title: Accessing Nature's diversity through metabolic engineering and synthetic biology.
abstract: In this perspective, we highlight recent examples and trends in metabolic engineering and synthetic biology that demonstrate the synthetic potential of enzyme and pathway engineering for natural product discovery. In doing so, we introduce natural paradigms of secondary metabolism whereby simple carbon substrates are combined into complex molecules through "scaffold diversification", and subsequent "derivatization" of these scaffolds is used to synthesize distinct complex natural products. We provide examples in which modern pathway engineering efforts including combinatorial biosynthesis and biological retrosynthesis can be coupled to directed enzyme evolution and rational enzyme engineering to allow access to the "privileged" chemical space of natural products in industry-proven microbes. Finally, we forecast the potential to produce natural product-like discovery platforms in biological systems that are amenable to single-step discovery, validation, and synthesis for streamlined discovery and production of biologically active agents.
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: King
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Edgar
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Kangjian
authors.initials: K
authors.lastname: Qiao
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Stephanopoulos
keywords: metabolic engineering; natural product discovery; synthetic biology