Engineering synthetic recursive pathways to generate non-natural small molecules

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 alpha-keto acids (alpha KAs), which all use modular or iterative approaches for chain elongation. Recently, an artificial pathway for alpha KA elongation has been built that uses an engineered isopropylmalate synthase to recursively condense acetyl-CoA with alpha KAs. 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.