ENZYMES OF POLYAMINE METABOLISM

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 多胺，包括腐胺、亚精胺和精胺，对于原核和真核细胞的正常生长都是必不可少的。多胺生物合成的第二个限速步骤是由S腺苷蛋氨酸脱羧酶(ADOMetDC)催化的。在这个反应中，S-腺苷甲硫氨酸(ADOMet)被脱羧基生成S-腺苷蛋氨酸胺(DcADOMet)。由于adadMet可以作为DNA、蛋白质和磷脂甲基化的底物，而dcadadMet致力于多胺的生物合成，因此adadMetDC处于该途径的关键分支点。 我们解决了Thermotoga maritima、人和土豆的结构，以及人的酶与一些抑制剂的复合体。最近的生化研究表明，金黄色葡萄球菌属于布鲁氏锥虫(T.brucei)和克氏锥虫(T.ruzi)这两种寄生虫，它们导致数百万人患病和死亡，尤其是在发展中国家。布鲁氏旋毛虫引起西非形式的昏睡病，克鲁兹旋毛虫引起恰加斯病。目前治疗这两种疾病的疗法都是有限的，而且许多药物都有很高的毒性。在动物模型中，ADOMetDC抑制剂MDL73811能有效地抑制克氏锥虫和布氏锥虫的感染；因此，ADOMetDC是对抗这些锥虫寄生虫的一个有前途的可行药物靶点。 生化研究表明，锥虫ADOSAMDCs的催化活性是通过形成一个带有催化不活跃的调节亚基的杂二聚体来增强的，这种亚基称为酶。异源二聚体的形成使布氏毛滴虫的活性提高了1000倍，而克鲁氏毛滴虫酶使催化速率常数增加了近500倍。然而，这种酶激活的潜在机制仍不清楚。我们正在努力解决布鲁氏毛滴虫和克鲁兹毛滴虫的个体结构，酶，以及酶复合体。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Polyamines, including putrescine, spermidine, and spermine, are essential for normal cell growth in both prokaryotic and eukaryotic cells. The second rate-limiting step in polyamine biosynthesis is catalyzed by S-adenosylmethionine decarboxylase (AdoMetDC). In this reaction, S-adenosylmethionine (AdoMet) is decarboxylated to form S-adenosylmethioninamine (dcAdoMet). AdoMetDC is at a key branch point in the pathway as AdoMet can be used as a substrate for the methylation of DNA, proteins, and phospholipids, while dcAdoMet is committed to polyamine biosynthesis. We solved the structure of Thermotoga maritima, human, and potato AdoMetDC as well as complexes of the human enzyme with a number of inhibitors. Recent biochemical work has characterized AdoMetDC from the trypanosomatid parasites, Trypanosoma brucei (T. brucei) and Trypanosoma cruzi (T. cruzi), which cause disease and deaths for millions, particularly within developing countries. T. brucei causes the West African form of sleeping sickness and T. cruzi causes Chagas disease. Current therapies for treating both of these diseases are limited, and many of the drugs are highly toxic. In animal models, the AdoMetDC inhibitor MDL73811 was effective in inhibiting infection by both T. cruzi and T. brucei; thus, AdoMetDC is a promising, viable drug target for combating these trypanosomatid parasites. It is known from biochemical studies that the catalytic activity of the trypanosomatid AdoSAMDCs are enhanced by the formation of a heterodimer with a catalytically inactive regulatory subunit, termed the prozyme. Formation of a heterodimer stimulates T. brucei AdoMetDC activity 1000-fold, while the T. cruzi prozyme increases the catalytic rate constant almost 500-fold. However, the mechanism underlying this activation by the prozyme remains unknown. We are working on solving the individual structure of the T. brucei and T. cruzi AdoMet, prozyme, as well as the enzyme complex.