核糖核苷酸还原酶研究

Studies on Ribonucleotide Reductase and Its Inhibitors as Anticancer Drugs

核糖核苷酸还原酶广泛存在于各种生物中,是生物体内唯一的催化4种核糖核苷酸还原、生成相应的脱氧核糖核苷酸的酶。该酶是DNA合成和修复的关键酶和限速酶,对细胞的增殖和分化起着调控作用。不同生物中的RR根据其结合的金属辅助因子不同而分类。虽然不同类型RR之间的氨基酸序列相似性很低,但它们有十分相似的三级结构的活性中心和相同的催化功能。RR分子中包含2个变构位点,即酶活性中心和底物特异结合位点。活性中心通过生物有机自由基的作用催化核糖核苷酸还原;底物特异结合位点通过变构作用调控4种dNTPs在细胞内的平衡。因此,该酶不仅是研究DNA合成与修复、细胞增殖与分化及癌症的治疗与抗癌药物开发的重要靶点,同时也是研究酶的结构与功能以及酶的催化机理等的重要工具。本文总结了该酶的种类与分布、结构特征、催化机理及作为抗癌药物开发靶点等方面的研究进展。

Ribonucleotide reductases （RR, EC 1.174.1） exist in all kinds of living ceils and are the only type of enzymes that can catalyze the reduction of four kinds of ribonucleotides to deoxyribonucleotides necessary for DNA replication and repairing, As one of the key enzymes for DNA synthesis, it controls cell proliferation and differentiation. RR can be grouped into three classes based on their structures and catalytic mechanisms. Although the similarities in amino acids are very few （〈10%）among different classes, the three classes of RR do have similar active sites and have the same catalytic functions. All RR has two kinds of functional allosteric sites, the catalytic sites and the substrate specificity sites. The catalytic active centers of the enzymes activate and reduce ribonucleotides through protein free radicals. The substrate specificity site controls cellular balances of four dNTPs through its allosteric regulation. RR is not only an important target in the studies of DNA replication, cell proliferation or differentiation, and development of anticancer drugs, but also an important model for the elucidation of structure-function relationship and catalytic mechanisms of organic radical enzymes. This paper reviews recent advances of its distribution, structure, function and its inhibitors as anticancer substances.