A potent, covalent inhibitor of orotidine 5′-monophosphate decarboxylase with antimalarial activity
A potent, covalent inhibitor of orotidine 5′-monophosphate decarboxylase with antimalarial activity
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DOI：
10.1021/jm060827p
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发表时间：
2007-03-08
影响因子：
7.3
通讯作者：
Kotra, Lakshmi P.
中科院分区：
文献类型：
--
作者：
Bello, Angelica M.;Poduch, Ewa;Kotra, Lakshmi P.
Orotidine 5‘-单磷酸脱羧酶(ODCase)在没有任何共价中间体的情况下，可以催化5’-单磷酸的脱羧基反应。ODCase中的活性中心残基参与了广泛的氢键网络。我们发现6-碘-5‘-单磷酸(6-IODO-UMP)不可逆地抑制热自养甲烷杆菌和恶性疟原虫的ODCase的催化活性。酶-抑制剂复合体的质谱分析证实了抑制剂与ODCase的共价结合，并伴随着两个质子和碘部分的损失。缓蚀剂与ODCase形成的络合物的X-射线晶体结构(1.6A分辨率)清楚地表明与活性中心Lys-42残基形成共价键。6-Iodo-UMP以时间和浓度依赖的方式抑制ODCase。6-碘-尿嘧啶核苷具有较强的抗疟活性，对恶性疟原虫ITG株和3D7株的IC(50)S分别为4.4+/-1.3mU和6.2+/-0.7mU。6-碘-5‘-单磷酸是一种新型的ODCase共价抑制剂，其核苷类似物为一类新的抗疟疾药物铺平了道路。
Orotidine 5'-monophosphate decarboxylase (ODCase) has evolved to catalyze the decarboxylation of orotidine 5'-monophosphate without any covalent intermediates. Active site residues in ODCase are involved in an extensive hydrogen-bonding network. We discovered that 6-iodouridine 5'-monophosphate (6-iodo-UMP) irreversibly inhibits the catalytic activities of ODCases from Methanobacterium thermoautotrophicum and Plasmodium falciparum. Mass spectral analysis of the enzyme-inhibitor complex confirms covalent attachment of the inhibitor to ODCase accompanied by the loss of two protons and the iodo moiety. The X-ray crystal structure (1.6 A resolution) of the complex of the inhibitor and ODCase clearly shows the covalent bond formation with the active site Lys-42 residue. 6-Iodo-UMP inhibits ODCase in a time- and concentration-dependent fashion. 6-Iodouridine, the nucleoside form of 6-iodo-UMP, exhibited potent antiplasmodial activity, with IC(50)s of 4.4 +/- 1.3 mu M and 6.2 +/- 0.7 mu M against P. falciparum ItG and 3D7 isolates, respectively. 6-Iodouridine 5'-monophosphate is a novel covalent inhibitor of ODCase, and its nucleoside analogue paves the way to a new class of inhibitors against malaria.