MOLECULAR PATHOLOGY OF GENETIC DISORDERS IN MAN

人类遗传性疾病的分子病理学

• 批准号: 3340660
• 负责人: AKIRA Y YOSHIDA
• 金额: $ 25.13万
• 依托单位: BECKMAN RES INST OF THE CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-08-01 至 1987-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3340660
• 关键词: alcohol dehydrogenase; aldehyde dehydrogenases; alpha 1 antitrypsin; alpha 1 antitrypsin deficiency; analytical method; biochemical evolution; chemical fingerprinting; chemical structure function; clone cells; computer graphics /printing; enzyme structure; erythrocyte membrane; gene expression; genetic disorder; glucose 6 phosphate dehydrogenase; glutathione; hemolytic anemia; human population genetics; human tissue; immunoelectrophoresis; inborn metabolism disorder; isozymes; liver; mannosidase; mannosidosis; mental disorders; molecular pathology; phosphoglycerate kinase; phosphoglycerate kinase deficiency; radiotracer

The aim of the proposed project is to elucidate the molecular mechanism of gene action in man ghrough a biochemical approach. The project consists of the following studies: a) Determination of specific amino acid substitutions of several phosphoglycerate kinase (PGK) variants and glucose 6-phosphate dehydrogenase (G6PD) variants. Since we determined the complete amino acid sequence of normal PGK and G6PD, the structural abnormalities can be correlated to their functional abnormalities, which induce hemolytic anemia and mental disorders in the subjects with the enzyme defects; b) The proposed study of the glucose-monophosphate shunt pathway activity and G6PD activity in permeabilized red cells may lead us to understand the unexplained "intra cellular restraint" of G6PD activity and the inconsistency between the degree of red cell G6PD deficiency and the severity of hemolysis in some G6PD variants; c) Determination of the complete amino acid sequence of normal human alpha1-antitrypsin (A1AT) will disclose the complete structures of normal and variant A1AT molecules; d) Study of the usual and atypical alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) at the protein level, and study of the organization of genes for ADH and ALDH. Molecular difference between the usual and atypical ADH2 isozymes, and evolutional relationships of these two enzymes and other isozymes (ADH1 and ADH3) will become apparent. The subunit structure of ALDH, and the genetic mechanism of missing ALDH-2 isozyme in the atypical subjects will be elucidated. These studies are of particular interest, since the frequency of atypical ADH and ALDH and sensitivity of alcohol intoxication and alcoholism are distinctively different between Caucasians and Orientals, and e) Study of the enzymatic and immunological properties of alpha-mannosidase from the mannosidosis patient may make clear the molecular region of this disorder, and the determination of the active site of pseudocholinesterase will disclose the exact molecular difference between the usual enzyme and atypical enzyme which is related to prolonged paralysis induced by suxamethionium.

该项目的目的是阐明其分子机制 通过生化方法对人类进行基因作用。 该项目包括 以下研究： a) 特定氨基酸的测定 几种磷酸甘油酸激酶 (PGK) 变体和葡萄糖的替代 6-磷酸脱氢酶 (G6PD) 变体。 既然我们确定了 正常PGK和G6PD的完整氨基酸序列，结构 异常可能与其功能异常相关， 引起受试者溶血性贫血和精神障碍 酶缺陷； b) 葡萄糖-单磷酸分流的拟议研究 透化红细胞中的途径活性和 G6PD 活性可能会引导我们 了解 G6PD 活性无法解释的“细胞内抑制” 以及红细胞G6PD缺乏程度与 某些 G6PD 变异体溶血的严重程度； c) 确定 正常人α1-抗胰蛋白酶（A1AT）的完整氨基酸序列 公开正常和变异 A1AT 分子的完整结构； d) 常见和非典型乙醇脱氢酶（ADH）和醛的研究 蛋白质水平的脱氢酶（ALDH）及其组织研究 ADH 和 ALDH 基因。 普通和普通之间的分子差异 非典型 ADH2 同工酶以及这两种酶的进化关系 和其他同工酶（ADH1 和 ADH3）将变得明显。 亚基 ALDH的结构以及缺失ALDH-2同工酶的遗传机制 非典型主题将得到阐明。 这些研究具有特殊性 感兴趣，因为非典型 ADH 和 ALDH 的频率以及 酒精中毒和酒精中毒之间存在显着不同 白种人和东方人，以及 e) 酶学和免疫学研究 来自甘露糖苷中毒患者的α-甘露糖苷酶的特性可能使 清除这种疾病的分子区域，并确定 假胆碱酯酶的活性位点将揭示确切的分子 普通酶和非典型酶之间的区别与 琥珀甲硫铵引起的长时间麻痹。