Review Article
Aldehyde dehydrogenases in cellular responses to oxidative/electrophilicstress

https://doi.org/10.1016/j.freeradbiomed.2012.11.010Get rights and content

Abstract

Reactive oxygen species (ROS) are continuously generated within living systems and the inability to manage ROS load leads to elevated oxidative stress and cell damage. Oxidative stress is coupled to the oxidative degradation of lipid membranes, also known as lipid peroxidation. This process generates over 200 types of aldehydes, many of which are highly reactive and toxic. Aldehyde dehydrogenases (ALDHs) metabolize endogenous and exogenous aldehydes and thereby mitigate oxidative/electrophilic stress in prokaryotic and eukaryotic organisms. ALDHs are found throughout the evolutionary gamut, from single-celled organisms to complex multicellular species. Not surprisingly, many ALDHs in evolutionarily distant, and seemingly unrelated, species perform similar functions, including protection against a variety of environmental stressors such as dehydration and ultraviolet radiation. The ability to act as an “aldehyde scavenger” during lipid peroxidation is another ostensibly universal ALDH function found across species. Upregulation of ALDHs is a stress response in bacteria (environmental and chemical stress), plants (dehydration, salinity, and oxidative stress), yeast (ethanol exposure and oxidative stress), Caenorhabditis elegans (lipid peroxidation), and mammals (oxidative stress and lipid peroxidation). Recent studies have also identified ALDH activity as an important feature of cancer stem cells. In these cells, ALDH expression helps abrogate oxidative stress and imparts resistance against chemotherapeutic agents such as oxazaphosphorine, taxane, and platinum drugs. The ALDH superfamily represents a fundamentally important class of enzymes that contributes significantly to the management of electrophilic/oxidative stress within living systems. Mutations in various ALDHs are associated with a variety of pathological conditions in humans, highlighting the fundamental importance of these enzymes in physiological and pathological processes.

Highlights

Aldehyde dehydrogenases (ALDHs) metabolize electrophilic aldehydes. ► ALDHs are expressed in all forms of life from simple to complex multicellular organisms. ► ALDHs are elevated by stress in these organisms to protect against oxidative damage. ► Mutations in ALDH genes are associated with a variety of diseases in humans.

Introduction

Aldehyde dehydrogenases (ALDHs)1 are involved in a variety of biological processes in prokaryotic and eukaryotic organisms. Their expression is upregulated in response to abiotic and biotic stress generated by perturbed endobiotic and/or xenobiotic metabolism. Such stress-responsive expression of ALDHs manifests in a broad range of plant and animal species, highlighting the evolutionary conservation of biological adaptions to oxidative and electrophilic stresses (Table 1). Living organisms are constantly confronted by oxidative stress and the reactive oxygen species (ROS) derived therefrom. In animals, inflammation, mitochondrial respiration, xenobiotic metabolism, and other processes generate oxidants that contribute to ROS formation. ALDHs are known to decrease oxidative stress, particularly that caused by aldehydes [1], [2]. ALDH induction has been observed in a variety of plants species exposed to heat, dehydration, salinity, oxidants, ultraviolet (UV) radiation, pesticides, or metals. Mechanical trauma and fungal infection can also elicit ALDH upregulation in plants[3]. Pathogenic bacteria encounter oxidative stress emanating from the host immune response that must be overcome during invasion and sustained infection [4], [5]. Organisms, including yeast and Caenorhabditis elegans, also express a variety of ALDHs in response to oxidative stress [6], [7]. The representation of the ALDH gene superfamily in all three taxonomic domains (Archaea, Eubacteria, and Eukarya) is suggestive of a crucial role for these enzymes throughout evolutionary history[8].

Aldehydes are strongly electrophilic, highly reactive, and relatively long-lived compounds. Reactive aldehydes readily form adducts with DNA, RNA, and proteins, leading to impaired cellular homeostasis, enzyme inactivation, DNA damage, and cell death [9], [10], [11]. They have been implicated in oxidative stress-associated diseases, such as atherosclerosis, cancer, diabetes, chronic alcohol exposure, and acute lung injury and in neurodegenerative diseases such as Alzheimer and Parkinson diseases [9], [12], [13]. The ALDH superfamily contains NAD(P)+-dependent enzymes that oxidize a wide range of endogenous and exogenous aldehydes to their corresponding carboxylic acids[1]. The ability of ALDHs to act as “aldehyde scavengers” is grounded in the observation that many have broad substrate specificities and can metabolize a wide range of chemically and structurally diverse aldehydes. Many of the ALDH isozymes overlap in relation to substrate specificities, tissue distribution, and subcellular localization but vary in their efficiency in metabolizing specific aldehydes [14], [15], [16], [17]. The human genome contains 19 protein-coding ALDH genes. ALDH proteins are found in one or more subcellular compartments including the cytosol, mitochondria, endoplasmic reticulum, and nucleus, as well as plastids in plants [14]. Mutations and polymorphisms in ALDH genes are associated with various pathophysiological conditions in humans and rodents [1], [18], including Sjögren-Larsson syndrome [19], type II hyperprolinemia [20], γ-hydroxybutyric aciduria [21], pyridoxine-dependent epilepsy [22], hyperammonemia [23], alcohol-related diseases [24], cancer [25], and late-onset Alzheimer disease [14], [26] (Table 2). ALDH enzymes may also play important antioxidant roles by producing NAD(P)H [27], [28], directly absorbing UV radiation [29], [30], and scavenging hydroxyl radicals via cysteine and methionine sulfhydryl groups [31].

Section snippets

Aldehyde generation and metabolism

Aldehydes are generated during metabolism of various endobiotic and xenobiotic compounds. For example, aldehydes are associated with the metabolism of alcohols, amino acids (e.g., lysine, valine, proline, and arginine), anticancer drugs (e.g., cyclophosphamide), and neurotransmitters (e.g., γ-aminobutyric acid (GABA), serotonin, noradrenaline, adrenaline, dopamine) [1], [32], [33]. Lipid peroxidation (LPO) of cellular phospholipids induces the formation of more than 200 highly reactive aldehyde

Bacteria

Bacteria are constantly confronted by oxidative stress. ROS are generated from a number of sources including leakage of single electrons from respiratory enzymes, environmental stresses (e.g., UV radiation), and redox cycling agents (e.g., menadione and paraquat), as well as metal-catalyzed oxidation via exposure to free copper (Cu2+) or iron (Fe2+)[4]. Pathogenic bacteria also encounter oxidative stress related to a host immune response. Owing to their longer half-lives relative to reactive

Conclusion

The ALDH gene superfamily comprises NAD(P)H-dependent enzymes catalyzing the irreversible oxidation of endogenously and exogenously generated aromatic and aliphatic aldehydes. ALDHs play important roles in fundamental pathways involved in the synthesis of various biomolecules including vitamins, carbohydrates, amino acids, and lipids. In plants, they metabolize the toxic aldehyde intermediate betaine aldehyde into glycine betaine, an osmolyte that also protects plants from dehydration,

Acknowledgments

We thank our colleagues for critically reviewing the manuscript. This work was supported, in part, by the following National Institutes of Health grants: EY17963, EY11490, Skaggs Scholars (V.V.), F31AA018248 (C.B.) and F31AA020728 (B.J.). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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