Microbially guided discovery and biosynthesis of biologically active natural products

项目摘要 我们的实验室试图理解和利用生物物理关系和逻辑结构 允许生物催化网络控制复杂的细胞行为。我们对(I)动力学很感兴趣 以及允许它们共同工作以协调非线性过程的酶的结构特征(例如， 新陈代谢、信号处理和生物显示)，(Ii)自然限制对生物分子的作用 限制生物催化网络结构的多样性(如有限数量的蛋白质折叠)和 代谢物的进化轨迹，以及(Iii)允许多酶系统控制的逻辑结构 非布尔运算。这些兴趣构成了对靶向的生物合成的规划重点， 生物活性分子。天然产品是药品和药用产品的长期来源。 准备工作。这些分子--也许，由于它们的生物起源--往往表现出有利的 药理特性(例如，生物利用度和类代谢物)，并可发挥惊人的多样性 治疗效果(例如，止痛、抗病毒、抗肿瘤、抗炎、细胞毒性、免疫抑制、 和免疫刺激作用)。合成生物学的最新进展为高效生物合成提供了新的途径 已知的、与药物有关的天然产物的生物合成和功能化；互补 发现和优化具有特定治疗相关活性的新产品的方法， 然而，仍处于欠发达状态。这个项目开发了一个使用治疗性药物的实验框架 目的(例如，对人类药物靶标的抑制)作为基因编码的约束来指导分子 微生物宿主中的生物合成。它背离了当代利用微生物合成 通过使用已知的、与药物相关的天然产品来构建新的生物活性 分子。在抽象的意义上，它描述了一种生物计算(即，微生物组装 基因编码设计挑战的分子解决方案)。未来五年，我们将发展 蛋白酪氨酸磷酸酶(PTPs)的选择性抑制物和激活剂。这些酶有助于一种 数量巨大的疾病(如糖尿病、肥胖症、癌症、阿尔茨海默病、自身免疫和心脏 疾病)，但缺乏任何类型的有针对性的治疗。产生的分子将提供一个重要的来源 (I)用于研究PTP介导的信号事件的化学探针和(Ii) PTP靶向疗法的发展。这项工作是朝着我们的长期目标--使用工程化的 指导新的小分子药物的发现、生物合成和进化的微生物。

Project Summary Our laboratory seeks to understand—and exploit—the biophysical relationships and logic structures that allow biocatalytic networks to control complex cellular behaviors. We are broadly interested in (i) the kinetic and structural features of enzymes that allow them to work together to coordinate nonlinear processes (e.g., metabolism, signal processing, and biological display), (ii) the role of natural constraints on biomolecular diversity (e.g., a limited number of protein folds) in restricting the structures of biocatalytic networks and the evolutionary trajectories of metabolites, and (iii) the logic structures that allow multi-enzyme systems to control non-Boolean operations. These interests underlie a programmatic focus on the biosynthesis of targeted, biologically active molecules. Natural products are a longstanding source of pharmaceuticals and medicinal preparations. These molecules—perhaps, as a result of their biological origin—tend to exhibit favorable pharmacological properties (e.g., bioavailability and “metabolite-likeness”) and can exert a striking variety of therapeutic effects (e.g., analgesic, antiviral, antineoplastic, anti-inflammatory, cytotoxic, immunosuppressive, and immunostimulatory). Recent advances in synthetic biology have supplied new approaches for the efficient biosynthesis and functionalization of known, pharmaceutically relevant natural products; complementary methods for the discovery and optimization new products with specific therapeutically relevant activities, however, remain poorly developed. This program develops an experimental framework for using a therapeutic objective (e.g., the inhibition of a human drug target) as a genetically encoded constraint to guide molecular biosynthesis in microbial hosts. It departs from contemporary efforts to use microorganisms for the synthesis of known, pharmaceutically relevant natural products by using them, instead, to build new biologically active molecules. In an abstract sense, it describes a kind of biological computation (i.e., the microbial assembly of molecular solutions to genetically encoded design challenges). Over the next five years, we will develop selective inhibitors and activators of protein tyrosine phosphatases (PTPs). These enzymes contribute to an enormous number of disease (e.g., diabetes, obesity, cancer, Alzheimer's disease, autoimmunity, and heart disease) but lack targeted therapeutics of any kind. The resulting molecules will supply an important source of both (i) chemical probes for studying PTP-mediated signaling events and (ii) starting points for the development of PTP-targeted therapeutics. This work builds toward our long-term goal of using engineered microorganisms to guide the discovery, biosynthesis, and evolution of new small-molecule pharmaceuticals.