ADH - Alcohol dehydrogenase | Elisa - Clia - Antibody - Protein

Background

Alcohol dehydrogenase (ADH) is an enzyme involved in the metabolism of ethanol (alcohol) in the body. ADH catalyzes the conversion of ethanol into acetaldehyde by removing hydrogen from ethanol. This reaction is the first step in the metabolism of alcohol in the liver. ADH is a member of the oxidoreductase family of enzymes and is typically found in the liver, although it is also present in other tissues. It exists in several isoforms, each encoded by a different gene, and varies in its affinity for ethanol and its kinetics. Genetic polymorphisms in the genes encoding ADH enzymes can lead to individual differences in alcohol metabolism. Certain variations in ADH genes can result in altered enzyme activity, affecting how quickly alcohol is metabolized and contributing to differences in alcohol tolerance and susceptibility to alcohol-related health issues.Role in alcohol metabolism: After ADH converts ethanol to acetaldehyde, acetaldehyde is further metabolized into acetate by the enzyme aldehyde dehydrogenase (ALDH). Acetate is then broken down into carbon dioxide and water, which can be excreted from the body.In humans, ADH exists in multiple forms as a dimer and is encoded by at least seven genes. Among the five classes (I-V) of alcohol dehydrogenase, the hepatic forms that are used primarily in humans are class 1.

Protein Structure

ADH enzymes typically exist as dimers or tetramers, each subunit containing the following components:

• Catalytic Domain: The active site where alcohol oxidation occurs, binding both the NAD+ coenzyme and the alcohol substrate.
• Zinc Binding Sites: Many ADH enzymes contain zinc ions critical for catalytic activity and structural integrity.
• Coenzyme Binding Site: Binds NAD+ (or NADP+ in some variants), essential for the oxidation-reduction reaction.

Classification and Subtypes

In humans, ADH enzymes are encoded by several genes, resulting in multiple isoforms with varying properties. These include:

• ADH1 (ADH1A, ADH1B, ADH1C): Primarily found in the liver, with ADH1B and ADH1C being major players in ethanol metabolism.
• ADH2 (ADH4): Found in the liver and other tissues, this enzyme has broader substrate specificity.
• ADH3 (ADH5): Ubiquitously expressed, involved in the metabolism of formaldehyde and other alcohols.
• ADH4 (ADH7): Predominantly in the stomach, contributes to gastric alcohol metabolism.
• ADH5 (ADH6): Less understood, with limited expression and function information.

Function and Biological Significance

ADH enzymes serve several critical biological roles:

1. Ethanol Metabolism: ADH1 enzymes oxidize ethanol to acetaldehyde, a crucial step in alcohol metabolism.
2. Detoxification: ADH enzymes convert toxic alcohols like methanol to formaldehyde and ethylene glycol to glycolaldehyde.
3. Retinol Metabolism: Some ADH isoforms (e.g., ADH4) convert retinol (vitamin A) to retinal, important for vision.
4. Xenobiotic Metabolism: ADH enzymes metabolize various endogenous and exogenous compounds, including certain drugs and toxins.

Interactions

ADH enzymes interact with various molecules for their metabolic functions:

1. Substrates: Alcohols such as ethanol, methanol, and other primary and secondary alcohols.
2. Coenzymes: NAD+ (and sometimes NADP+), necessary for the oxidation-reduction reactions.
3. Other Metabolic Enzymes: ADH enzymes work alongside aldehyde dehydrogenase (ALDH) enzymes to further metabolize aldehydes into less harmful compounds.
4. Regulatory Proteins: Various cellular proteins modulate ADH activity and stability.

Clinical Significance

Variations in ADH genes and enzyme activity are associated with several clinical conditions:

1. Alcohol Metabolism Disorders: Polymorphisms in ADH1B and ADH1C can affect alcohol tolerance and predispose individuals to alcoholism. Rapid conversion of ethanol to acetaldehyde can cause adverse reactions such as flushing and increase cancer risk.
2. Alcoholic Liver Disease: Excessive ADH activity from chronic alcohol consumption can lead to high levels of acetaldehyde, contributing to liver damage and disease.
3. Metabolic Disorders: Mutations in ADH3 (ADH5) are linked to formaldehyde toxicity and related metabolic disorders.
4. Cancer Risk: Elevated acetaldehyde levels due to high ADH activity and low ALDH activity are associated with an increased risk of cancers, especially in the upper gastrointestinal tract.

Summary

Alcohol dehydrogenase (ADH) is a critical enzyme family involved in the oxidation of alcohols to aldehydes or ketones. Encoded by multiple genes (ADH1, ADH2, ADH3, ADH4, ADH5), these enzymes play significant roles in alcohol metabolism, detoxification, retinol metabolism, and xenobiotic metabolism. ADH enzymes interact with substrates, coenzymes, and other metabolic enzymes, with variations in ADH genes linked to various clinical conditions, including alcohol metabolism disorders, alcoholic liver disease, metabolic disorders, and cancer risk. Understanding the structure, function, and interactions of ADH enzymes is vital for insights into their role in health and disease.