The Study of Human Sulfuryl-Transfer Biology

人类硫酰基转移生物学的研究

• 批准号: 10225670
• 负责人: Thomas S. Leyh
• 金额: $ 30.32万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-08 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225670
• 关键词: Agonist; Allosteric Site; Binding Sites; Biology; Brain; Catalogs; 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/antagonist; man; microbiota; monoamine-sulfating phenol sulfotransferase; neurotransmitter biosynthesis; novel; novel therapeutics; prevent; receptor; screening; small molecule; steroid hormone; sulfotransferase; tetrahydrobiopterin; tool

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，科学界已经对数百种信号小分子进行了编目 通过磺化-信息素，药物，毒素，类固醇和肽激素， 核和多巴胺受体配体在体内控制特定代谢物的磺化将允许 实验学家以前所未有的精度探测和控制硫生物。我们最近的结构/功能 研究结果表明，一种稳健的策略，用于防止体内单一化合物的磺化，而不改变其 受体相互作用或抑制磺基转移酶（SULT）。许多疾病都与 单个代谢物的磺化。现在，我们第一次有希望控制这些反应。我们 最近将该策略应用于雌激素受体激动剂，并将其体内功效提高了约10，000倍。 我们将创造并在体内测试三种化合物（两种FDA批准的药物）的抗磺化衍生物 和一种内源性代谢物），目的是提高我们预防某些帕金森氏症的能力， 症状，控制避孕，调节甲状腺激素代谢。 SULT小分子变构的研究还处于起步阶段。13种人类SULT同种型中的11种， 每一种都在独立的代谢结构域中起作用，具有一个或多个变构位点。代谢物- 结合这些位点的变构体以及因此与同种型连接的途径仍然未知。我们正在隔离 来自小分子人体组织和微生物群的生物医学相关的同工酶特异性SULT变构体 文库、生物活性筛选文库和计算机模拟代谢物文库。我们最近发现， 四氢生物蝶呤（THB）是儿茶酚胺类神经递质生物合成中的一种重要辅因子， SULT 1A 3的高度特异性变构抑制剂，可使神经递质失活。磺化依赖性 人类大脑中神经递质活性的调节推荐THB口袋作为一种新的 神经药理学靶点我们已经开发了允许SULT配体结合位点结构被 在几天内从配体的1D NMR光谱确定。我们正在使用这些结构， 结合MD建模和蛋白质功能研究，了解变构素的分子基础 功能的目的是创造化合物，可以抑制，激活和改变底物特异性的 单个SULT亚型。利用这些方法，我们创造了第一个“人造”SULT变构抑制剂 - 一种强效、高选择性的SULT 1A 3抑制剂。 该实验室中蛋白质功能研究的持续暗流是发现的源泉。我们 现在揭示了混杂的半位点酶（例如，SULT）构象耦合的能量 它们对彼此不同的反应--这一发现的意义超越了硫酰转移代谢。 此外，我们正在创建SULT变构和催化的尖端模型，我们打算将我们的 UDP-葡糖基转移酶-另一个主要的II相酶系统的专业知识。