Conversion of Inactive Cobalamins to Coenzyme B12

无活性钴胺素转化为辅酶 B12

• 批准号: 6951391
• 负责人: THOMAS Aquinas BOBIK
• 金额: $ 19.42万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6951391
• 关键词: Escherichia coli; alkyltransferase; bacterial genetics; bacterial proteins; biotechnology; cobalamin; enzyme induction /repression; enzyme mechanism; genetic mapping; methionine; microorganism metabolism; miscellaneous oxidoreductase; nutrition related tag; transfection /expression vector; vitamin B12 coenzyme; vitamin metabolism; Escherichia coli; alkyltransferase; bacterial genetics; bacterial proteins; biotechnology; cobalamin; enzyme induction /repression; enzyme mechanism; genetic mapping; methionine; microorganism metabolism; miscellaneous oxidoreductase; nutrition related tag; transfection /expression vector; vitamin B12 coenzyme; vitamin metabolism

DESCRIPTION (provided by applicant): Coenzyme B12-dependent processes are vital to human health and play important roles in ecological niches and industrial applications. The long-term goal of the proposed research is to improve our general understanding of the genetics and biochemistry of coenzyme B 12. The proposed studies focus on the metabolism of inactive cobalamins into the B 12 coenzymes. This process is needed for the assimilation of exogenous cobalamins, and because the B 12 coenzymes are unstable, for the maintenance of adequate B 12 pools to meet physiological needs. The human cob(I)alamin adenosyltransferase which functions in cobalamin metabolism will be characterized biochemically and its 3-dimensional structure will be determined. The reduction of cob(II) alamin to cob(I)alamin for coenzyme B 12 synthesis will also be investigated. Preliminary studies showed that the human methionine synthase reductase can reduce cob(II)alamin to cob(I)alamin for coenzyme B 12 synthesis, and results indicated a highly specific interaction between the human methionine synthase reductase and adenosyltransferase enzymes. The reduction of cob(II)alamin to cob(I)alamin by the human methionine synthase reductase will be more fully characterized. The results of bioinformatic analyses have indicated that the bacterial YgfD protein and its homologues are involved in cobalamin metabolism The specific function of the YgfD protein will be determined by a series of biochemical tests. The final aim of the project will be to use the genes identified in this study to construct gene therapy vectors for expression of enzymes involved in cobalamin metabolism. The proposed studies will provide information directly applicable to improved methods of diagnosis and treatment of inherited diseases of B 12 metabolism. Furthermore, since changes in B 12 metabolism have been linked to chronic liver disease, cancer, elevated serum homocysteine (a possible risk factor in heart disease), increased rates of DNA damage, impaired cognitive function, and HIV infection, the proposed studies may also provide information relevant to understanding these diseases.

描述（由申请人提供）：辅酶B12依赖性过程对人类健康至关重要，并且在生态壁ni和工业应用中起重要作用。拟议的研究的长期目标是提高我们对辅酶B 12的遗传学和生物化学的一般理解。拟议的研究集中于无活性钴胺素的代谢中的代谢。需要此过程来吸收外源钴胺素，并且由于B 12辅酶不稳定，因此可以维持足够的B 12池以满足生理需求。将在生物化学上表征钴胺素代谢中的人蛋白棒（I）腺苷腺苷转移酶，并将确定其3维结构。还将研究将COB（II）酰胺蛋白降低为COB（I）丙烯酶B 12合成。初步研究表明，人蛋氨酸合酶还原酶可以将COB（II）丙氨酸降低到COB（I）丙酰蛋白酶B 12合成，结果表明人类蛋氨酸合酶还原酶还原酶和腺苷基转移酶之间具有高度特异性的相互作用。人蛋氨酸合酶还原酶还将cob（ii）呈酸（I）将其还原为cob（I）alamin。生物信息学分析的结果表明，细菌YGFD蛋白及其同源物与钴胺素代谢有关YGFD蛋白的特定功能将由一系列生化测试确定。该项目的最终目的是使用本研究中鉴定的基因来构建基因疗法向量来表达参与钴胺素代谢的酶。拟议的研究将提供直接适用于改进B 12代谢遗传疾病的诊断和治疗方法的信息。此外，由于B 12代谢的变化与慢性肝病，癌症，血清同型同半胱氨酸的升高（心脏病的可能危险因素）有关，DNA损伤的率提高，认知功能受损和HIV感染，拟议的研究也可能提供与理解这些疾病有关的信息。