SPECIES-SPECIFIC OR ISOZYME-SPECIFIC ENZYME-INHIBITORS .6. SYNTHESIS AND EVALUATION OF 2-SUBSTRATE CONDENSATION PRODUCTS AS INHIBITORS OF HEXOKINASES AND THYMIDINE KINASES
SPECIES-SPECIFIC OR ISOZYME-SPECIFIC ENZYME-INHIBITORS .6. SYNTHESIS AND EVALUATION OF 2-SUBSTRATE CONDENSATION PRODUCTS AS INHIBITORS OF HEXOKINASES AND THYMIDINE KINASES
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DOI：
10.1021/jm00349a007
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发表时间：
1982-01-01
影响因子：
7.3
通讯作者：
CHAWLA, RR
中科院分区：
文献类型：
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作者：
HAMPTON, A;HAI, TT;CHAWLA, RR
描述了P1-（腺苷-5“）-P3-（葡萄糖-6）三磷酸（Ap 3葡萄糖）、Ap 4葡萄糖和P1-（腺苷-5”）-P3-（胸苷-5“）三磷酸（Ap 3 T）的合成。这些化合物不是本研究中使用的任何酶的底物。Ap 3葡萄糖和Ap 4葡萄糖是酵母己糖激酶（HK）和大鼠同工酶HK I-III的抑制剂;一般来说，它们对酶的亲和力低于底物ATP和葡萄糖。在恒定饱和ATP水平下测定可变胸苷（TdR）和恒定饱和TdR下测定Ap 3 T与大鼠线粒体胸苷激酶（M-TK）和大鼠胞质TK（C-TK）的抑制常数（Ki值）。与C-TK [Km（TdR）/Ki = 0.006，Km（ATP）/Ki = 0.7，可变ATP]相比，Ap 3 T对M-TK [Km（TdR）/Ki = 1.6，Km（ATP）/Ki = 38，可变TdR]有较强的选择性抑制作用; Km（TdR）/Ki = 0.001，Km（ATP）/Ki = 0.12，TdR可变]。Ap 3 T对M-TK和C-TK的抑制与代谢反馈抑制剂TTP在相同条件下的抑制在定性和定量上不同。[TK和Hk作为癌症化疗中的靶标是令人感兴趣的。
Syntheses are described of P1-(adenosine-5'')-P3-(glucose-6) triphosphate (Ap3 glucose), Ap4 glucose, and P1-(adenosine-5'')-P3-(thymidine-5'') triphosphate (Ap3T). The compounds were not substrates of any of the enzymes used in the present studies. Ap3 glucose and Ap4 glucose were inhibitors of yeast hexokinase (HK) and the rat isozymes HK I-III; in general, they had less affinity for the enzymes than the substrates ATP and glucose. Inhibition constants (Ki values) of Ap3T with rat mitochondrial thymidine kinase (M-TK) and rat cytoplasmic TK (C-TK) were determined for variable thymidine (TdR) with a constant saturating level of ATP and for variable ATP with constant saturating TdR. Ap3T was a potent and selective inhibitor of M-TK [Km (TdR)/Ki = 1.6, Km (ATP)/Ki = 38 with variable ATP; Km (TdR)/Ki = 0.6, Km (ATP)/Ki = 1.4 with variable TdR] relative to C-TK [Km (TdR)/Ki = 0.006, Km (ATP)/Ki = 0.7 with variable ATP; Km (TdR)/Ki = 0.001, Km (ATP)/Ki = 0.12 with variable TdR]. Inhibition of M-TK and C-TK by Ap3T differed qualitatively and quantitatively from inhibition under the same conditions by the metabolic feedback inhibitor TTP. [TK and Hk are of interest as targets in cancer chemotherapy.].