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Structure and Function of Heme-based Dioxygenases

血红素双加氧酶的结构和功能

基本信息

批准号：
10614501
负责人：
Syun-Ru Yeh
金额：
$ 42万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614501
关键词：
Address Binding Binding Sites Biochemical Biological Process Biophysics Clinical Clinical Treatment Clinical Trials Crystallography Data Dioxygenases Disease Drug Binding Site Drug Targeting Enzymes Essential Amino Acids Exhibits Family Funding Goals Guidelines Heme Human Knowledge Kynurenine Malignant Neoplasms Mass Spectrum Analysis Mental Depression Metabolite Interaction Molecular Neurodegenerative Disorders Outcome Study Pathway interactions Pharmaceutical Preparations Physiological Physiology Property Protein Isoforms Public Health Reaction Role Site Structure Sulfamethoxazole Techniques Technology Testing Therapeutic Therapeutic Intervention Tryptophan Tryptophan 2,3 Dioxygenase Tumor Escape X-Ray Crystallography biophysical techniques cancer cell cancer immunotherapy dietary disorder control disorder prevention drug development indoleamine inhibitor innovation insight member new therapeutic target novel rational design screening small molecule three dimensional structure

项目摘要

SUMMARY Tryptophan (Trp) is the least abundant essential amino acid. The majority of our dietary Trp is metabolized through the kynurenine (KYN) pathway. The first and rate-limiting step of the KYN pathway is catalyzed by three heme-based dioxygenases, tryptophan dioxygenase (hTDO), indoleamine 2,3-dioxygenase 1 (hIDO1), and indoleamine 2,3-dioxygenase 2 (hIDO2). Recently it was found that the three dioxygenases are expressed in cancer cells to promote cancer immune escape. Consequently they have been considered as key drug targets for cancer immunotherapy. Despite their importance, the structural and functional properties of these enzymes remain elusive, which has hindered the progress of the field. The central hypothesis of this project, as supported by our preliminary data, is (i) the functional properties of the three dioxygenases are regulated by cellular metabolites and (ii) each dioxygenase exhibits distinct structural features and possesses unique drug binding sites. We will test our hypothesis by addressing two specific aims: (i) identify cellular metabolites that interact with each dioxygenase and define the related regulatory mechanisms, and (ii) define structural differences between the three dioxygenases and determine new small molecule binding sites in each dioxygenase. We will use a new high- throughput mass spectrometry-based screening technology to identify metabolites that interact with each dioxygenase and use X-ray crystallography and spectroscopic techniques to define their specific molecular interactions and functional consequences. These studies will reveal previously unknown cellular players in dioxygenase-related human physiology that may impact the specific functions of these enzymes in cancer and other diseases, thereby offering novel information enabling innovative molecular approaches for disease prevention and control. In parallel, we will use an integrated approach, involving a wide spectrum of biochemical and biophysical techniques, and a group of structurally diverse inhibitors as probes to define unique structural features and new small molecule binding sites in each dioxygenase. The outcome of these studies will offer important knowledge enabling better understanding of structure-and-function relationships of the three heme- based dioxygenases and expanding our toolkit for rational design of enzyme-selective inhibitors. We have assembled a team of experts to carry out this innovative project with the multifaceted approach. These studies will address significant gaps in our knowledge of molecular mechanisms underlying the biological functions of the three dioxygenases and provide important new insights into related drug development and disease treatment.

总结色氨酸（Trp）是最不丰富的必需氨基酸。我们饮食中的Trp大部分被代谢犬尿氨酸（kynurenine，KYN）KYN途径的第一步和限速步骤由以下物质催化：三种基于血红素的双加氧酶，色氨酸双加氧酶（hTDO）、吲哚胺2，3-双加氧酶1（hIDO 1），和吲哚胺2，3-双加氧酶2（hIDO 2）。最近发现，这三种双加氧酶在大肠杆菌中表达。促进癌细胞免疫逃逸。因此，它们被认为是关键的药物靶点，癌症免疫疗法尽管它们的重要性，这些酶的结构和功能特性仍然存在这阻碍了该领域的进展。这个项目的中心假设，正如我们所支持的，初步数据是（i）这三种双加氧酶的功能特性受细胞代谢物的调节和（ii）每种双加氧酶表现出不同的结构特征并具有独特的药物结合位点。我们将通过解决两个具体目标来测试我们的假设：（i）识别与每个细胞相互作用的细胞代谢物双加氧酶和定义相关的调节机制，和（ii）定义三者之间的结构差异双加氧酶和确定每个双加氧酶中新的小分子结合位点。我们将用一个新的高度- 基于通量质谱的筛选技术，以识别与每个代谢物相互作用的代谢物，双加氧酶，并使用X射线晶体学和光谱技术来确定其特定的分子相互作用和功能后果。这些研究将揭示以前未知的细胞参与者，双加氧酶相关的人体生理学，可能影响这些酶在癌症中的特定功能，其他疾病，从而提供新的信息，使创新的分子方法的疾病防治的攻坚同时，我们将采用综合方法，涉及广泛的生化和生物物理技术，以及一组结构多样的抑制剂作为探针，以确定独特的结构特征和新的小分子结合位点。这些研究的结果将提供重要的知识，使更好地了解三个血红素的结构和功能关系，的双加氧酶和扩大我们的工具包，合理设计酶选择性抑制剂。我们有组织了一个专家小组，以多方面的方法实施这一创新项目。这些研究将解决我们对生物学功能的分子机制的知识中的重大空白，这三种双加氧酶，并为相关药物开发和疾病治疗提供了重要的新见解。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Conformational Plasticity in Human Heme-Based Dioxygenases.

DOI：
10.1021/jacs.0c09970
发表时间：
2021-02-03
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Pham KN;Lewis-Ballester A;Yeh SR
通讯作者：
Yeh SR

Proton-coupled electron transfer reactivities of electronically divergent heme superoxide intermediates: a kinetic, thermodynamic, and theoretical study.

电子发散血红素超氧化物中间体的质子耦合电子转移反应性：动力学、热力学和理论研究。

DOI：
10.1039/d1sc01952j
发表时间：
2021-07-01
期刊：
Chemical science
影响因子：
8.4
作者：
Mondal P;Ishigami I;Gérard EF;Lim C;Yeh SR;de Visser SP;Wijeratne GB
通讯作者：
Wijeratne GB

Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1.

DOI：
10.1038/s41467-017-01725-8
发表时间：
2017-11-22
期刊：
Nature communications
影响因子：
16.6
作者：
Lewis-Ballester A;Pham KN;Batabyal D;Karkashon S;Bonanno JB;Poulos TL;Yeh SR
通讯作者：
Yeh SR

Structural Basis of Inhibitor Selectivity in Human Indoleamine 2,3-Dioxygenase 1 and Tryptophan Dioxygenase.