土壤中的尿素在脲酶的作用下能够被分解为氨气,致使氮利用率降低,人体中的脲酶会引起各种疾病。本文介绍了不同来源的脲酶活性中心的结构及若干抑制剂与活性中心的结合方式,综述了金属离子类、羟肟酸类、磷酰胺类、磷酸盐类、杂环化合物、金属配合物等脲酶抑制剂的研究进展和存在的问题。 Urea in soil can be decomposed into ammonia under the action of urease, which reduces the utili-zation rate of nitrogen. Urease in human body causes various diseases. The structure of urease ac-tive centers from different sources and the binding modes of several inhibitors with active centers are introduced. The urease inhibitors of metal ions, hydroxamic acids, phosphoramides, phosphates, heterocyclic compounds and metal complexes are reviewed; the problems and prospect are put forward.
脲酶,脲酶活性中心,脲酶抑制剂, Urease Urease Active Center Urease Inhibitor脲酶抑制剂的研究综述
脲酶对微量的金属离子是十分敏感的,有许多关于过渡金属离子抑制脲酶活性的报导,J. B. Sumner [9] 等人发现重金属离子能够使高纯化的脲酶蛋白失活,Ambrose [10] 团队报道了关于银离子抑制脲酶活性的研究,SHAW等人的研究表明过渡金属离子能够与脲酶活性中心部位的巯基反应,从某种意义上讲,与形成硫化物相似。
3.2. 羟肟酸类
在Kobashi K. [11] 等人的研究发现氧肟酸是一种特异性并且很高效的脲酶抑制剂,这些抑制剂能够与脲酶活性位点的巯基基团结合。在对来自于日本的剑刀豆脲酶抑制活性研究当中,乙酰氧肟酸的Ki大约为2.2 × 10−7 M,-CONHOH是作为脲酶抑制剂的一个不可缺少的基团,羟肟酸对脲酶的抑制程度也跟酰基连接的基团有着密切的关系。
Fishbein和Carbone [12] 在洋刀豆和菌源脲酶的研究中,羟肟酸可以作为一种潜在的非竞争性抑制的脲酶抑制剂,后来又被发现氧肟酸及其衍生物是可逆的,慢结合(数小时)抑制剂。Benini [13] 利用X射线衍射技术,在1.55Å分辨率下得到了杆菌脲酶与AHA的结合模型。Mishra [14] 对二肽氧肟酸抑制幽门螺旋杆菌进行了一个分子立场的比较分析,在三维结构和抑制活性的关系提出了自己的见解。Fishbein W. N.等人 [12] 试图将乙酰氧肟酸用于临床治疗肝昏迷,该方法是将乙酰氧肟酸用不同的给药方式注入体内水解14C标记的尿素产生二氧化碳,通过测量产生的14CO2来评价乙酰氧肟酸的抑制效果,实验的数据表明,不论是从口腔注射,皮下注射还是腹膜,乙酰氧肟酸在体内都是一个很好的抑制尿素分解的药物。Griffith D. P. [15] 等人研究发现乙酰氧肟酸在治疗由脲酶分解杆菌引起的的泌尿系统感染疾病上有着潜在的应用价值,乙酰氧肟酸被应用于尿素分解杆菌引起的泌尿系统感染可以减小感染有机体的致病性,同时还可以防止泌尿结的形成或者溶解结石。Phillips [16] 等人研究了乙酰氧肟酸对幽门螺旋杆菌的杀菌抑菌作用,并发现了乙酰氧肟酸与抗菌药物作用于幽门螺旋杆菌的相互作用。在对八个菌株进行测试,乙酰氧肟酸的存在能够降低四环素、甲硝唑、阿莫西林、胶态果胶铋的MIC,在体外测试,乙酰氧肟酸与其他抗菌药物连用,同样有着抗菌的活性。Kosikowska P. [17] 对脲酶抑制剂,其中包括氧肟酸及其衍生物的专利进行了回顾整理。
吴孝婧,石 蕊,聂琬纯,张晓琳,秦 洁. 脲酶抑制剂的研究综述A Review of Studies on Urease Inhibitors[J]. 药物化学, 2019, 07(01): 1-6. https://doi.org/10.12677/HJMCe.2019.71001
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