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首页> 外文期刊>Biochemistry >Adenosine deaminase prefers a distinct sugar ring conformation for binding and catalysis: kinetic and structural studies.
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Adenosine deaminase prefers a distinct sugar ring conformation for binding and catalysis: kinetic and structural studies.

机译：腺苷脱氨酶更喜欢结合和催化的独特糖环构象：动力学和结构研究。

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Several recent X-ray crystal structures of adenosine deaminase (ADA) in complex with various adenosine surrogates have illustrated the preferred mode of substrate binding for this enzyme. To define more specific structural details of substrate preferences for binding and catalysis, we have studied the ADA binding efficiencies and deamination kinetics of several synthetic adenosine analogues in which the furanosyl ring is biased toward a particular conformation. NMR solution studies and pseudorotational analyses were used to ascertain the preferred furanose ring puckers (P, nu(MAX)) and rotamer distributions (chi and gamma) of the nucleoside analogues. It was shown that derivatives which are biased toward a "Northern" (3'-endo, N) sugar ring pucker were deaminated up to 65-fold faster and bound more tightly to the enzyme than those that preferred a "Southern" (2'-endo, S) conformation. This behavior, however, could be modulated by other structural factors. Similarly, purine riboside inhibitors of ADA that prefer the N hemisphere were more potent inhibitors than S analogues. These binding propensities were corroborated by detailed molecular modeling studies. Docking of both N- and S-type analogues into the ADA crystal structure coordinates showed that N-type substrates formed a stable complex with ADA, whereas for S-type substrates, it was necessary for the sugar pucker to adjust to a 3'-endo (N-type) conformation to remain in the ADA substrate binding site. These data outline the intricate structural details for optimum binding in the catalytic cleft of ADA.
机译：与各种腺苷替代物复合的腺苷脱氨酶（ADA）的几种最近的X射线晶体结构已经说明了该酶与底物结合的优选方式。为了定义对结合和催化的底物偏好的更具体的结构细节，我们研究了呋喃糖基环偏向特定构象的几种合成腺苷类似物的ADA结合效率和脱氨动力学。 NMR溶液研究和伪旋转分析用于确定核苷类似物的首选呋喃糖环折叠（P，nu（MAX））和旋转异构体分布（chi和γ）。结果表明，偏向“北方”（3'-endo，N）糖环褶皱的衍生物比那些偏爱“南方”（2'）的衍生物的脱氨基速度最高快65倍，并且与酶的结合更紧密。 -endo，S）构象。但是，此行为可能会受到其他结构因素的调节。同样，偏好于N半球的ADA嘌呤核糖苷抑制剂比S类似物更有效。这些结合倾向通过详细的分子模型研究得到证实。将N型和S型类似物对接到ADA晶体结构坐标中均显示，N型底物与ADA形成稳定的络合物，而对于S型底物，糖曲折必须调节至3'-内（N型）构象保留在ADA底物结合位点。这些数据概述了在ADA催化裂隙中实现最佳结合的复杂结构细节。

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