Mechanism of Trypanosoma Cruzi's Transsialidase in Chagas' Disease
克鲁兹锥虫转唾液酸酶在恰加斯病中的作用机制
基本信息
- 批准号:7898547
- 负责人:
- 金额:$ 23.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-07-30 至 2012-06-30
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAffectAffinityAmberAreaArgentinaBindingBiological AssayBloodBrazilCatalysisCessation of lifeChagas DiseaseChronic DiseaseCollaborationsComplexDatabasesDeath RateDiagnosisDiseaseDockingEnzymesFamilyFloridaFree EnergyFutureGleanGlycoconjugatesHuman BitesHybridsHydrolaseHydrolysisInstitutesKineticsLatin AmericaLibrariesLigand BindingLinkMastigophoraMethodsModelingModificationMolecularNamesNeuraminic AcidsNeuraminidaseOseltamivirParasitesProceduresPropertyPupilReactionReduviidaeResearchResearch DesignRoentgen RaysRoleRouteScreening procedureSialic AcidsSouth AmericaStructureStudy modelsSurfaceTechniquesTestingTheoretical StudiesTherapeuticTransferaseTriatomaTrypanosomaTrypanosoma cruziTrypanosoma cruzi trans-sialidaseUniversitiesVirulenceWaterZincbasedesignenzyme activityenzyme mechanismenzyme structurefeedingflexibilityinhibitor/antagonistinorganic phosphateinterestmethod developmentmolecular dynamicsmolecular mechanicsmutantnovelprogramspublic health relevancequantumscaffoldsmall molecule librariessuccesstooltrans-sialidasevirtualwater diffusion
项目摘要
DESCRIPTION (provided by applicant): Chagas' disease (American Trypanosomiasis) affects 16-18 million people in Latin America. It has a 25-30% death rate among infected people and causes between 45,000 and 50,000 deaths a year. The flagellate protozoan parasite Trypanosoma cruzi, the causative agent of Chagas' disease is transmitted to humans by bites of blood-feeding "Assassin bugs". The most common agent is Triatoma infestans (vinchucas in Argentina, or barbeiros in Brazil).
The enzyme trans-sialidase in T.cruzi catalyzes the transfer of sialic acids from host aloglycoconjugates to other parasite glycoconjugates and has a critical role in virulence of T.cruzi, the etiological agent of Chagas' disease. T.cruzi trans-sialidase (TcTS) is a validated target for inhibition with therapeutic possibilities for the cure for this lethal chronic disease. TcTS is also of interest due to its strong similarity in sequence and structure to a strict hydrolase, Trypanosoma rangeli sialidase (TrSA). An extensive comparison of the two will reveal structural requirements for sialyl-transferase activity and also be a guide for future efforts to transform sialidases into trans-sialidases that are of synthetic value. This theoretical study will focus on the reaction mechanisms for hydrolysis reactions of TcTS and TrSA and sialyl-transfer reaction of TcTS using hybrid (mixed quantum and classical, QM/MM) methods on entire enzyme structures. There is a methods development part of this proposal associated with two different QM/MM implementations, one native to the program Amber, and one that links Amber with the QM program Gaussian, via a program we designed name Pupil. Molecular dynamics (MD) simulations on various X-ray crystal structures of the enzymes which correspond to different points on the reaction paths will also be performed. Critical active site interactions and dynamical properties for sialyl-transfer reaction will be uncovered analyzing MD simulations of wild type and mutant enzymes and comparing the results. We will also perform extensive research into inhibitor design for TcTS, using a combination of docking, free energy calculations and mechanism-based leads.
Public Health Relevance: A broader impact of the present research is the contribution to the understanding of the general principles of catalysis. From a synthetic point of view, trans-sialidases can be used to perform complex syntheses of O-linked and S-linked glycoconjugates of industrial and medicinal value. A deeper understanding of the mechanisms of the enzymes could be a guide for inhibitor design studies of the entire family.
描述(申请人提供):恰加斯病(美洲锥虫病)影响拉丁美洲1600万至1800万人。它在感染者中的死亡率为25%-30%,每年造成4.5万至50000人死亡。鞭毛虫原生动物锥虫克氏锥虫是查加斯病的病原体,通过叮咬喂血的“刺客虫”传播给人类。最常见的病原体是致病三角菌(阿根廷的葡萄藤或巴西的Barbeiros)。
克鲁氏毛滴虫中的反式唾液酸酶催化唾液酸从宿主糖偶联物向其他寄生虫糖结合物转移,在查加斯病的病原体克氏毛滴虫的毒力中起着关键作用。克鲁兹转唾液酸酶(TCTS)是一种有效的抑制靶点,具有治愈这种致命慢性病的治疗可能性。TCTS还因为在序列和结构上与严格的水解酶--兰氏锥虫唾液酸酶(TRSA)有很强的相似性而引起人们的兴趣。对两者的广泛比较将揭示唾液酸基转移酶活性的结构要求,并为未来将唾液酸酶转化为具有合成价值的反式唾液酸酶的努力提供指导。本论文的理论研究将集中在TCTS与TRSA的水解反应和TCTS的唾液酰基转移反应的反应机理研究上。本提案的方法开发部分与两种不同的QM/MM实现相关联,一种是Amber程序的原生实现,另一种是通过我们设计的名为Pilil的程序将Amber与QM程序Gauss链接起来。还将对反应路径上不同点对应的各种酶的X射线晶体结构进行分子动力学(MD)模拟。将揭示唾液酰基转移反应的关键活性部位相互作用和动力学性质,分析野生型和突变酶的MD模拟并比较结果。我们还将结合对接、自由能计算和基于机制的引线,对TCTS的缓蚀剂设计进行广泛的研究。
公共卫生相关性:本研究的一个更广泛的影响是有助于理解催化的一般原理。从合成的角度来看,反式唾液酸酶可用于合成具有工业和医药价值的O-键和S-键的糖偶联物。更深入地了解这些酶的机制可能会为整个家族的抑制剂设计研究提供指导。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ADRIAN ENRIQUE ROITBERG其他文献
ADRIAN ENRIQUE ROITBERG的其他文献
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{{ truncateString('ADRIAN ENRIQUE ROITBERG', 18)}}的其他基金
Infrared laser spectroscopy of mass-separated metabolites
质量分离代谢物的红外激光光谱
- 批准号:
9215689 - 财政年份:2014
- 资助金额:
$ 23.78万 - 项目类别:
Mechanism of Trypanosoma Cruzi's Transsialidase in Chagas' Disease
克鲁兹锥虫转唾液酸酶在恰加斯病中的作用机制
- 批准号:
7533799 - 财政年份:2008
- 资助金额:
$ 23.78万 - 项目类别:
Mechanism of Trypanosoma Cruzi's Transsialidase in Chagas' Disease
克鲁兹锥虫转唾液酸酶在恰加斯病中的作用机制
- 批准号:
8099410 - 财政年份:2008
- 资助金额:
$ 23.78万 - 项目类别:
MODELING STUDIES OF BIOMOLECULAR SYSTEMS AND NANOMATERIALS
生物分子系统和纳米材料的建模研究
- 批准号:
7723151 - 财政年份:2008
- 资助金额:
$ 23.78万 - 项目类别:
Mechanism of Trypanosoma Cruzi's Transsialidase in Chagas' Disease
克鲁兹锥虫转唾液酸酶在恰加斯病中的作用机制
- 批准号:
7665461 - 财政年份:2008
- 资助金额:
$ 23.78万 - 项目类别:
MODELING STUDIES OF BIOMOLECULAR SYSTEMS AND NANOMATERIALS
生物分子系统和纳米材料的建模研究
- 批准号:
7601339 - 财政年份:2007
- 资助金额:
$ 23.78万 - 项目类别:
MODELING STUDIES OF BIOMOLECULAR SYSTEMS AND NANOMATERIALS
生物分子系统和纳米材料的建模研究
- 批准号:
7181769 - 财政年份:2004
- 资助金额:
$ 23.78万 - 项目类别:
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