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.

在过去的半个世纪中，科学界已经分类了数百个信号小分子 可能通过硫化来调节 - 信息素，药物，毒素，类固醇和肽激素， 核和多巴胺受体配体…。在体内控制特定代谢产物的硫将允许 实验者以前所未有的精度探测和控制硫的生物学。我们最近的结构/功能 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而不改变其硫 受体相互作用或抑制硫代转移酶（Sults）。许多疾病已随便连接到 单个代谢产物的硫化。现在，我们第一次希望控制这些反应。我们 最近将该策略应用于雌激素受体激动剂，并提高了其体内效率约10,000倍。 我们将在体内创建和测试三种化合物的耐硫化衍生物（两种FDA批准的药物 和一种内源代谢物），目的是提高我们防止某些帕金森氏症的能力 症状，控制避孕和调节甲状腺激素代谢。 小型分子变构的主题仍处于起步阶段。十三个人类同工型中的11个， 每个都在单独的代谢领域运行，藏有一个或多个变构位点。代谢物- 结合这些位点的变构物，因此与同工型相关的途径仍然未知。我们正在孤立 来自小分子人组织和微生物群的生物医学相关，同工酶特异 图书馆，生物活性筛选库和silico内代谢库。我们最近发现 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，是一种潜力， Sult1a3的高度特异性变构抑制剂，它使神经递质失活。硫化依赖性 人脑中神经递质活性的调节建议将thb口袋作为一种新颖 神经药理靶标。我们开发了允许配体结合位点结构的方法 从配体的1D NMR光谱中确定的几天。我们正在使用这些结构 与MD模型和蛋白质功能研究的联系，以了解分子的基础 功能的目的是创建可以抑制，激活和更改底物规范的化合物 单个苏特同工型。使用这些方法，我们创建了第一个“人造” Sult变构抑制剂 - 潜在的高度选择性Sult1a3抑制剂。 该实验室中蛋白质功能研究的恒定潜流是发现的良好源。我们是 现在揭示了这种混杂的半地点酶（例如，苏尔特）在构象上融为一体 他们彼此之间的不同反应 - 这一发现超越了磺胺转移代谢。 此外，我们正在创建苏尔特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。