Structural Basis for Hormone and Neurotransmitter Processing by Gut Microbial Enzymes

肠道微生物酶处理激素和神经递质的结构基础

基本信息

批准号：
10205109
负责人：
Matthew R Redinbo
金额：
$ 36.46万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10205109
关键词：
Analgesics Animal Model Antineoplastic Agents Atlases Automobile Driving Bacteria Beta-glucuronidase Biological Models Brain Carbon Cardiovascular Diseases Cells Chemicals Cleaved cell Communication Crystallization Culture Techniques Data Development Disease Dose-Limiting Drug Targeting Drug toxicity Endometrial Carcinoma Enzymes Estrogens Estrone Evolution Excretory function Feces Galaxy Gastrointestinal tract structure Genes Glucuronic Acids Glucuronides Glucuronosyltransferase Gnotobiotic Graves&apos Disease Hashimoto Disease Homeostasis Hormone imbalance Hormones Human Human Microbiome Human body In Vitro Individual Lead Life Link Liver Malignant Neoplasms Medicine Mental disorders Metabolism Microbe Molecular Neurotransmitters Oncology Orthologous Gene Pharmaceutical Preparations Phase Physiology Play Postmenopause Process Proteins Proteome Reaction Recurrence Role Serotonin Source Steroids Structure Sugar Acids System Technology Testing Therapeutic Therapeutic Agents Thyroid Hormones Thyroxine Tissues Toxic effect Woman Yang Yin deep sequencing drug efficacy gut health gut microbiome gut microbiota human tissue improved inhibitor/antagonist intestinal epithelium malignant breast neoplasm microbial microbiota novel novel strategies response serotonin receptor sugar

项目摘要

Abstract Breakthroughs in deep-sequencing and gnotobiotic animal model systems have established that the gut microbiota, the trillions of bacteria that live within the gastrointestinal tract, play important roles in normal mammalian physiology and transitions to disease. However, the exact reactions catalyzed by microbial enzymes and their influence on mammalian tissues still remain poorly understood. The study of microbial enzymes is challenging because the gut microbiome encodes roughly five million proteins – not a proteome that can be tackled easily. As outlined here, we have focused on a specific set of gut microbial enzymes that play critical roles in reversing mammalian metabolic processes that are crucial in responses to a range of therapeutic agents. These microbial enzymes did not co-evolve with their mammalian hosts to process drugs; instead, they naturally act on the abundant inactivated metabolites of hormones and neurotransmitters that reach the gut. In this proposal, we concentrate on two hormones, the primary circulating thyroid hormone thyroxine and the cancer-promoting steroid estrone, and one neurotransmitter, serotonin, that are all processed by Phase II drug metabolizing UDP-glucuronosyltransferase enzymes that attach inactivating glucuronic acid sugar moieties to mark these compounds for excretion. Thyroxine, estrone, and serotonin metabolites reach the gut as glucuronide conjugates and are subject to reactivation by the focus of our project – the intestinal microbiome-encoded b-glucuronidase (GUS) enzymes that cleave off the glucuronic acid sugar. We have pioneered the study of gut microbial GUS enzymes and have established the roles they play in drug efficacy and toxicity, and have developed GUS-targeted inhibitors that improve the treatment of disease in animal models. We have also shown that there are 279 unique GUS orthologs in the human gut microbiome. Here, our overarching hypotheses are that the human gut microbiome encodes a range of structurally – and functionally – distinct GUS enzymes capable of acting on chemically discrete, endobiotic glucuronide substrates and that such enzymes are susceptible to selective inhibition by novel chemotypes or existing drugs. We will test these hypotheses by completing three aims focused on the endobiotic-glucuronide conjugates of thyroid hormones, estrogens, and neurotransmitters. The results we obtain will crucially advance our basic understanding of the chemical crosstalk between human tissues and the microbiota and may lead to novel approaches for the treatment of hormone imbalances, cancer, gut health, cardiovascular disease, and even psychological disorders.

抽象的深层和gnotobiotic动物模型系统的突破已经确定了肠道微生物群，这是生活在胃肠道内的数万亿个细菌，在正常中起重要作用哺乳动物生理和向疾病的过渡。但是，由微生物催化的确切反应酶及其对哺乳动物组织的影响仍然知之甚少。微生物的研究酶具有挑战性，因为肠道微生物组编码大约五百万个蛋白质 - 不是蛋白质组可以很容易地解决。如下所述，我们专注于一组特定的肠道微生物酶在逆转对一系列范围至关重要的哺乳动物代谢过程中发挥关键作用治疗剂。这些微生物酶未与其哺乳动物宿主共进化来处理药物。取而代在此提案中，我们专注于两匹马，这是主要的甲状腺马甲状腺素和促癌类固醇雌激素和一种神经递质5-羟色胺都是通过II期药物代谢的UDP-葡萄糖基转移酶处理，该酶附着失活葡萄糖酸糖部分标记这些化合物以进行排泄。甲状腺素，雌酮和硒素代谢物作为糖苷缀合物达到肠道，并受到我们项目的重新激活的重新激活 - 肠道微生物组编码的B-葡萄糖醛酸苷酶（GUS）酶，清除葡萄糖酸糖。我们开创了肠道微生物GUS酶的研究，并确定了它们在药物中起起的作用功效和毒性，并产生了靶向GUS的抑制剂，以改善疾病治疗动物模型。我们还表明，人类肠道微生物组中有279个独特的GUS直系同源物。在这里，我们的总体假设是人类的肠道微生物组编码一系列结构上 - 在功能上 - 能够作用于化学离散的内生糖苷的不同GUS酶底物，这种酶容易受到新型化学型或现有的选择性抑制毒品。我们将通过完成三个目的以内向生物 - 葡萄糖醛酸化为目的来检验这些假设甲状腺激素，雌激素和神经递质的结合物。我们获得的结果将是克鲁克利促进我们对人组织与菌群之间的化学串扰的基本理解，可能会导致新的方法来治疗马门失衡，癌症，肠道健康，心血管疾病，甚至心理疾病。