Aldehyde dehydrogenases

Aldehyde dehydrogenase (ALDH, EC 1.2.1.3) enzymes catalyze the NAD(P) + -dependent oxidation of aldehydes to carboxylic acids. Nineteen ALDH genes coding for enzymes with broad substrate specificities have been identified in the human genome. These enzymes cluster into nine families, ALDH1-9, with members of the ALDH1 and ALDH3 families most strongly asssociated with xenobiotic metabolism.67 The nomenclature for this enzyme system follows closely that used for the P450s. ALDH1A1, 1A2, and 1A3 are cytosolic and mitochondrial enzymes that are involved in the biosynthesis of retinoic acid from retinal in humans. Retinoic acid is important for modulating cell differentiation, particularly during embryogenesis. ALDH1 forms are also implicated in the metabolic pathway leading to inactivation of antineoplastic agent, cyclophosphamide. ALDH2 is a mitochondrial enzyme that is mainly responsible for the metabolism of ethanol-derived acetaldehyde. An E487 K mutation (ALDH2*2) results in a large increase in the Km for NAD+, which almost inactivates the enzyme.68 This polymorphism is responsible for alcohol flushing in up to 40% of Asians. Members of the ALDH3A subfamily are dioxin-inducible and are overexpressed in some tumors. These enzymes are involved in the metabolism of medium- to long-chain aliphatic and aromatic aldehydes. Individual members of gene families ALDH4-9 metabolize a variety of usually endogenous aldehydes, although some may also have activity towards some xenobiotic substrates. Structurally, these enzymes are homotetramers, with subunit molecular weights of ~ 55 kDa.69

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