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Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters

  1. Louise K. Charkoudianc,1
  1. aStanford Genome Technology Center, Stanford University, Palo Alto, CA 94304;
  2. bDepartment of Biochemistry, Stanford University, Palo Alto, CA 94305;
  3. cDepartment of Chemistry, Haverford College, Haverford, PA 19041

  1. Edited by Jerrold Meinwald, Cornell University, Ithaca, NY, and approved September 29, 2015 (received for review June 15, 2015)

Significance

Type II polyketide natural products are powerful antimicrobial agents that are biosynthesized within bacteria by enzyme-encoding clusters of genes. We present a method to elucidate the evolution of these gene clusters as a whole, illuminating how natural selection has led to the chemical diversity of type II polyketides. Our approach can be applied to understand how other natural product gene clusters evolve. This understanding may aid efforts to access novel natural products and to design rational enzyme assemblies that produce chemicals of desired structures and activities.

Abstract

Natural product biosynthetic pathways generate molecules of enormous structural complexity and exquisitely tuned biological activities. Studies of natural products have led to the discovery of many pharmaceutical agents, particularly antibiotics. Attempts to harness the catalytic prowess of biosynthetic enzyme systems, for both compound discovery and engineering, have been limited by a poor understanding of the evolution of the underlying gene clusters. We developed an approach to study the evolution of biosynthetic genes on a cluster-wide scale, integrating pairwise gene coevolution information with large-scale phylogenetic analysis. We used this method to infer the evolution of type II polyketide gene clusters, tracing the path of evolution from the single ancestor to those gene clusters surviving today. We identified 10 key gene types in these clusters, most of which were swapped in from existing cellular processes and subsequently specialized. The ancestral type II polyketide gene cluster likely comprised a core set of five genes, a roster that expanded and contracted throughout evolution. A key C24 ancestor diversified into major classes of longer and shorter chain length systems, from which a C20 ancestor gave rise to the majority of characterized type II polyketide antibiotics. Our findings reveal that (i) type II polyketide structure is predictable from its gene roster, (ii) only certain gene combinations are compatible, and (iii) gene swaps were likely a key to evolution of chemical diversity. The lessons learned about how natural selection drives polyketide chemical innovation can be applied to the rational design and guided discovery of chemicals with desired structures and properties.

Footnotes

  • ↵1To whom correspondence may be addressed. Email: maureenh{at}stanford.edu or lcharkou{at}haverford.edu.

  • Author contributions: M.E.H., G.A.V., E.E.B., and L.K.C. designed research; M.E.H., G.A.V., E.E.B., and L.K.C. performed research; M.E.H., G.A.V., E.E.B., and L.K.C. contributed new reagents/analytic tools; M.E.H., G.A.V., E.E.B., and L.K.C. analyzed data; and M.E.H., G.A.V., and L.K.C. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • Data deposition: Data are available for download and visualization at sequence.stanford.edu/TypeIIPKS/.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1511688112/-/DCSupplemental.

Freely available online through the PNAS open access option.

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