Structural Basis for Hormone and Neurotransmitter Processing by Gut Microbial Enzymes

摘要 深度测序和gnotobiotic动物模型系统的突破已经确定， 微生物群，生活在胃肠道内的数万亿细菌，在正常的胃肠道中发挥着重要作用。 哺乳动物生理学和疾病的转变。然而，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 酶是具有挑战性的，因为肠道微生物组编码大约500万种蛋白质-而不是蛋白质组 很容易解决的问题正如这里所概述的，我们集中在一组特定的肠道微生物酶， 在逆转哺乳动物的代谢过程中起着关键作用，这些代谢过程对一系列 治疗剂。这些微生物酶并没有与其哺乳动物宿主共同进化来加工药物; 相反，它们自然地作用于激素和神经递质的大量失活代谢物， 到达肠道。在这个建议中，我们集中在两个激素，主要循环甲状腺激素 甲状腺素和促癌类固醇雌酮，还有一种神经递质血清素， 通过II期药物代谢UDP-葡萄糖醛酸基转移酶处理， 葡萄糖醛酸糖部分标记这些化合物的排泄。甲状腺素、雌酮和血清素 代谢产物以葡糖苷酸结合物的形式到达肠道，并通过我们项目的重点进行再活化 - 肠道微生物组编码的β-葡萄糖醛酸酶（GUS），可切割葡萄糖醛酸糖。 我们率先研究了肠道微生物GUS酶，并确定了它们在药物治疗中的作用。 疗效和毒性，并已开发出GUS靶向抑制剂，改善疾病的治疗， 动物模型我们还表明，在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，人类肠道微生物组编码一系列结构上的-和 功能上不同的GUS酶能够作用于化学上离散的、内生的葡糖苷酸 这些酶易受新化学型或现有化学型的选择性抑制， 毒品我们将通过完成三个目标来测试这些假设，重点是内源性葡萄糖醛酸苷 甲状腺激素、雌激素和神经递质的结合物。我们获得的结果将至关重要 推进我们对人体组织和微生物群之间化学串扰的基本理解， 可能导致治疗激素失衡，癌症，肠道健康，心血管疾病的新方法。 疾病，甚至是心理疾病。

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.