The Study of Human Sulfuryl-Transfer Biology

人类硫酰基转移生物学的研究

基本信息

批准号：
10472518
负责人：
Thomas S. Leyh
金额：
$ 43.42万
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：
2018
资助国家：
美国
起止时间：
2018-09-08 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10472518
关键词：
Agonist Allosteric Site Binding Sites Biology Brain Catalysis Catecholamines Communities Contraceptive methods Disease Dopamine Receptor Enzymes Estrogen Receptors FDA approved Glucosyltransferases Goals Human Individual Isoenzymes Laboratories Lead Libraries Ligand Binding Ligands Link Metabolic Metabolism Methods Modeling Molecular Molecular Conformation Neurotransmitters Nuclear Receptors Organism Parkinson Disease Pathway interactions Peptide Hormones Receptors Pharmaceutical Preparations Phase Pheromone Protein Isoforms Proteins Reaction Regulation Research Resistance Signal Transduction Site Structure Substrate Specificity Sulfur Symptoms System Testing Thyroid Hormones Time Toxin Transcend Work cofactor hormone metabolism human disease human tissue improved in silico in vivo infancy inhibitor man microbiota monoamine-sulfating phenol sulfotransferase neurotransmitter biosynthesis novel novel therapeutics prevent receptor screening small molecule steroid hormone sulfotransferase tetrahydrobiopterin tool

项目摘要

During the last half century the scientific community has catalogued hundreds of signaling small molecules that are potently regulated via sulfonation — pheromones, drugs, toxins, steroid and peptide hormones, nuclear- and dopamine-receptor ligands… . Controlling sulfonation of specific metabolites in vivo would allow experimentalists to probe and control sulfur biology with unprecedented precision. Our recent structure/function studies resulted in a robust strategy for preventing sulfonation of a single compound in vivo without altering its receptor interactions or inhibiting sulfotransferases (SULTs). Numerous diseases have been causally linked to sulfonation of individual metabolites. Now, for the first time, we can hope to control these reactions. We recently applied the strategy to an estrogen-receptor agonist and increased its in vivo efficacy ~10,000-fold. We will create, and test in vivo, sulfonation-resistant derivatives of three compounds (two FDA-approved drugs and one endogenous metabolite) with the goal of improving our ability to prevent certain Parkinson's symptoms, control contraception, and regulate thyroid-hormone metabolism. The subject of SULT small-molecule allostery is in its infancy. Eleven of the thirteen human SULT isoforms, each of which operates in separate metabolic domain, harbor one or more allosteric sites. The metabolite- allosteres that bind these sites, and hence pathways linked to the isoforms, remain unknown. We are isolating biomedically relevant, isozyme specific SULT allosteres from small-molecule human-tissue and microbiota libraries, bioactive screening libraries, and in-silico metabolite libraries. We have recently discovered that tetrahydrobiopterin (THB), an essential cofactor in catecholamine neurotransmitter biosynthesis, is a potent, highly specific allosteric inhibitor of SULT1A3, which inactivates neurotransmitters. The sulfonation-dependent regulation of neurotransmitter activity in human brain recommends the THB pocket as a novel neuropharmacological target. We have developed methods that allow SULT ligand-binding site structures to be determined in a matter of days from a ligand's 1D NMR spectrum. We are using these structures, in conjunction with MD-modelling and protein-function studies, to understand the molecular basis of allostere function with the goal of creating compounds that can inhibit, activate and change the substrate specificities of individual SULT isoforms. Using these methods, we have created the first “man-made” SULT allosteric inhibitor — a potent, highly selective SULT1A3 inhibitor. The constant undercurrent of protein-function studies in this laboratory is a well-spring of discovery. We are now revealing that promiscuous, half-site enzymes (e.g., SULTs) conformationally couple the energetics of their disparate reactions to one another — a finding whose implications transcend sulfuryl-transfer metabolism. In addition, we are creating cutting-edge models of SULT allostery and catalysis, and we intend to apply our expertise to the UDP-glucosyltransferases — the other major phase II enzyme system.

在过去的半个世纪中，科学界已经分类了数百个信号小分子通过硫化来强烈调节 - 信息素，药物，毒素，类固醇和肽激素，核和多巴胺受体配体……控制特定代谢物的硫实验者以前所未有的精度探测和控制表面生物学研究产生了一种强大的策略，以防止体内单个化合物的硫化随着改变而改变受体相互作用或抑制硫代转移酶（Sults）。单个代谢物的硫，我们首次可以控制这些反应最近将该策略应用于雌激素受体激动剂，并提高了其体内功效约10,000倍。我们将在体内创建和测试三种化合物（两种FDA批准的药物）的耐硫化衍生物和一种内源代谢物），目的是提高我们预防某些人的能力症状，控制收缩并调节甲状腺激素代谢。小分子的主题处于起步阶段。每个都在单独的代谢域中运行一个或多个变构位点。结合这些位点的变构，因此与同工型相关的途径仍然未知来自小分子人组织和微生物群的生物医学相关的，同工酶特异性的分配。我们最近发现了库，生物活性筛选图书馆和silico代谢图书馆。四氢无生蛋白（THB）是儿茶酚胺神经递质生物合成中必不可少的辅助因子，是一种有效的 Sult1a3的高度特异性变构抑制剂，它使神经递质失活人脑中神经递质活性的调节建议这样的新颖神经药理学目标。在几天内从配体的1D NMR光谱确定。与MD模型和蛋白质功能研究的结合，以了解分子基础功能的目的是创建可以抑制，激活和改变底物特异性的化合物使用这些方法，我们创建了第一个“人造的” sult抑制剂 - 有效的高度选择性Sult1A3抑制剂。在该实验室中，蛋白质功能研究的恒定潜流是我们的发现现在陶醉于那个烟雾，半地点酶（例如，苏尔特）构象上的能量学。他们彼此之间的不同反应 - 这一发现的含义是硫酸转移代谢。此外，我们正在创建SULLT变构和催化的尖端模型，我们打算应用我们的 UDP-葡萄糖基转移酶的专业知识 - 另一个主要的II期酶系统。