Schramm Vern L
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Nucleic Acids Res Suppl. 2003(3):107-8. doi: 10.1093/nass/3.1.107.
Knowledge of enzymatic transition states permits the logical design of transition state analogues. Kinetic isotope effects have been used to solve transition state structures for several N-ribosyltransferases. Nucleoside hydrolases from protozoan parasites show ribooxacarbenium ion character at their transition states, but with different extents of activation at the leaving group and the oxacarbenium ion. Transition state analogues are designed to capture these interactions and provide isozyme-specific inhibitors. Ricin A-chain is an RNA N-ribohydrolase for a single site on 28S rRNA. Its transition state resembles a fully dissociated ribooxacarbenium ion. A transition state analogue for ricin A-chain mimics the fully dissociated purine and cationic ribosyl transition state. The transition state for human purine nucleoside phosphorylase (PNP) is more dissociated than for the bovine enzyme. Immucillin-H, a powerful transition state inhibitor for human PNP, has entered clinical trials as an anti T-cell agent.
对酶促过渡态的了解有助于合理设计过渡态类似物。动力学同位素效应已被用于解析几种N - 核糖基转移酶的过渡态结构。原生动物寄生虫的核苷水解酶在其过渡态显示出核糖氧碳鎓离子特征，但离去基团和氧碳鎓离子的活化程度不同。过渡态类似物旨在捕捉这些相互作用并提供同工酶特异性抑制剂。蓖麻毒素A链是28S rRNA上单个位点的RNA N - 核糖水解酶。其过渡态类似于完全解离的核糖氧碳鎓离子。蓖麻毒素A链的过渡态类似物模拟完全解离的嘌呤和阳离子核糖基过渡态。人嘌呤核苷磷酸化酶（PNP）的过渡态比牛酶的过渡态解离程度更高。Immucillin - H是一种强大的人PNP过渡态抑制剂，已作为抗T细胞药物进入临床试验。
