Review ArticleAldehyde dehydrogenases in cellular responses to oxidative/electrophilicstress
Graphical abstract
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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