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.

对急性酒精毒化的敏感性在 东方比高加索人。 差异被认为与 与酒精代谢有关的酶的遗传差异。 它有 有人提出，酒精敏感性的高频可能到期 通过非典型酒精脱氢酶的快速乙醛形成 ADH2/2具有高活性，在东方人中很常见，或者是由于 由于缺乏主要的乙醛的积累 醛脱氢酶同工酶（ALDH-2）具有高亲和力，对乙醛 在许多东方。 我们最近确定了活跃的位点结构 通常的ADH1/2和非典型ADH2/2。 我们还证明了 在许多东方的缺乏ALDH-2并不是由于基因缺失，废话 突变或调节突变，但这是由于结构突变引起的 产生酶促的非活性但具有免疫学同源性的 蛋白质。 拟议的项目包括：a）动力学特性的研究 以及其他常规和非典型酒精的主动地点结构 由ADH1，ADH2和ADH3，LOCI和B）控制的脱氢酶同工酶 研究两个主要醛脱氢酶的活性位点结构 同工酶，即ALDH-1和ALDH-2，以及酶上的结构 非典型东方肝脏中存在的无活性缺陷蛋白。 这些 研究将扩展我们对结构功能关系的知识 在两种脱氢酶中，可能有助于我们对 常规酶和非典型酶的进化差异过程 在高加索人和东方的酒精代谢中。