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Characterization of the novel Trypanosoma brucei inosine 5??-monophosphate dehydrogenase

机译：新型布氏锥虫肌苷5′-单磷酸脱氢酶的表征

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SUMMARY There is an alarming rate of human African trypanosomiasis recrudescence in many parts of sub-Saharan Africa. Yet, the disease has no successful chemotherapy. Trypanosoma lacks the enzymatic machinery for the de novo synthesis of purine nucleotides, and is critically dependent on salvage mechanisms. Inosine 5??-monophosphate dehydrogenase (IMPDH) is responsible for the rate-limiting step in guanine nucleotide metabolism. Here, we characterize recombinant Trypanosoma brucei IMPDH (TbIMPDH) to investigate the enzymatic differences between TbIMPDH and host IMPDH. Size-exclusion chromatography and analytical ultracentrifugation sedimentation velocity experiments reveal that TbIMPDH forms a heptamer, different from type 1 and 2 mammalian tetrameric IMPDHs. Kinetic analysis reveals calculated K m values of 30 and 1300? ?? m for IMP and NAD, respectively. The obtained K m value of TbIMPDH for NAD is approximately 20-200-fold higher than that of mammalian enzymes and indicative of a different NAD binding mode between trypanosomal and mammalian IMPDHs. Inhibition studies show K i values of 3??2? ?? m, 21 nM and 3??3 nM for ribavirin 5??-monophosphate, mycophenolic acid and mizoribine 5??-monophosphate, respectively. Our results show that TbIMPDH is different from its mammalian counterpart and thus may be a good target for further studies on anti-trypanosomal drugs. ? Cambridge University Press 2013.
机译：发明内容在撒哈拉以南非洲的许多地区，人类非洲锥虫病的复发率令人震惊。然而，该疾病没有成功的化学疗法。锥虫缺乏用于从头合成嘌呤核苷酸的酶机制，并且严重依赖于挽救机制。肌苷5′-单磷酸脱氢酶（IMPDH）负责鸟嘌呤核苷酸代谢中的限速步骤。在这里，我们表征了重组布鲁氏锥虫IMPDH（TbIMPDH），以研究TbIMPDH与宿主IMPDH之间的酶促差异。尺寸排阻色谱法和分析超速离心沉降速度实验表明，TbIMPDH形成七聚体，不同于1型和2型哺乳动物四聚体IMPDH。动力学分析表明，计算出的K m值为30和1300？ ?? m分别用于IMP和NAD。对于NAD，获得的TbIMPDH的K m值比哺乳动物酶的K m值高约20-200倍，这表明锥虫和哺乳动物IMPDH之间的NAD结合方式不同。抑制研究表明K i值为3≤2？ ??利巴韦林5′-单磷酸，霉酚酸和咪唑啉碱5′-单磷酸的m，m分别为21nM和3′3nM。我们的结果表明，TbIMPDH与哺乳动物的TbIMPDH不同，因此可能是抗锥虫病药物进一步研究的良好靶标。 ？剑桥大学出版社，2013年。

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