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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Enhanced subunit interactions with gemcitabine-5'-diphosphate inhibit ribonucleotide reductases
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Enhanced subunit interactions with gemcitabine-5'-diphosphate inhibit ribonucleotide reductases

机译：与吉西他滨5'-二磷酸的增强的亚基相互作用抑制了核糖核苷酸还原酶

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摘要

Ribonucleotide reductases (RNRs) catalyze the conversion of nu-cleotides to deoxynucleotides in all organisms. The class I RNRs are composed of two subunits, α and β, with proposed quaternary structures of α2β2, α6β2, or α6/β6, depending on the organism. The α subunits bind the nucleoside diphosphate substrates and the dNTP/ATP allosteric effectors that govern specificity and turnover. The β2 subunit houses the dif erric Y~* (1 radical per β2) cof actor that is required to initiate nucleotide reduction. 2',2'-Difluoro-2-deoxycytidine (F_2C) is presently used clinically in a variety of cancer treatments and the 5'-diphosphorylated F_2C (F_2CDP) is a potent inhibitor of RNRs. The studies with [1'-~3H]-F_2CDP and [5-~3H]-F_2CDP have established that F_2CDP is a substoichiometric mechanism based inhibitor (0.5 eq F_2CDP/α) of both the Escherichia coli and the human RNRs in the presence of reductant. Inactivation is caused by covalent labeling of RNR by the sugar of F_2CDP (0.5 eq/α) and is accompanied by release of 0.5 eq cytosine/α. Inactivation also results in loss of 40% of β2 activity. Studies using size exclusion chromatography reveal that in the E. coli RNR, an α2β2 tight complex is generated subsequent to enzyme inactivation by F_2CDP, whereas in the human RNR, an α6β6 tight complex is generated. Isolation of these complexes establishes that the weak interactions of the subunits in the absence of nucleotides are substantially increased in the presence of F_2CDP and ATP. This information and the proposed asymmetry between the interactions of αnβn provide an explanation for complete inactivation of RNR with substoichiometric amounts of F_2CDP.
机译：核糖核苷酸还原酶（RNRs）在所有生物中催化核核苷酸向脱氧核苷酸的转化。 I类RNRs由两个亚基α和β组成，取决于生物体，它们具有建议的四元结构α2β2，α6β2或α6/β6。 α亚基与控制特异性和周转率的核苷二磷酸底物和dNTP / ATP变构效应子结合。 β2亚基包含启动核苷酸还原所需的不同的Y〜*（每个β2中有1个自由基）。 2'，2'-二氟-2-脱氧胞苷（F_2C）目前在临床上用于各种癌症治疗，而5'-二磷酸化F_2C（F_2CDP）是一种有效的RNRs抑制剂。用[1'-〜3H] -F_2CDP和[5-〜3H] -F_2CDP进行的研究已确定，F_2CDP是在存在下大肠埃希氏菌和人RNR的基于亚化学计量机制的抑制剂（0.5 eq F_2CDP /α）还原剂。失活是由F_2CDP的糖（0.5 eq /α）对RNR进行共价标记引起的，并伴随有0.5 eq胞嘧啶/α的释放。失活也导致β2活性丧失40％。使用尺寸排阻色谱法进行的研究表明，在大肠杆菌RNR中，F_2CDP使酶失活后会生成α2β2紧密复合物，而在人类RNR中，会生成α6β6紧密复合物。这些复合物的分离建立了在不存在核苷酸的情况下亚基的弱相互作用在存在F_2CDP和ATP的情况下显着增加。该信息以及拟议的αnβn相互作用之间的不对称性为使用亚化学计量量的F_2CDP使RNR完全失活提供了解释。

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