Aldehyde dehydrogenase

Aldehyde Dehydrogenase

Aldehyde dehydrogenase (ALDH) is a group of enzymes that catalyze the oxidation of aldehydes to carboxylic acids. This reaction is crucial in the metabolism of alcohols and the detoxification of aldehydes, which can be toxic to cells. ALDH enzymes are found in various tissues throughout the body and play a significant role in the metabolism of endogenous and exogenous compounds.

Structure

Aldehyde dehydrogenases are typically composed of multiple subunits, forming either dimers or tetramers. Each subunit contains a catalytic domain that binds to the aldehyde substrate and the cofactor NAD+ or NADP+. The active site of ALDH is highly conserved and includes key amino acids that facilitate the oxidation reaction.

Monomer of ALDH with NAD+

The enzyme's structure allows it to efficiently convert aldehydes into their corresponding acids, with the release of NADH or NADPH as a byproduct. The tetrameric form of ALDH is often more stable and active than the monomeric form.

Tetramer of ALDH with NAD+

Mechanism

The catalytic mechanism of aldehyde dehydrogenase involves the formation of a thiohemiacetal intermediate. The enzyme's active site contains a cysteine residue that forms a covalent bond with the aldehyde substrate. This intermediate is then oxidized by NAD+ to form a thioester, which is subsequently hydrolyzed to release the carboxylic acid product.

Mechanism of aldehyde dehydrogenase

Function

Aldehyde dehydrogenases are involved in several metabolic pathways, including the breakdown of ethanol in the liver. The enzyme converts acetaldehyde, a toxic intermediate of ethanol metabolism, into acetic acid, which is less harmful and can be further metabolized by the body.

ALDH also plays a role in the metabolism of neurotransmitters such as noradrenaline, where it helps in the breakdown of aldehyde intermediates.

Breakdown of noradrenaline involving ALDH

Genetic Variability

There are multiple isoforms of aldehyde dehydrogenase, encoded by different genes. One of the most studied isoforms is ALDH2, which is involved in alcohol metabolism. Genetic polymorphisms in the ALDH2 gene can lead to variations in enzyme activity. For example, the ALDH2*2 variant is associated with reduced enzyme activity and is prevalent in East Asian populations. This variant can lead to the accumulation of acetaldehyde after alcohol consumption, causing the "Asian flush" reaction.

Mutant active site of ALDH2*2

Clinical Significance

Deficiencies or mutations in aldehyde dehydrogenase enzymes can lead to various health issues. For instance, a deficiency in ALDH2 is linked to an increased risk of alcoholism, cancer, and cardiovascular disease. ALDH enzymes are also targets for drug development, as modulating their activity can have therapeutic benefits in conditions such as cancer and neurodegenerative diseases.

Related Pages

• Alcohol dehydrogenase
• Metabolism
• Enzyme
• NAD+

Gallery

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  Active site with labeled amino acids and NAD+