Effects of modifications in the pentose moiety and conformational changes on the binding of nucleoside ligands to uridine phosphorylase from Toxoplasma gondii.
Effects of modifications in the pentose moiety and conformational changes on the binding of nucleoside ligands to uridine phosphorylase from Toxoplasma gondii.
复制标题
戊糖部分的修饰和构象变化对核苷配体与弓形虫尿苷磷酸化酶结合的影响。
DOI：
10.1016/0006-2952(96)00213-4
复制
发表时间：
1996
影响因子：
5.8
通讯作者：
Iltzsch,MH
中科院分区：
文献类型：
--
作者：
elKouni,MH;Naguib,FN;Panzica,RP;Otter,BA;Chu,SH;Gosselin,G;Chu,CK;Schinazi,RF;Shealy,YF;Goudgaon,N;Ozerov,AA;Ueda,T;Iltzsch,MH
对尿嘧啶和戊糖部分进行了各种修饰的150种尿苷类似物进行了测试，并与尿苷进行了比较，比较了它们与来自刚地弓形虫的尿苷磷酸化酶（Urdplasma gondii，EC 2.4.2.3）结合的效力。检查了α-和β-端基异构体、l-和d-对映异构体以及限制性顺式和反式旋转异构体对结合的影响。假-、lyxo-、2，3-t-脱水-2 ′-脱氧-、6，5 ′-环-、6，3 ′-亚甲基-、O 5 ′，6-亚甲基-和碳环尿苷不与酶结合。核糖核苷的结合优于相应的木糖苷，木糖苷优于脱氧核糖核苷。脱氧核苷的结合方式为：2′，3 ′-双脱氧核苷> 2′，5 ′-双脱氧核苷> 2′-脱氧核苷> 3′-和5′-脱氧核苷。α-2′-脱氧核苷与酶结合，尽管不如相应的β-端基异构体紧密。无环和2，2 ′-脱水尿苷结合较强，2，2 ′-脱水尿苷衍生物是较好的配体。2，5 ′-脱水尿苷与尿苷的结合效率低于2，2 ′-脱水尿苷和无环尿苷。阿拉伯糖基尿嘧啶充其量是一个非常差的配体，但如果苄基存在于嘧啶环的5位，则结合更好。通过加入5-苄氧基苄基进一步增强这种结合。在核苷、2′-脱氧核苷的α-和β-端基异构体、无环核苷和2，2 ′-脱水核苷中观察到嘧啶环5位疏水性增加对结合的类似增强。在所测试的化合物中，5-苄氧基苄基-2，2 ′-脱水尿苷被确定为T.表观Ki值为60 ± 3 nM。得出的结论是，N-糖基键的存在是核苷配体与T结合的先决条件。弓形虫另一方面，2′-、3′-或5′-羟基或β-构型中的N-糖基键的存在增强了结合，但不是必需的。此外，与6，1 ′-脱水-或2，5 ′-脱水尿苷（固定的顺式异构体）的较弱结合相比，2，2 ′-脱水尿苷（固定的高顺式异构体）的结合效力，以及6，5 ′-环，O 5 ′，6-亚甲基-和6，3 ′-亚甲基尿苷（固定的反式异构体）与T. Gondii Urdurs的研究表明，配体与该酶的结合是围绕N-糖基键的syn/high syn构象。结果还表明，寄生虫，而不是哺乳动物宿主Urdurs可以参与与核苷配体的嘧啶环的N3的氢键。T.与宿主酶相比，刚地弓形虫在嘧啶部分的C5附近还具有更大的疏水口袋，并且可以容纳宿主酶不能耐受的戊糖部分中的修饰。在这些修饰中最突出的是3′-羟基的核糖取向的缺失和/或缺乏，这是配体结合哺乳动物Urdurine的必要条件。寄生虫和宿主酶之间的这些差异可用于设计T的特异性抑制剂或“破坏性”底物。弓形虫
One hundred and fifty analogues of uridine, with various modifications to the uracil and pentose moieties, have been tested and compared with uridine with respect to their potency to bind to uridine phosphorylase (UrdPase, EC 2.4.2.3) from Toxoplasma gondii. The effects of the α- and β-anomers, the l- and d-enantiomers, as well as restricted syn and anti rotamers, on binding were examined. Pseudo-, lyxo-, 2,3t- ́ anhydro-2′-deoxy-, 6,5′-cyclo-, 6,3′-methano-, O5′,6-methano- and carbocyclic uridines did not bind to the enzyme. Ribosides bound better than the corresponding xylosides, which were better than the deoxyribosides. The binding of deoxyribosides was in the following manner: 2′,3′-dideoxynucleosides > 2′,5′-dideoxynucleosides > 2′-deoxyribosides > 3′- and 5′-deoxyribosides. α-2′-Deoxyribosides bound to the enzyme, albeit less tightly than the corresponding β-anomers. The acyclo- and 2,2′-anhydrouridines bound strongly, with the 2,2′-anhydro-derivatives being the better ligands. 2,5′-Anhydrouridine bound to UrdPase less effectively than 2,2′-anhydrouridine and acyclouridine. Arabinosyluracil was at best a very poor ligand, but bound better if a benzyl group was present at the 5-position of the pyrimidine ring. This binding was enhanced further by adding a 5-benzyloxybenzyl group. A similar enhancement of the binding by increased hydrophobicity at the 5-position of the pyrimidine ring was observed with ribosides, α- and β-anomers of the 2′-deoxyribosides, acyclonucleosides, and 2,2′-anhydronucleosides. Among all the compounds tested, 5-(benzyloxybenzyl)-2,2′-anhydrouridine was identified as the best ligand of T. gondii UrdPase with an apparent Kivalue of 60 ± 3 nM. It is concluded that the presence of an N-glycosyl bond is a prerequisite for a nucleoside ligand to bind to T. gondii UrdPase. On the other hand, the presence of a 2′-, 3′-, or 5′-hydroxyl group, or an N-glycosyl bond in the β-configuration, enhanced but was not essential for binding. Furthermore, the potency of the binding of 2,2′-anhydrouridines (fixed high syn isomers) in contrast to the weaker binding of the 6,1′-anhydro- or 2,5′-anhydrouridines (fixed syn isomers), and the complete lack of binding of the 6,5′-cyclo, O5′,6-methano- and 6,3′-methanouridines (fixed anti isomers) to T. gondii UrdPase indicate that the binding of ligands to this enzyme is in the syn/high syn conformation around the N-glycosyl bond. The results also indicate that the parasite but not the mammalian host UrdPase can participate in hydrogen bonding with N3 of the pyrimidine ring of nucleoside ligands. T. gondii UrdPase also has a larger hydrophobic pocket adjacent to the C5 of the pyrimidine moiety than the host enzyme, and can accommodate modifications in the pentose moiety which cannot be tolerated by the host enzyme. Most prominent among these modifications is the absence and/or lack of the ribo orientation of the 3′-hydroxyl group, which is a requirement for a ligand to bind to mammalian UrdPase. These differences between the parasite and host enzymes can be useful in designing specific inhibitors or “subversive” substrates for T. gondii UrdPase.
登录
查看更多内容
5-苄基和 5-苄氧基苄基 2,2-脱水尿苷及相关核苷类似物作为尿苷磷酸化酶抑制剂的合成
DOI：
10.1080/07328318808068705
发表时间：
1988
期刊：
Nucleosides, Nucleotides & Nucleic Acids
影响因子：
--
作者：
S. Chu;Zum;Zhi;Elizabeth C. Rowe;E. Chu;F. Naguib;M. H. Kouni;S. Cha;M. Chu
通讯作者：
M. Chu
影响因子：
7.3
作者：
LIN, TS;YANG, JH;HSIUNG, GD
通讯作者：
HSIUNG, GD
3-OH基团对脱水嘧啶核苷的构象和尿苷磷酸化酶结合能力的影响。
影响因子：
3.9
作者：
Z. Veres;A. Neszmélyi;A. Szabolcs;Á. Kiss;G. Dénes
通讯作者：
G. Dénes
3′,4′-二脱氢-2′-脱氧呋喃核糖基-2,4(1H,3H)-嘧啶二酮的碳环类似物
DOI：
--
发表时间：
1994
期刊：
影响因子：
--
作者：
C. O'dell;Y. Shealy
通讯作者：
Y. Shealy
利用[1,2]-氢化物移位和β-消除反应合成2-叠氮基-2,3-二脱氧核苷的通用方法
DOI：
--
发表时间：
1992
期刊：
影响因子：
--
作者：
M. Kawana;H. Kuzuhara
通讯作者：
H. Kuzuhara