Analysis and update of the human aldehyde dehydrogenase (ALDH) gene family

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Abstract

The aldehyde dehydrogenase ( ALDH) gene superfamily encodes enzymes that are critical for certain life processes and detoxification via the NAD(P) ⁺-dependent oxidation of numerous endogenous and exogenous aldehyde substrates, including pharmaceuticals and environmental pollutants. Analysis of the ALDH gene superfamily in the latest databases showed that the human genome contains 19 putatively functional genes and three pseudogenes. A number of ALDH genes are upregulated as a part of the oxidative stress response and inexplicably overexpressed in various tumours, leading to problems during cancer chemotherapy. Mutations in ALDH genes cause inborn errors of metabolism -- such as the Sjögren - Larsson syndrome, type II hyperprolinaemia and γ-hydroxybutyric aciduria -- and are likely to contribute to several complex diseases, including cancer and Alzheimer's disease. The ALDH gene products appear to be multifunctional proteins, possessing both catalytic and non-catalytic properties.

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Most cited references 32

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Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis.

Daniel Nebert, Amy L Roe, Matthew Dieter … (2000)

The chronology and history of characterizing the aromatic hydrocarbon [Ah] battery is reviewed. This battery represents the Ah receptor (AHR)-mediated control of at least six, and probably many more, dioxin-inducible genes; two cytochrome P450 genes-P450 1A1 and 1A2 (Cypla1, Cypla2-and four non-P450 genes, have experimentally been documented to be members of this battery. Metabolism of endogenous and exogenous substrates by perhaps every P450 enzyme, but certainly CYP1A1 and CYP1A2 (which are located, in part, in the mitochondrion), have been shown to cause reactive oxygenated metabolite (ROM)-mediated oxidative stress. Oxidative stress activates genes via the electrophile response element (EPRE) DNA motif, whereas dioxin (acutely) activates genes via the AHR-mediated aromatic hydrocarbon response element (AHRE) DNA motif. In contrast to dioxin, AHR ligands that are readily metabolized to ROMs (e.g. benzo[a]pyrene, beta-naphthoflavone) activate genes via both AHREs and the EPRE. The importance of the AHR in cell cycle regulation and apoptosis has just begun to be realized. Current evidence suggests that the CYP1A1 and CYP1A2 enzymes might control the level of the putative endogenous ligand of the AHR, but that CYPA1/1A2 metabolism generates ROM-mediated oxidative stress which can be ameliorated by the four non-P450 EPRE-driven genes in the [Ah] battery. Oxidative stress is a major signal in precipitating apoptosis; however, the precise mechanism, or molecule, which determines the cell's decision between apoptosis and continuation with the cell cycle, remains to be elucidated. The total action of AHR and the [Ah] battery genes therefore represents a pivotal upstream event in the apoptosis cascade, providing an intricate balance between promoting and preventing ROM-mediated oxidative stress. These proposed endogenous functions of the AHR and [Ah] enzymes are, of course, in addition to the frequently described functions of "metabolic potentiation" and "detoxification" of various foreign chemicals.

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Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants.

Hester Wain, Darryl C. Zeldin, Lois Maltais … (2003)

Completion of both the mouse and human genome sequences in the private and public sectors has prompted comparison between the two species at multiple levels. This review summarizes the cytochrome P450 (CYP) gene superfamily. For the first time, we have the ability to compare complete sets of CYP genes from two mammals. Use of the mouse as a model mammal, and as a surrogate for human biology, assumes reasonable similarity between the two. It is therefore of interest to catalog the genetic similarities and differences, and to clarify the limits of extrapolation from mouse to human. Data-mining methods have been used to find all the mouse and human CYP sequences; this includes 102 putatively functional genes and 88 pseudogenes in the mouse, and 57 putatively functional genes and 58 pseudogenes in the human. Comparison is made between all these genes, especially the seven main CYP gene clusters. The seven CYP clusters are greatly expanded in the mouse with 72 functional genes versus only 27 in the human, while many pseudogenes are present; presumably this phenomenon will be seen in many other gene superfamily clusters. Complete identification of all pseudogene sequences is likely to be clinically important, because some of these highly similar exons can interfere with PCR-based genotyping assays. A naming procedure for each of four categories of CYP pseudogenes is proposed, and we encourage various gene nomenclature committees to consider seriously the adoption and application of this pseudogene nomenclature system.

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Author and article information

Journal

Journal ID (nlm-ta): Hum Genomics

Journal ID (iso-abbrev): Hum. Genomics

Title: Human Genomics

Publisher: BioMed Central

ISSN (Print): 1473-9542

ISSN (Electronic): 1479-7364

Publication date Collection: 2005

Publication date (Electronic): 1 June 2005

Volume: 2

Issue: 2

Pages: 138-143

Affiliations

[1 ]Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, CO, USA

[2 ]Department of Environmental Health and Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati, OH, USA

Article

Publisher ID: 1479-7364-2-2-138

DOI: 10.1186/1479-7364-2-2-138

PMC ID: 3525259

PubMed ID: 16004729

SO-VID: 4d0e37e5-8f0f-44bc-990d-d2114d34d1f4

History

Date received : 23 February 2005

Date accepted : 23 February 2005

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Analysis and update of the human aldehyde dehydrogenase ( ALDH) gene family

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