O01).

2 Comments

  1. Really interesting!

    You say “This build-up of acetaldehyde adducts with thiol and amino groups in proteins can inhibit the function of these proteins as well as cause an inflammatory immune response. ”

    Is this the chemical basis behind physiological symptoms such as altered mental status, raised internal body temp, and hypertension associated with alcohol consumption? I realize this may be outside the scope of your research, but think it would be very cool to relate the chemistry to the broader picture. I found an NIH article that mentions “Some researchers believe that acetaldehyde may be responsible for some of the behavioral and physiological effects previously attributed to alcohol (6). For example, when acetaldehyde is administered to lab animals, it leads to incoordination, memory impairment, and sleepiness, effects often associated with alcohol” and have attached the link below.

    http://pubs.niaaa.nih.gov/publications/AA72/AA72.htm

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