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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：
8099410
负责人：
ADRIAN ENRIQUE ROITBERG
金额：
$ 23.71万
依托单位：
UNIVERSITY OF FLORIDA
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 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8099410
关键词：
Active Sites Affect Affinity Amber Area Argentina Binding Biological Assay Blood Brazil Catalysis Cessation of life Chagas Disease Chronic Disease Collaborations Complex Databases Death Rate Diagnosis Disease Docking Enzymes Family Florida Free Energy Future Glean Glycoconjugates Human Bites Hybrids Hydrolase Hydrolysis Institutes Kinetics Latin America Libraries Ligand Binding Link Mastigophora Methods Modeling Modification Molecular Names Neuraminic Acids Neuraminidase Oseltamivir Parasites Procedures Property Pupil Reaction Reduviidae Research Research Design Roentgen Rays Role Route Screening procedure Sialic Acids South America Structure Study models Surface Techniques Testing Theoretical Studies Therapeutic Transferase Triatoma Trypanosoma Trypanosoma cruzi Trypanosoma cruzi trans-sialidase Universities Virulence Water base design enzyme activity enzyme mechanism enzyme structure feeding flexibility inhibitor/antagonist inorganic phosphate interest method development molecular dynamics molecular mechanics mutant novel programs public health relevance quantum scaffold small molecule libraries success tool trans-sialidase virtual water 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（由申请人提供）：恰加斯病（美洲锥虫病）影响拉丁美洲1600万至1800万人。感染者的死亡率为25-30%，每年造成4.5万至5万人死亡。鞭毛原生动物寄生虫克氏锥虫是恰加斯病的病原体，通过吸血“刺客虫”的叮咬传播给人类。最常见的病原体是Triatoma infestans（阿根廷的vinchucas或巴西的barbeiros）。