Brocker Chad, Lassen Natalie, Estey Tia, Pappa Aglaia, Cantore Miriam, Orlova Valeria V, Chavakis Triantafyllos, Kavanagh Kathryn L, Oppermann Udo, Vasiliou Vasilis
Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado 80045, USA.
J Biol Chem. 2010 Jun 11;285(24):18452-63. doi: 10.1074/jbc.M109.077925. Epub 2010 Mar 5.
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.
哺乳动物的醛脱氢酶7A1（ALDH7A1）与植物醛脱氢酶7B1同源，后者是一种能抵御多种形式应激的酶，如盐胁迫、脱水和渗透胁迫。已知人类ALDH7A1基因突变会导致吡哆醇依赖性和叶酸反应性癫痫发作。在此，我们首次表明，人类ALDH7A1通过生成渗透溶质和代谢有毒醛类来抵御高渗胁迫。中国仓鼠卵巢细胞中人类ALDH7A1的表达减轻了由细胞外蔗糖或氯化钠浓度增加引起的渗透胁迫诱导的细胞凋亡。纯化的重组ALDH7A1能有效代谢多种醛底物，包括渗透溶质前体甜菜碱醛、脂质过氧化衍生的醛以及赖氨酸降解中间产物α-氨基己二酸半醛。ALDH7A1的晶体结构支持了该酶的底物特异性。对小鼠的组织分布研究表明，ALDH7A1蛋白在肝脏、肾脏和大脑中的表达最高，其次是胰腺和睾丸。在细胞质、细胞核和线粒体中均发现了ALDH7A1蛋白，这使其在醛脱氢酶中独具特色。对人和小鼠cDNA序列的分析揭示了线粒体和细胞质转录本在小鼠中以组织特异性方式差异表达。总之，ALDH7A1是一种在多个亚细胞区室中表达的新型醛脱氢酶，它通过生成渗透溶质和代谢有毒醛类来抵御高渗胁迫。
