Metabolic model for diversity-generating biosynthesis

Proc Natl Acad Sci U S A. 2016 Feb 16;113(7):1772-7. doi: 10.1073/pnas.1525438113. Epub 2016 Feb 1.


A conventional metabolic pathway leads to a specific product. In stark contrast, there are diversity-generating metabolic pathways that naturally produce different chemicals, sometimes of great diversity. We demonstrate that for one such pathway, tru, each ensuing metabolic step is slower, in parallel with the increasing potential chemical divergence generated as the pathway proceeds. Intermediates are long lived and accumulate progressively, in contrast with conventional metabolic pathways, in which the first step is rate-limiting and metabolic intermediates are short-lived. Understanding these fundamental differences enables several different practical applications, such as combinatorial biosynthesis, some of which we demonstrate here. We propose that these principles may provide a unifying framework underlying diversity-generating metabolism in many different biosynthetic pathways.

Keywords: RiPP; biosynthesis; cyanobactin; natural products; secondary metabolism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Escherichia coli / metabolism
  • Metabolism*
  • Mevalonic Acid / metabolism
  • Models, Biological*
  • Protein Prenylation


  • Mevalonic Acid