Engineering synthetic recursive pathways to generate non-natural small molecules

Nat Chem Biol. 2012 May 17;8(6):518-26. doi: 10.1038/nchembio.959.

Abstract

Recursive pathways are broadly defined as those that catalyze a series of reactions such that the key, bond-forming functional group of the substrate is always regenerated in each cycle, allowing for a new cycle of reactions to begin. Recursive carbon-chain elongation pathways in nature produce fatty acids, polyketides, isoprenoids and α-keto acids (αKAs), which all use modular or iterative approaches for chain elongation. Recently, an artificial pathway for αKA elongation has been built that uses an engineered isopropylmalate synthase to recursively condense acetyl-CoA with αKAs. This synthetic approach expands the possibilities for recursive pathways beyond the modular or iterative synthesis of natural products and serves as a case study for understanding the challenges of building recursive pathways from nonrecursive enzymes. There exists the potential to design synthetic recursive pathways far beyond what nature has evolved.

Publication types

  • Review

MeSH terms

  • 2-Isopropylmalate Synthase / chemistry*
  • 2-Isopropylmalate Synthase / genetics
  • Acetyl Coenzyme A / chemistry*
  • Binding Sites
  • Carbon Cycle
  • Catalysis
  • Keto Acids / chemistry*
  • Models, Molecular
  • Molecular Structure
  • Protein Engineering / methods
  • Small Molecule Libraries / chemical synthesis*
  • Small Molecule Libraries / chemistry
  • Substrate Specificity
  • Synthetic Biology / methods

Substances

  • Keto Acids
  • Small Molecule Libraries
  • Acetyl Coenzyme A
  • 2-Isopropylmalate Synthase