Characterization of adenine phosphoribosyltransferase (APRT) activity in Trypanosoma brucei brucei: Only one of the two isoforms is kinetically active.
Characterization of adenine phosphoribosyltransferase (APRT) activity in Trypanosoma brucei brucei: Only one of the two isoforms is kinetically active.
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DOI：
10.1371/journal.pntd.0009926
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发表时间：
2022-03
影响因子：
3.8
通讯作者：
Katzfuss A
中科院分区：
文献类型：
--
作者：
Glockzin K;Meek TD;Katzfuss A
非洲人类锥虫病，又称昏睡病，是一种被忽视的热带病，在36个非洲国家流行，目前约有7000万人面临感染风险。由于毒性、不良副作用和新出现的耐药性，目前的治疗方法不是最佳的。因此，迫切需要有效和负担得起的治疗方法。HAT的病原体是原生动物布鲁氏锥虫。其基因组的注释证实了先前的观察，即布鲁氏体是嘌呤营养不良动物。这些原生动物寄生虫不能从头合成嘌呤，它们依靠嘌呤磷酸核糖基转移酶从宿主体内回收嘌呤以合成单磷酸嘌呤。完整和准确的基因组注释结合嘌呤挽救酶催化活性的鉴定和表征，除了提供对布鲁氏T.嘌呤代谢的更深入了解之外，还可以开发靶向特异性治疗。在锥虫中，嘌呤磷酸核糖基转移酶由于其在嘌呤回收中必不可少的核心作用而成为有希望的药物靶点。参与腺嘌呤和腺苷回收的酶，如腺嘌呤磷酸核糖基转移酶（APRTs, EC 2.4.2.7），因其在激活腺嘌呤和基于腺苷的前药中的潜在作用而受到特别关注。对布鲁氏体基因组进行分析，发现两个可能的aprt基因：APRT1 （Tb927.7.1780）和APRT2 （Tb927.7.1790）。在这里，我们报告了对每个假定的APRT的催化活性的研究，揭示了两个布鲁氏T.推定的APRT中，只有APRT1具有动力学活性，从而表明Tb927.7.1790（假定的APRT2）的基因组错误注释。可靠的基因组注释对于确定潜在的药物靶点和鉴定参与腺嘌呤和腺苷为基础的前药物激活的酶是必要的。被忽视的热带病，包括非洲人类锥虫病，被世界卫生组织定义为由20种不同疾病组成的一组，不成比例地影响世界上最贫穷的人口。HAT在36个非洲国家流行，目前全世界约有7000万人面临感染风险。由于毒性、不良副作用和新出现的耐药性，目前的治疗方法不是最佳的。HAT的病原体是布氏锥虫。与人类不同的是，这些原生动物寄生虫依靠嘌呤磷酸核糖基转移酶从宿主那里挽救嘌呤碱基以合成DNA和RNA。本文报道了布鲁氏锥虫腺嘌呤磷酸核糖基转移酶（APRT）活性的表征。参与腺嘌呤和腺苷回收的酶，如aprt，因其在腺嘌呤和基于腺苷的前药激活中的潜在作用而受到特别关注。我们的研究表明，在两种假定的APRTs中，只有APRT1在生理条件下具有动力学活性。准确的基因组注释与嘌呤挽救酶的表征相结合，可以开发靶向特异性治疗。
Human African Trypanosomiasis (HAT), also known as sleeping sickness, is a Neglected Tropical Disease endemic to 36 African countries, with approximately 70 million people currently at risk for infection. Current therapeutics are suboptimal due to toxicity, adverse side effects, and emerging resistance. Thus, both effective and affordable treatments are urgently needed. The causative agent of HAT is the protozoan Trypanosoma brucei ssp. Annotation of its genome confirms previous observations that T. brucei is a purine auxotroph. Incapable of de novo purine synthesis, these protozoan parasites rely on purine phosphoribosyltransferases to salvage purines from their hosts for the synthesis of purine monophosphates. Complete and accurate genome annotations in combination with the identification and characterization of the catalytic activity of purine salvage enzymes enables the development of target-specific therapies in addition to providing a deeper understanding of purine metabolism in T. brucei. In trypanosomes, purine phosphoribosyltransferases represent promising drug targets due to their essential and central role in purine salvage. Enzymes involved in adenine and adenosine salvage, such as adenine phosphoribosyltransferases (APRTs, EC 2.4.2.7), are of particular interest for their potential role in the activation of adenine and adenosine-based pro-drugs. Analysis of the T. brucei genome shows two putative aprt genes: APRT1 (Tb927.7.1780) and APRT2 (Tb927.7.1790). Here we report studies of the catalytic activity of each putative APRT, revealing that of the two T. brucei putative APRTs, only APRT1 is kinetically active, thereby signifying a genomic misannotation of Tb927.7.1790 (putative APRT2). Reliable genome annotation is necessary to establish potential drug targets and identify enzymes involved in adenine and adenosine-based pro-drug activation. Neglected Tropical Diseases, including Human African Trypanosomiasis (HAT), are defined by the World Health Organization as a diverse group of 20 different diseases that disproportionally affect the world’s poorest populations. HAT is endemic to 36 African countries and approximately 70 million people worldwide are currently at risk for infection. Current therapeutics are suboptimal due to toxicity, adverse side effects, and emerging resistance. The causative agent of HAT is Trypanosoma brucei ssp. Unlike humans, these protozoan parasites rely on purine phosphoribosyltransferases to salvage purine bases from their hosts for the synthesis of DNA and RNA. Here we report on the characterization of adenine phosphoribosyltransferase (APRT) activity in Trypanosoma brucei brucei. Enzymes involved in adenine and adenosine salvage, such as APRTs, are of particular interest for their potential role in the activation of adenine and adenosine-based pro-drugs. Our studies reveal that of the two putative APRTs, only APRT1 is kinetically active under physiological conditions. Accurate genome annotations in combination with the characterization of purine salvage enzymes allows the development of target-specific therapies.
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影响因子：
4.6
作者：
Doleželová E;Klejch T;Špaček P;Slapničková M;Guddat L;Hocková D;Zíková A
通讯作者：
Zíková A
影响因子：
3.8
作者：
Dolezelova, Eva;Teran, David;Zikova, Alena
通讯作者：
Zikova, Alena
DOI：
10.1152/ajprenal.00142.2018
发表时间：
2019-04-01
影响因子：
4.2
作者：
Dos Santos, Ingrid F.;Sheriff, Sulaiman;Amlal, Hassane
通讯作者：
Amlal, Hassane
影响因子：
2.9
作者：
Bashor, C;Denu, JM;Ullman, B
通讯作者：
Ullman, B
影响因子：
--
作者：
Breda, Ardala;Rosado, Leonardo Astolfi;Santos, Diogenes Santiago
通讯作者：
Santos, Diogenes Santiago