Microbially guided discovery and biosynthesis of biologically active natural products

项目摘要 我们的实验室寻求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。我们广泛关注（i）动力学 以及允许它们一起工作以协调非线性过程的酶的结构特征（例如， 代谢，信号处理和生物显示），（ii）生物分子的自然约束的作用 多样性（例如，有限数量的蛋白质折叠）限制生物催化网络的结构， 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是对靶向， 生物活性分子。天然产品是药物和药用的长期来源 准备工作这些分子--也许是由于它们的生物学来源--往往表现出有利的 药理学性质（例如，生物利用度和“代谢物相似性”），并可以发挥惊人的各种 治疗效果（例如，镇痛剂、抗病毒剂、抗炎剂、细胞毒性剂、免疫抑制剂， 和免疫刺激）。合成生物学的最新进展为高效合成提供了新的途径。 已知的、药学相关的天然产物的生物合成和功能化; 用于发现和优化具有特定治疗相关活性的新产品的方法， 但仍然发展不良。该计划开发了一个实验框架， 目标（例如，人药物靶抑制）作为遗传编码的约束来引导分子 微生物宿主的生物合成。它背离了当代利用微生物合成 已知的、药学上相关的天然产物，而不是使用它们来构建新的生物活性物质。 分子。在抽象意义上，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（PTP）的选择性抑制剂和激活剂。这些酶有助于 大量的疾病（例如，糖尿病、肥胖症、癌症、阿尔茨海默病、自身免疫和心脏病 疾病），但缺乏任何种类的靶向治疗。由此产生的分子将提供一个重要的来源， （i）用于研究PTP介导的信号传导事件的化学探针和（ii）用于研究PTP介导的信号传导事件的起始点。 PTP靶向治疗的发展。这项工作是为了实现我们的长期目标， 微生物来指导新的小分子药物的发现，生物合成和进化。

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.