Bisubstrate analogue inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: New design with improved properties.
Bisubstrate analogue inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: New design with improved properties.
复制标题
DOI：
10.1016/j.bmc.2011.11.032
复制
发表时间：
2012-01-01
影响因子：
3.5
通讯作者：
Ji, Xinhua
中科院分区：
文献类型：
--
作者：
Shi, Genbin;Shaw, Gary;Liang, Yu-He;Subburaman, Priadarsini;Li, Yue;Wu, Yan;Yan, Honggao;Ji, Xinhua
6-羟甲基-7,8-二氢蝶呤焦磷酸激酶（HPPK）是叶酸生物合成途径中的关键酶，可催化焦磷酸基从ATP转化为6-羟甲基-7,8-二氢蝶呤。这种酶是微生物所必需的，在人体中不存在，也不是任何现有抗生素的目标。因此，HPPK是开发新型抗菌药物的一个有吸引力的靶点。之前，我们表征了hppk催化的焦磷酰基转移的反应轨迹，并通过2、3或4个磷酸基团将6-羟甲基蝶呤与腺苷连接，合成了一系列双底物类似抑制剂。在这里，我们报告了新一代双基质类似物抑制剂。为了改善这类抑制剂的蛋白质结合和连接特性，我们用7,7-二甲基-7,8-二氢蝶呤取代了蝶呤片段，用哌啶连接的硫醚取代了磷酸桥。我们合成了新的抑制剂，测定了它们的Kd和IC50值，确定了它们与HPPK配合物的晶体结构，并建立了它们的构效关系。6-羧酸乙酯-7,7-二甲基-7,8-二氢蝶呤是我们最近开发的一种新的中间体，可以在7,7-二甲基-7,8-二氢蝶呤的6位上很容易衍生化，它可以比以前建立的方法合成高得多的双底物类似物。
6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), a key enzyme in the folate biosynthetic pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin. The enzyme is essential for microorganisms, is absent from humans, and is not the target for any existing antibiotics. Therefore, HPPK is an attractive target for developing novel antimicrobial agents. Previously, we characterized the reaction trajectory of HPPK-catalyzed pyrophosphoryl transfer and synthesized a series of bisubstrate analog inhibitors of the enzyme by linking 6-hydroxymethylpterin to adenosine through 2, 3, or 4 phosphate groups. Here, we report a new generation of bisubstrate analog inhibitors. To improve protein binding and linker properties of such inhibitors, we have replaced the pterin moiety with 7,7-dimethyl-7,8-dihydropterin and the phosphate bridge with a piperidine linked thioether. We have synthesized the new inhibitors, measured their Kd and IC50 values, determined their crystal structures in complex with HPPK, and established their structure-activity relationship. 6-Carboxylic acid ethyl ester-7,7-dimethyl-7,8-dihydropterin, a novel intermediate that we developed recently for easy derivatization at position 6 of 7,7-dimethyl-7,8-dihydropterin, offers a much high yield for the synthesis of bisubstrate analogs than that of previously established procedure.
登录
查看更多内容
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
56.9
作者：
COHEN, ML
通讯作者：
COHEN, ML
影响因子：
5.6
作者：
Hennig, M;Dale, GE;Oefner, C
通讯作者：
Oefner, C
影响因子：
2.9
作者：
Li, Guangyu;Felczak, Krzysztof;Yan, Honggao
通讯作者：
Yan, Honggao
DOI：
10.1002/prot.10286
发表时间：
2003-02-15
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
Lovell, SC;Davis, IW;Richardson, DC
通讯作者：
Richardson, DC