Aldehyde Dehydrogenase 7A1 (ALDH7A1) Is a Novel Enzyme Involved in Cellular Defense against Hyperosmotic Stress

Abstract

Mammalian ALDH7A1 is homologous to plant ALDH7B1, an enzyme that protects against various forms of stress, such as salinity, dehydration, and osmotic stress. It is known that mutations in the human ALDH7A1 gene cause pyridoxine-dependent and folic acid-responsive seizures. Herein, we show for the first time that human ALDH7A1 protects against hyperosmotic stress by generating osmolytes and metabolizing toxic aldehydes. Human ALDH7A1 expression in Chinese hamster ovary cells attenuated osmotic stress-induced apoptosis caused by increased extracellular concentrations of sucrose or sodium chloride. Purified recombinant ALDH7A1 efficiently metabolized a number of aldehyde substrates, including the osmolyte precursor, betaine aldehyde, lipid peroxidation-derived aldehydes, and the intermediate lysine degradation product, ␣-aminoadipic semialdehyde. The crystal structure for ALDH7A1 supports the enzyme's substrate specificities. Tissue distribution studies in mice showed the highest expression of ALDH7A1 protein in liver, kidney, and brain, followed by pancreas and testes. ALDH7A1 protein was found in the cytosol, nucleus, and mitochondria, making it unique among the aldehyde dehydrogenase enzymes. Analysis of human and mouse cDNA sequences revealed mitochondrial and cytosolic transcripts that are differentially expressed in a tissue-specific manner in mice. In conclusion, ALDH7A1 is a novel aldehyde dehydrogenase expressed in multiple subcellular compartments that protects against hyperosmotic stress by generating osmolytes and metabolizing toxic aldehydes. The human aldehyde dehydrogenase (ALDH)3 superfamily contains 19 enzymes involved in the NAD(P)ϩ -dependent oxidation of aldehydes to their corresponding carboxylic acids. These enzymes play crucial roles in a number of physiological processes by efficiently metabolizing a wide array of endogenous and exogenous aldehydes (1). Aldehydes are highly reactive molecules that can form adducts resulting in DNA damage and enzyme inactivation. As such, their removal is of the utmost importance. ALDH enzymes also couple the removal of these potentially toxic aldehydes to NAD(P)H production, which, in turn, helps maintain cellular redox balance. Finally, ALDH activity generates a number of important cellular molecules, including retinoic acid, the neurotransmitter ␥-aminobutyric acid, the major dietary folate tetrahydrofolate, and the osmolyte betaine (1).Human ALDH7A1 was originally identified as sharing 60% homology with the osmotic stress-induced 26g pea turgor protein (according to the official nomenclature now referred to as ALDH7B1), found in the common garden pea (Pisum sativum) (2). Initially named "antiquitin," the ALDH7A1 protein has been highly conserved throughout evolution. Indeed, the degree of homology noted between ALDH7A1 and ALDH7B1 is comparable with that observed between the human and pea histone H2A proteins, which are among the most evolutionarily conserved of all eukaryotic proteins (2, 3). Such a high degree of sequence similarity between species ofte...

Polar and brown bear genomes reveal ancient admixture and demographic footprints of past climate change

“…One such interval with selective potential in bears contains the homologue of ALDH7A1. This gene has been shown to protect humans against hyperosmotic stress (23), and it is conceivable that PB-like variants may have provided a selective advantage for PBs and coastal brown bears, such as the ABC brown bears, in a shift to a marine environment ( Fig. 4C and SI Appendix).…”

Volatile and Intravenous Anesthesia Alter Rat Liver Proteins: Proteomic Time Course Analysis of Rat Liver Proteins

“…ALDH7A1 is located in mitochondria where it mainly metabolizes betaine aldehyde to betaine. ALDH7A1 was recently reported to protect hepatic cells from oxidative stress by metabolizing lipid peroxidation molecules [9,10]. In this study, expression of CAT, Cu-Zn SOD, GST, and ALDH7A1 was significantly downregulated in P-0 and S-0, and their expression ratios returned to control levels 72 h after anesthesia.…”

“…Many *Address correspondence to this author at the Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan; Tel: +81 3 5814 6243; Fax: +81 3 5685 3077; E-mail: s00-098@nms.ac.jp factors such as antioxidant enzymes, hepatic detox enzymes, heat shock proteins (HSPs), and direct effects of anesthetics may mediate hepatocellular protection from biological stresses [7,8]. Other hepatocellular antioxidant enzymes such as catalase (CAT), glutathione S transferase (GST), superoxide dismutase (SOD), and aldehyde dehydrogenase-7A1 (ALDH7A1) also show liver protective functions by scavenging reactive oxygen species (ROS) or in other ways [9][10][11][12][13]. Intravenous anesthetics such as propofol do not seem to have comparable protective properties [14].…”

Genome-wide analysis of lysine catabolism in bacteria reveals new connections with osmotic stress resistance

“…In plants and animals, the genes encoding LKR/SDH and AASADH are induced in response to osmotic and oxidative stresses (Guerrero et al, 1990;Stroeher et al, 1995;Deleu et al, 1999;Buchanan et al, 2005;Kirch et al, 2005;Rodrigues et al, 2006;Brocker et al, 2010) but the mechanism by which the enzymes protect against these stress remains to be elucidated.…”