Microbially guided discovery and biosynthesis of biologically active natural products

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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.