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

被引:155
作者
Brocker, Chad [1 ]
Lassen, Natalie [1 ]
Estey, Tia [1 ]
Pappa, Aglaia [1 ]
Cantore, Miriam [1 ]
Orlova, Valeria V. [2 ]
Chavakis, Triantafyllos [2 ]
Kavanagh, Kathryn L. [3 ]
Oppermann, Udo [3 ,4 ]
Vasiliou, Vasilis [1 ]
机构
[1] Univ Colorado Denver, Dept Pharmaceut Sci, Mol Toxicol & Environm Hlth Sci Program, Aurora, CO 80045 USA
[2] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA
[3] Univ Oxford, Struct Genom Consortium, Headington OX3 7DQ, England
[4] Univ Oxford, Nuffield Dept Orthoped Surg Rheumatol & Musculosk, Botnar Res Ctr, Biomed Res Unit, Oxford OX3 7LD, England
基金
美国国家卫生研究院; 英国惠康基金;
关键词
PIPECOLIC ACID METABOLISM; TURGOR-RESPONSIVE GENE; MOLECULAR-CLONING; TISSUE DISTRIBUTION; BACULOVIRUS EXPRESSION; SEABREAM ANTIQUITIN; LIPID-PEROXIDATION; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; HUMAN LIVER;
D O I
10.1074/jbc.M109.077925
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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, alpha-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.
引用
收藏
页码:18452 / 18463
页数:12
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