Begley Darren W, Edwards Thomas E, Raymond Amy C, Smith Eric R, Hartley Robert C, Abendroth Jan, Sankaran Banumathi, Lorimer Donald D, Myler Peter J, Staker Bart L, Stewart Lance J
Seattle Structural Genomics Center for Infectious Disease (http://www.ssgcid.org), USA.
Acta Crystallogr Sect F Struct Biol Cryst Commun. 2011 Sep 1;67(Pt 9):1070-7. doi: 10.1107/S1744309111029009. Epub 2011 Aug 16.
Babesiosis is a tick-borne disease caused by eukaryotic Babesia parasites which are morphologically similar to Plasmodium falciparum, the causative agent of malaria in humans. Like Plasmodium, different species of Babesia are tuned to infect different mammalian hosts, including rats, dogs, horses and cattle. Most species of Plasmodium and Babesia possess an essential bifunctional enzyme for nucleotide synthesis and folate metabolism: dihydrofolate reductase-thymidylate synthase. Although thymidylate synthase is highly conserved across organisms, the bifunctional form of this enzyme is relatively uncommon in nature. The structural characterization of dihydrofolate reductase-thymidylate synthase in Babesia bovis, the causative agent of babesiosis in livestock cattle, is reported here. The apo state is compared with structures that contain dUMP, NADP and two different antifolate inhibitors: pemetrexed and raltitrexed. The complexes reveal modes of binding similar to that seen in drug-resistant malaria strains and point to the utility of applying structural studies with proven cancer chemotherapies towards infectious disease research.
巴贝斯虫病是一种由真核巴贝斯虫寄生虫引起的蜱传疾病，这些寄生虫在形态上与人类疟疾的病原体恶性疟原虫相似。与疟原虫一样，不同种类的巴贝斯虫倾向于感染不同的哺乳动物宿主，包括大鼠、狗、马和牛。疟原虫和巴贝斯虫的大多数种类都拥有一种用于核苷酸合成和叶酸代谢的必需双功能酶：二氢叶酸还原酶-胸苷酸合成酶。尽管胸苷酸合成酶在生物体中高度保守，但这种酶的双功能形式在自然界中相对不常见。本文报道了家畜牛巴贝斯虫病病原体牛巴贝斯虫中二氢叶酸还原酶-胸苷酸合成酶的结构特征。将无配体状态与含有dUMP、NADP和两种不同抗叶酸抑制剂（培美曲塞和雷替曲塞）的结构进行了比较。这些复合物揭示了与耐药疟疾病株中所见相似的结合模式，并指出将已证实的癌症化疗的结构研究应用于传染病研究的实用性。
