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人胸苷激酶1和2以及脱氧胞苷激酶对抗病毒和细胞抑制核苷类似物的底物特异性比较。

Comparison of the substrate specificities of human thymidine kinase 1 and 2 and deoxycytidine kinase toward antiviral and cytostatic nucleoside analogs.

作者信息

Eriksson S, Kierdaszuk B, Munch-Petersen B, Oberg B, Johansson N G

机构信息

Department of Biochemistry I, Karolinska Institutet, Stockholm, Sweden.

出版信息

Biochem Biophys Res Commun. 1991 Apr 30;176(2):586-92. doi: 10.1016/s0006-291x(05)80224-4.

Abstract

Deoxynucleoside kinases are required for the 5'-phosphorylation of deoxynucleoside analogs used in chemotherapy. Cytoplasmic thymidine kinase (TK1), deoxycytidine kinase (dCK) and mitochondrial thymidine kinase (TK2) were completely purified from human leukemic spleen and their capacities to phosphorylate 43 nucleoside analogs were compared. TK1 showed the most restricted substrate specificity but tolerated 3'-modifications of the sugar ring and some 5-substitutions of the pyrimidine ring. TK2 showed a much broader specificity and phosphorylated pyrimidine bases with bulky 5-substitutions, including cytosine analogs, while sugar analogs with substituents other than OH in the 2' and 3' positions were very poor substrates. dCK showed a very broad specificity phosphorylating several cytosine analogs with 2' and 3' modifications as well as acyclic sugar analogs. Purine deoxyribonucleosides were also efficiently phosphorylated by dCK but in this case sugar modifications led to drastically decreased activity.

摘要

脱氧核苷激酶是化疗中使用的脱氧核苷类似物5'-磷酸化所必需的。从人白血病脾脏中完全纯化出细胞质胸苷激酶(TK1)、脱氧胞苷激酶(dCK)和线粒体胸苷激酶(TK2),并比较了它们磷酸化43种核苷类似物的能力。TK1表现出最受限的底物特异性,但能耐受糖环的3'-修饰和嘧啶环的一些5-取代。TK2表现出更广泛的特异性,能磷酸化具有大体积5-取代的嘧啶碱基,包括胞嘧啶类似物,而在2'和3'位具有除OH以外取代基的糖类似物是非常差的底物。dCK表现出非常广泛的特异性,能磷酸化几种具有2'和3'修饰的胞嘧啶类似物以及无环糖类似物。嘌呤脱氧核糖核苷也能被dCK有效磷酸化,但在这种情况下,糖修饰会导致活性急剧下降。

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