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Engineering synthetic recursive pathways to generate non-natural small molecules

Nature Chemical Biology volume 8, pages 518–526 (2012)Cite this article

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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.

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Figure 1: The design principle of recursive chain elongation.
Figure 2: αKA family of recursively synthesized carbon-chain molecules.
Figure 3: Homology modeling of IPMS, IPMS* and MAM3 reveals evolution of iterative behavior.
Figure 4: Workflow for engineering recursive behavior into a nonrecursive enzyme as the basis for a synthetic pathway.
Figure 5: Four potential modes of intersubunit communication that can be introduced into a recursive pathway to prevent premature chain termination.

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  1. Department of Chemical and Biomolecular Engineering, University of California–Los Angeles, Los Angeles, California, USA

    Elizabeth A Felnagle & James C Liao

  2. Department of Chemistry and Biochemistry, University of California–Los Angeles, Los Angeles, California, USA

    Asha Chaubey, Elizabeth L Noey, Kendall N Houk & James C Liao

  3. Indian Institute of Integrative Medicine, Jammu, India

    Asha Chaubey

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Correspondence to James C Liao.

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J.C.L. is a cofounder of Easel Biotechnologies, LLC, which licensed related technologies from University of California–Los Angeles.

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Felnagle, E., Chaubey, A., Noey, E. et al. Engineering synthetic recursive pathways to generate non-natural small molecules. Nat Chem Biol 8, 518–526 (2012). https://doi.org/10.1038/nchembio.959

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