权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

摘要