Phosphoramidate pronucleotides:比较人类和大肠杆菌phosphoramidase底物特异性的组氨酸三核苷酸结合蛋白。

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周TF, Baraniak J, Kaczmarek R,周X,程J, Ghosh B,瓦格纳CR

Phosphoramidate pronucleotides:比较人类和大肠杆菌phosphoramidase底物特异性的组氨酸三核苷酸结合蛋白。

摩尔制药。2007;3 - 4月4(2):208 - 17所示。Epub 2007年1月12日。

PubMed ID

17217311 (在PubMed

]

文摘

促进nucleotide-based疗法的细胞和组织,各种pronucleotide方法已经开发出来。我们的实验室和其他证明核苷phosphoramidates可以激活细胞的相应的5 '一磷酸核苷酸和组氨酸三核苷酸结合蛋白(暗示)可能负责bioactivation。提示是守恒的,无处不在的酶水解phosphoramidate债券之间的核苷5 '一磷酸胺离去基团。核苷的能力的基础上的荧光熄灭共价链接包含吲哚胺,敏感,连续荧光技术分析。一系列基质连接自然fluorogenic吲哚衍生物核苷5 ' -monophosphates合成,其稳态动力学参数由人类Hint1水解和大肠杆菌提示进行评估。描述元素和立体化学的影响反应,两个P-diastereoisomers腺苷或鸟苷phosphoramidothioates被合成和研究揭示了15 - 200倍降低特异性常数(kcat /公里)当磷酰氧硫所取代。而立体化学的偏好没有观察到大肠杆菌提示,hHint1展出300倍偏好d-tryptophan phosphoramidates l-isomers。最有效的基质评估日期是那些包含sterically阻碍胺离去基团越少,色胺,kcat和公里为腺苷酸激酶值与发现。明显的二阶速率常数(kcat /公里)腺苷色胺phosphoramidate单酯被发现是107 m - 1 s - 1为大肠杆菌hHint1和106 m - 1 s - 1提示。人类和大肠杆菌酶首选嘌呤嘧啶类似物。 Consistent with observed hydrogen bonding between the 2'-OH group of adenosine monophosphate and the active site residue, Asp43, the second-order rate constant (kcat/Km) for thymidine tryptamine phosphoramidate was found to be 3-4 orders of magnitude smaller than that for uridine tryptamine phosphoramidate for hHint1 and 2 orders of magnitude smaller than that for E. coli hinT. Ara-A tryptamine phosphoramidate was, however, shown to be a good substrate with a specificity constant (kcat/Km) only 10-fold lower than the value for adenosine tryptamine phosphoramidate. Consequently, nucleoside phosphoramidates containing unhindered primary amines and either an alpha or beta 2'-OH group should be easily bioactivated by Hints with efficiencies rivaling those for the 5'-monophosphorylation of nucleosides by nucleoside kinases. The differential substrate specificity observed for human and E. coli enzymes represents a potential therapeutic rationale for the development of selective antibiotic phosphoramidate pronucleotides.

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药物靶点

药物	目标	类	生物	药理作用	行动
磷酸腺苷	组氨酸三nucleotide-binding蛋白质1	蛋白质	人类	未知的	产品的	细节