HUMAN ALCOHOL DEHYDROGENASE AND ALDEHYDE DEHYDROGENASE

人类乙醇脱氢酶和乙醛脱氢酶

• 批准号: 3109064
• 负责人: AKIRA Y YOSHIDA
• 金额: $ 8.9万
• 依托单位: BECKMAN RES INST OF THE CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-04-01 至 1986-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3109064
• 关键词: Asians; acetaldehyde; affinity chromatography; alcohol dehydrogenase; alcoholic beverage consumption; aldehyde dehydrogenases; autoradiography; chemical fingerprinting; chemical reaction; chemical structure function; gel electrophoresis; human tissue; isozymes; molecular site; radiotracer

The sensitivity to acute alcohol intoxication is far more commonly found in Orientals than in Caucasians. The difference is thought to be related to genetic differences in the enzymes involved in alcohol metabolism. It has been suggested that the high frequency in alcohol sensitivity could be due to the rapid acetaldehyde formation by the atypical alcohol dehydrogenase ADH2/2 with high activity which is common among Orientals, or due to the accumulation of acetaldehyde caused by the absence of one of the major aldehyde dehydrogenase isozymes (ALDH-2) with high affinity to acetaldehyde in many Orientals. We recently determined the active site structures of the usual ADH1/2 and atypical ADH2/2. We also demonstrated that the absence of ALDH-2 in many Orientals is not due to gene deletion, nonsense mutation or regulatory mutation, but it is due to a structural mutation producing an enzymatically inactive but immunologically homologous protein. The proposed project includes: a) Study of kinetic properties and active site structures of other usual and atypical alcohol dehydrogenase isozymes controlled by ADH1, ADH2, and ADH3, loci, and b) study of active site structures of two major aldehyde dehydrogenase isozymes, i.e., ALDH-1 and ALDH-2, and the structure of the enzymatically inactive defective protein existing in an atypical Oriental liver. These studies will extend our knowledge on the structure-function relationships of the two dehydrogenases, and may contribute to our understanding of the process of evolutional divergence of the usual and atypical enzymes related to alcohol metabolism in Caucasians and Orientals.

对急性酒精中毒的敏感性更常见于 东方人多于白种人。 这种差异被认为与 参与酒精代谢的酶的遗传差异。 它有 有人认为酒精敏感性的高频率可能是由于 非典型乙醇脱氢酶快速形成乙醛 ADH2/2 具有高活性，这在东方人中很常见，或者是由于 由于缺乏其中一种主要物质而导致乙醛积聚 与乙醛具有高亲和力的乙醛脱氢酶同工酶 (ALDH-2) 在很多东方人看来。 我们最近确定了活性位点结构 常见的 ADH1/2 和非典型的 ADH2/2。 我们还证明了 很多东方人体内缺乏 ALDH-2 并不是因为基因缺失，胡说八道 突变或调节突变，但它是由于结构突变引起的 产生酶无活性但免疫学同源的 蛋白质。 拟议项目包括： a) 动力学特性研究 以及其他常见和非典型酒精的活性位点结构 由 ADH1、ADH2 和 ADH3、位点和 b) 控制的脱氢酶同工酶 两种主要醛脱氢酶活性位点结构的研究 同工酶，即 ALDH-1 和 ALDH-2，以及酶促结构 非典型东方肝脏中存在无活性的缺陷蛋白。 这些 研究将扩展我们对结构与功能关系的认识 两种脱氢酶的关系，可能有助于我们理解 常见酶和非典型酶的进化分化过程相关 对白种人和东方人的酒精代谢的影响。