ENZYMES OF POLYAMINE METABOLISM

多胺代谢酶

• 批准号: 8169204
• 负责人: STEVEN E EALICK
• 金额: $ 0.01万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169204
• 关键词: Adenosylmethionine Decarboxylase; African; African Trypanosomiasis; Anabolism; Animal Model; Biochemical; Cessation of life; Chagas Disease; Commit; Complex; Computer Retrieval of Information on Scientific Projects Database; DNA Methylation; Developing Countries; Disease; Drug Delivery Systems; Enzymes; Eukaryotic Cell; Funding; Grant; Human; Individual; Infection; Institution; Metabolism; Multienzyme Complexes; Normal Cell; Parasites; Pathway interactions; Pharmaceutical Preparations; Phospholipids; Polyamines; Potato; Proteins; Putrescine; Reaction; Research; Research Personnel; Resources; S-Adenosylmethionine; Source; Spermidine; Spermine; Structure; Thermotoga maritima; Trypanosoma brucei brucei; Trypanosoma cruzi; United States National Institutes of Health; Work; cell growth; combat; inhibitor/antagonist

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 多胺，包括腐霉菌，精子和精子，对于原核细胞和真核细胞的正常细胞生长至关重要。 多胺生物合成中的第二速率限制步骤是由S-腺苷甲硫代脱羧酶（ADOMETDC）催化的。 在此反应中，S-腺苷甲硫氨酸（ADOMEM）被脱羧以形成S-腺苷甲胺胺（DCADOMET）。 AdometDC处于途径中的一个关键分支点，因为ADOMET可以用作DNA，蛋白质和磷脂甲基化的底物，而DCADOMET则致力于多胺生物合成。 我们解决了Thermotoga Maritima，Human和Mota AdometDC的结构，以及与许多抑制剂的人类酶的复合物。 最近的生化工作表征了来自锥虫寄生虫，布鲁氏锥虫（T. Brucei）和克鲁氏锥虫（T. cruzi）的AdometDC，这些疾病造成了数百万，尤其是在发展中国家内部。布雷西（T. Brucei）引起了西非的熟睡状态，而克鲁兹（T. cruzi）则引起chagas病。 当前治疗这两种疾病的疗法都是有限的，许多药物都是剧毒的。 在动物模型中，ADOMETDC抑制剂MDL73811可有效抑制Cruzi和T. brucei的感染。因此，AdometDC是对抗这些锥虫寄生虫的有前途的可行药物靶标。 从生化研究中知道，通过形成杂二聚体具有催化性的调节亚基，称为prozyme，可以增强锥形剂adosAMDC的催化活性。 杂化二聚体的形成刺激了Brucei AdometDC活性为1000倍，而Cruzi Prozyme的催化速率则增加了几乎500倍。 然而，prozyme激活这种激活的机制仍然未知。 我们正在努力解决Brucei和Cruzi Adomet，Prozyme以及酶复合物的单个结构。