Targeting the polyamine pathway with transition-state analogue inhibitors of 5′-methylthioadenosine phosphorylase
Targeting the polyamine pathway with transition-state analogue inhibitors of 5′-methylthioadenosine phosphorylase
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DOI：
10.1021/jm0306475
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发表时间：
2004-06-03
影响因子：
7.3
通讯作者：
Tyler, PC
中科院分区：
文献类型：
--
作者：
Evans, GB;Furneaux, RH;Tyler, PC
多胺生物合成途径是增殖性疾病的治疗靶标，因为细胞增殖需要升高水平的多胺。多胺生物合成的后期阶段（亚精胺和精胺的合成）的副产物是5 '-甲硫基腺苷（MTA）。在人类中，MTA由5 '-甲硫腺苷磷酸化酶（MTAP）处理，因此不会积累大量的NITA。MTAP的有效抑制剂可能允许足够水平的NITA的积累以产生多胺生物合成的反馈抑制。我们已经设计和合成了一个家庭的潜在的过渡态类似物抑制剂的MTAP的基础上，我们的知识的嘌呤核苷磷酸化酶的过渡态结构和假设，这是可能的两种酶共享一个共同的催化机制。几种抑制剂显示出缓慢起效的紧密结合特性，这与它们是过渡态类似物相一致，其中最有效的具有166 pM的解离常数。
The polyamine biosynthetic pathway is a therapeutic target for proliferative diseases because cellular proliferation requires elevated levels of polyamines. A byproduct of the latter stages of polyamine biosynthesis (the synthesis of spermidine and spermine) is 5'-methylthioadenosine (MTA). In humans, MTA is processed by 5'-methylthioadenosine phosphorylase (MTAP) so that significant amounts of NITA do not accumulate. Potent inhibitors of MTAP might allow the buildup of sufficient levels of NITA to generate feedback inhibition of polyamine biosynthesis. We have designed and synthesized a family of potential transition-state analogue inhibitors of MTAP on the basis of our knowledge of the transition-state structure of purine nucleoside phosphorylase and the assumption that it is likely the two enzymes share a common catalytic mechanism. Several of the inhibitors display slow-onset tight-binding properties, consistent with them being transition-state analogues, with the most potent having a dissociation constant of 166 pM.