ADH

Alcohol Dehydrogenase (ADH) is the enzyme that catalyzes the first step in the metabolism of alcohol in humans.

ADH catalyzes the oxidation of a broad range of substrates containing hydroxyl groups, including ethanol. In the case of ethanol, the alcohol is converted into acetaldehyde, another toxic compound, which is then metabolized further.

To proceed, the reaction requires the oxidizing agent Nicotinamide Adenine Dinucleotide, NAD⁺. NAD⁺ is a co-enzyme that acts as an electron acceptor, accepting 2 electrons and an H⁺ from ethanol [1]. N A D plus. N A D plus is a co-enzyme that acts as an electron acceptor, accepting 2 electrons and a proton from ethanol Thus, ADH catalyzes the following reaction:

Figure 1: Chemical formula of a reaction using the enzyme ADH and beneath it a structure of alcohol dehydrogenase ADH1B*1 (from PDB entry 1HSZ).

When performing kinetic assays, it is important to start measuring immediately after the enzyme is added, because this reaction occurs as soon as ADH is mixed with NAD⁺ and ethanol.

Alcohol Flush syndrome

Humans possess various isozymes of ADH, with ADH1B*1 and ADH1B*2 being notable examples differing by just one amino acid. Despite the minor change from arginine to histidine at position 47, these isozymes exhibit significant kinetic disparities. ADH1B*2, prevalent in East Asians, and ADH1B*1, common among Caucasians, diverge due to the distinct chemical properties of arginine and histidine [2,3].

In ADH1B*1, arginine forms robust hydrogen bonds with NAD⁺ pyrophosphate group, whereas histidine in ADH1B*2 creates weaker bonds. Consequently, ADH1B*2 exhibits a higher K_m value, as NAD⁺ is less tightly bound. The rate-determining step, NADH dissociation, results in ADH1B*2 having higher turnover numbers and V_max due to weaker NADH binding. Moreover, ADH1B*2 optimal pH (8.5) is lower than ADH1B*1 (10.0) due to histidine's lower pK_a value [4]. In ADH1B 1, arginine forms robust hydrogen bonds with N A D plus pyrophosphate group, whereas histidine in ADH1B 2 creates weaker bonds. Consequently, ADH1B 2 exhibits a higher K M value, as N A D plus is less tightly bound. The rate-determining step, N A D H dissociation, results in ADH1B 2 having higher turnover numbers and V max due to weaker N A D H binding. Moreover, ADH1B 2 optimal pH (8.5) is lower than ADH1B 1 (10.0) due to histidine's lower p K a value.

Individuals with ADH1B*2 often experience the Alcohol Flush syndrome. Even small alcohol amounts cause flushing and hangover-like symptoms due to elevated blood acetaldehyde levels from heightened ADH1B*2 activity. This syndrome stems from a single amino acid substitution caused by a DNA mutation in ADH1B*2. Thus, the seemingly minor change in the ADH isozyme has a remarkable impact on alcohol metabolism and related physiological responses [5]. Individuals with ADH1B 2 often experience the Alcohol Flush syndrome. Even small alcohol amounts cause flushing and hangover-like symptoms due to elevated blood acetaldehyde levels from heightened ADH1B 2 activity. This syndrome stems from a single amino acid substitution caused by a DNA mutation in ADH1B 2. Thus, the seemingly minor change in the ADH isozyme has a remarkable impact on alcohol metabolism and related physiological responses.

References

1. Hurley, T.D., Bosron, W.F., Stone, C.L. and Amzel, L.M. (1994) Structures of three human ß alcohol dehydrogenase variants. J. Mol. Biol. 239, 415-429.

2. Shou-Lun Lee, Gar-Yang Chau, Chung-Tay Yao, Chew-Wun Wu, and Shih-Jiun Yin (2006) Functional assessment of Human Alcohol Dehydrogenase Family in Ethanol Metabolism: Significance of First-Pass Metabolism. Alcohol. Clin. Exp. Res. 30, 1132-1142.

3. Jornvall H., Hempel J., Vallee, B.T., Bosron, W.F. and Li, T.K. (1984) Human liver alcohol dehydrogenase: Amino acid substitution in the ß2ß2 Oriental isozyme explains functional properties, establishes an active site structure, and parallels mutational exchanges in the yeast enzyme. Proc. Natl. Acad. Sci. USA, 81, 3024-3028.

4. Thomasson, H.R., Crabb, D.W., Edenberg, H.J., and Li, T.K (1993) Alcohol and Aldehyde Dehydrogenase Polymorphisms and Alcoholism. Behav. Genet. 23, 131-136.