Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily

Abstract

Background: Aldehydes are highly reactive molecules. While several non-P450 enzyme systems participate in their metabolism, one of the most important is the aldehyde dehydrogenase (ALDH) superfamily, composed of NAD(P)+-dependent enzymes that catalyze aldehyde oxidation.

Objective: This article presents a review of what is currently known about each member of the human ALDH superfamily including the pathophysiological significance of these enzymes.

Methods: Relevant literature involving all members of the human ALDH family was extensively reviewed, with the primary focus on recent and novel findings.

Conclusion: To date, 19 ALDH genes have been identified in the human genome and mutations in these genes and subsequent inborn errors in aldehyde metabolism are the molecular basis of several diseases, including Sjögren-Larsson syndrome, type II hyperprolinemia, gamma-hydroxybutyric aciduria and pyridoxine-dependent seizures. ALDH enzymes also play important roles in embryogenesis and development, neurotransmission, oxidative stress and cancer. Finally, ALDH enzymes display multiple catalytic and non-catalytic functions including ester hydrolysis, antioxidant properties, xenobiotic bioactivation and UV light absorption.

Figure 1. Non-P450 enzymatic metabolism of aldehydes

ADH: Alcohol dehydrogenase; AKR: Aldo-keto reductase; ALDH: Aldehyde dehydrogenase; AO: Aldehyde oxidase; CAT: Catalase; SDR: Short chain dehydrogenase/reductase; XO: Xanthine oxidase.

Figure 2. Evolutionary relationship and mutational phenotypes of the nineteen human ALDH genes

Clustering dendogram illustrates the evolutionary relationship of the nineteen human ALDH genes from a common ancestral gene ~ 3 billion years ago. Chromosomal location is also described. (?) indicates phenotype demonstrated in animals but not yet described in humans.

Figure 3. Proposed non-CoA dependent ALDH catalysis mechanism

1, Cofactor binding results in a conformation change of the enzyme and activation of the catalytic thiol (Cys-S⁻); 2, Nucleophilic attack of the aldehyde substrate; 3, Oxyanion intermediate stabilized by two NH groups of the ALDH peptide chain; 4, Hydride transfer to cofactor. 5; Glutamate residue acts as a base catalyst in the hydrolysis of the thioacylenzyme intermediate; 6, Release of carboxylic acid product followed by cofactor.

Figure 4. The role of ALDH isozymes in the metabolism of malondialdehyde (MDA)

MDA is the major aldehyde product of lipid peroxidation. The proposed pathway of MDA metabolism involves ALDH1A1, ALDH2 and ALDH6A1.

Figure 5. The role of ALDH1L1 in methanol metabolism and toxicity

Methanol is metabolized to the end product, carbon dioxide, through a pathway in which it is first converted to formaldehyde by ADH, which in turn is rapidly metabolized to formate by FDH. A build-up of formate is thought to cause the majority of the deleterious effects associated with methanol poisoning. Formate can enter the folate pathway through its conjugation to THF by MTHFD to form 10-FTHF, which is converted back into THF by ALDH1L1, accompanied by the release of carbon dioxide. 10-FTHF: 10-formyltetrahydrofolate; ADH: Alcohol dehydrogenase; ALDH1L1: Aldehyde dehydrogenase 1 family, member L1; FDH: Formaldehyde dehydrogenase; MTHFD: Methylenetetrahydrofolate dehydrogenase; THF: Tetrahydrofolate.

Figure 6. The role of ALDH isozymes in glutamate and GABA pathways

ALDH4A1, ALDH5A1, ALDH9A1 and ALDH18A1 play many important roles in the synthesis and catabolism of the neurotransmitters glutamate and γ-aminobutyric acid, and mutational defects in these ALDH genes result in a variety of neurological disorders. *Indicates enzymes that require pyridoxal phosphate (PLP) as cofactor. ABAT: 4-Aminobutyrate aminotransferase GABA, γ-aminobutyric acid; GAD: Glutamate decarboxylase; GHB: γ-hydroxybutyric acid; GLUD: Glutamate dehydrogenase; GOT: Glutamic-oxaloacetic transaminase; GPT: Glutamic-pyruvate transaminase; SSR: Succinic semialdehyde reductase.

Figure 7. The role of ALDH7A1 as an alpha-aminoadipic semialdehyde (AASA) dehydrogenase

AASA is in equilibrium with its cyclic Schiff base, piperideine-6-carboxylate (P6C). Pyridoxal phosphate (PLP) is the active form of vitamin B₆ and an important cofactor in many types of reactions. Mutations in ALDH7A1 result in the accumulation of P6C and Knoevenagel adduct products between P6C and PLP, leading to the inactivation and depletion of PLP and pyridoxine-dependent seizures.