REGULATION OF METABOLISM BY PURINE INTERCONVERSIONS

这个项目的主要目标是确定核苷酸代谢是如何 在酶和细胞水平上进行调节。 具体研究范围 从详细的动力学，物理和调节酶的研究， 某些细胞类型对预先形成的嘌呤的饮食来源的依赖性， 嘧啶碱基。 三种酶参与了 核苷酸的生物合成、降解和相互转化将是 研究了 第一种是腺苷酸琥珀酸合成酶， 从IMP形成AMP的第一个承诺步骤。详细的物理， 将进行机制和监管调查。 物理和 还将对腺苷脱氨酶进行机制研究， 催化腺苷或2 ′-脱氧腺苷的不可逆脱氨。 位点特异性突变将在第三项研究中以不寻常的形式进行 二氢叶酸还原酶，一种参与脱氧核苷酸 新陈代谢. 这种酶是从大肠杆菌中分离出来的。大肠杆菌质粒， 一个小的，稳定的蛋白质，这将提供一个很好的模型系统， 研究特定氨基酸残基在催化和 约束力 在一项相关的正在进行的研究中， 对于预先形成的嘌呤或嘧啶碱的饮食来源， 测定 对这种影响的生化基础的评价将 包括分析与免疫相关酶和代谢物变化 在不同的饮食条件下发挥作用。 的共同作用 抗代谢药和饮食对免疫系统和淋巴源性 将确定肿瘤。 这些研究应该提供新的信息 涉及核苷酸酶的功能和调节 代谢和潜在的新的移植治疗方案 接受者、肿瘤患者和接受胃肠外或 肠内营养支持

The major goal of this project is to determine how nucleotide metabolism is regulated at both the enzyme and cellular level. Specific studies range from detailed kinetic, physical and regulatory enzyme investigations to the dependence of certain cell types on dietary sources of preformed purine and pyrimidine bases. Three enzymes involved in critical steps in biosynthesis, degradation and interconversion of nucleotides will be studied. The first is adenylosuccinate synthetase which catalyzes the first committed step in AMP formation from IMP. Detailed physical, mechanistic and regulatory investigations will be done. Physical and mechanistic studies will also be done with adenosine deaminase, which catalyzes the irreversible deamination of adenosine or 2'-deoxyadenosine. Site specific mutations will be done in a third study with an unusual form of dihydrofolate reductase, an enzyme involved in deoxynucleotide metabolism. This enzyme which has been isolated from an E. coli plasmid is a small, stable protein which will provide an excellent model system for the study of the role of specific amino acid residues in catalysis and binding. In a related, ongoing study, the requirements of T lymphocytes for a dietary source of preformed purine or pyrimidine bases will be determined. Evaluation of the biochemical basis of this effect will involve analysis of enzyme and metabolite changes as correlated with immune function under different dietary conditions. The combined effect of antimetabolites and diet on the immune system and on lymphoid derived tumors will be determined. These studies should afford new information concerning function and regulation of enzymes involved in nucleotide metabolism and potential new therapeutic protocols for transplant recipients, tumor patients and other patients receiving parenteral or enteral nutritional support.