A riboside hydrolase that salvages both nucleobases and nicotinamide in the auxotrophic parasite Trichomonas vaginalis.
A riboside hydrolase that salvages both nucleobases and nicotinamide in the auxotrophic parasite Trichomonas vaginalis.
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DOI：
10.1016/j.jbc.2023.105077
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发表时间：
2023-09
影响因子：
4.8
通讯作者：
Degano, Massimo
中科院分区：
文献类型：
--
作者：
Patrone, Marco;Galasyn, Gregory S.;Kerin, Fiona;Nyitray, Mattias M.;Parkin, David W.;Stockman, Brian J.;Degano, Massimo
毛滴虫属的病原性寄生虫是影响全世界数百万人的性传播疾病的病原体，其结果可能包括死产和增加癌症风险和对艾滋病毒感染的易感性。阴道毛滴虫依赖于输入的嘌呤和嘧啶核苷和核碱基生存，因为它缺乏从头生物合成所必需的酶活性。在这里，我们表明，T. vagulovirus另外缺乏合成烟酰胺环所需的细菌或哺乳动物酶的同源物，烟酰胺环是氧化还原辅因子NAD+和NADP的关键组分。此外，我们发现，尚未完全表征的T. vagulovirus蛋白同源的细菌和原生动物的核苷水解酶是活性的嘧啶核苷酶，但显示出最高的特异性对NAD+代谢产物烟酰胺核苷。不同状态下的毛滴虫核苷水解酶的晶体结构揭示了核苷水解酶催化的水解反应中沿着的新中间体，包括在同源四聚体组装中的意想不到的不对称性。活性位点结构解释了对不同核苷的广泛特异性，并为可能同时靶向寄生虫中不同基本途径的特异性抑制剂的工程设计提供了精确的见解。
Pathogenic parasites of the Trichomonas genus are causative agents of sexually transmitted diseases affecting millions of individuals worldwide and whose outcome may include stillbirths and enhanced cancer risks and susceptibility to HIV infection. Trichomonas vaginalis relies on imported purine and pyrimidine nucleosides and nucleobases for survival, since it lacks the enzymatic activities necessary for de novo biosynthesis. Here we show that T. vaginalis additionally lacks homologues of the bacterial or mammalian enzymes required for the synthesis of the nicotinamide ring, a crucial component in the redox cofactors NAD+ and NADP. Moreover, we show that a yet fully uncharacterized T. vaginalis protein homologous to bacterial and protozoan nucleoside hydrolases is active as a pyrimidine nucleosidase but shows the highest specificity toward the NAD+ metabolite nicotinamide riboside. Crystal structures of the trichomonal riboside hydrolase in different states reveals novel intermediates along the nucleoside hydrolase–catalyzed hydrolytic reaction, including an unexpected asymmetry in the homotetrameric assembly. The active site structure explains the broad specificity toward different ribosides and offers precise insights for the engineering of specific inhibitors that may simultaneously target different essential pathways in the parasite.
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DOI：
10.1080/15257770.2016.1210805
发表时间：
2017-01-02
期刊：
Nucleosides, nucleotides & nucleic acids
影响因子：
--
作者：
Boswell-Casteel RC;Hays FA
通讯作者：
Hays FA
DOI：
10.1107/s0907444913010792
发表时间：
2013-08-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Giannese, Francesca;Berg, Maya;Degano, Massimo
通讯作者：
Degano, Massimo
影响因子：
3
作者：
Alam, Rayyan;Barbarovich, Allen T.;Stockman, Brian J.
通讯作者：
Stockman, Brian J.
影响因子：
2.9
作者：
Gopaul, DN;Meyer, SL;Schramm, VL
通讯作者：
Schramm, VL
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC