Is the anomeric effect an important factor in the rate of adenosine deaminase catalyzed hydrolysis of purine nucleosides? A direct comparison of nucleoside analogues constructed on ribose and carbocyclic templates with equivalent heterocyclic bases selected to promote hydration
Is the anomeric effect an important factor in the rate of adenosine deaminase catalyzed hydrolysis of purine nucleosides? A direct comparison of nucleoside analogues constructed on ribose and carbocyclic templates with equivalent heterocyclic bases selected to promote hydration
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DOI：
10.1016/s0968-0896(02)00099-8
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发表时间：
2002-08-01
影响因子：
3.5
通讯作者：
Marquez, VE
中科院分区：
文献类型：
--
作者：
Hernandez, S;Ford, H;Marquez, VE
(North)-methanocarbadeoxyadenosine [(N)-MCdA, (5)] 的糖苷配基，腺苷脱氨酶 (ADA) 相对较弱的底物，脱氨相对速率约为 100%。比腺苷低 100 倍，在 6 位（6-氟，化合物 6）和 8 位（8-氮杂，化合物 7）进行了取代修饰，目的是提高水合水平，从而提高 ADA 的水解水平。在这些底物中，稠合环丙烷部分限制环戊烷环模拟假旋转循环北半球的呋喃糖构象，这与与 ADA 复合的腺苷核糖环的构象相匹配。对ADA水解的敏感性顺序为腺苷>>(N)-MCdA(5)，近似为(N)-6F-MCdP(6)>(N)-8-aza-MCdA(7)。尽管已知 8-氮杂腺苷的水解速度是腺苷的两倍，但相应的碳环类似物 7 的水解速度约为母体 5 的一半。这些结果支持 O(4) 氧原子及其相关的异头效应在协助 ADA 水解中的关键作用。 (C) 2002 Elsevier Science Ltd. 保留所有权利。
The aglycone of (North)-methanocarbadeoxyadenosine [(N)-MCdA, (5)], a relatively weak Substrate for adenosme deaminase (ADA)-relative rate of deamination ca. 100 times lower than adenosine-was modified with substitutions at positions 6 (6-fluoro, compound 6) and 8 (8-aza, compound 7) with the intent to improve the level of hydration and hence hydrolysis by ADA. In these substrates the fused cyclopropane moiety constrains the cyclopentane ring to mimic the conformation of a furanose sugar in the North hemisphere of the pseudorotational cycle, which matches the conformation of the ribose ring of adenosine in complex with ADA. The order of susceptibility to ADA hydrolysis was adenosine > > (N)-MCdA (5)approximate to(N)-6F-MCdP (6) > (N)-8-aza-MCdA (7). Despite the known fact that 8-azaadenosine is hydrolyzed twice as fast as adenosine, the corresponding carbocyclic analogue 7 was hydrolyzed at approximately half the rate of the parent 5. These results argue in favor of the critical role of the O(4) oxygen atom and its associated anomeric effect in assisting hydrolysis by ADA. (C) 2002 Elsevier Science Ltd. All rights reserved.