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Elucidating and engineering thiopeptide biosynthesis

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Abstract

Initially discovered in the mid-twentieth century, thiopeptides constitute a diverse family of bacterially produced natural products exhibiting a remarkable array of biological properties. Only in the last several years have the details of thiopeptide biosynthesis been uncovered by a combination of genomic, genetic, and biochemical approaches. Thiopeptides are now known to be ribosomally synthesized and subsequently densely modified to carry azol(in)es, dehydro amino acids, and various other pathway-specific decorations. The defining feature of thiopeptides is a central six-membered nitrogenous ring that constrains peptide macrocycles of varying sequences and sizes. Recent landmark studies have defined the precisely orchestrated posttranslational modification cascade culminating in thiopeptide product formation. Because diverse thiopeptides are processed by a relatively small number of well-conserved enzymes, it has been suggested that artificial diversification of the precursor peptide could allow a vast new chemical space to be explored for clinically important activities. The success of this strategy depends on the plasticity of thiopeptide processing machinery, an open question that warrants further investigation. There is an urgent need therefore to leverage established thiopeptide research platforms to investigate substrate-enzyme specificity and devise intelligent diversification strategies for library generation. Meanwhile, the distinct genomic signatures of conserved thiopeptide-associated genes will enable the continued mining of nature for novel compounds and processing enzymes.

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Acknowledgements

We gratefully acknowledge Susan Miller and Kathryn Bewley for illuminating discussions and helpful suggestions in the preparation of this manuscript.

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Authors and Affiliations

  1. Vascular Biology Program, Boston Children’s Hospital, Harvard Medical School, Boston, 02115, USA

    Philip R. Bennallack

  2. Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, 84602, USA

    Joel S. Griffitts

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  1. Philip R. Bennallack
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Correspondence to Joel S. Griffitts.

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Bennallack, P.R., Griffitts, J.S. Elucidating and engineering thiopeptide biosynthesis. World J Microbiol Biotechnol 33, 119 (2017). https://doi.org/10.1007/s11274-017-2283-9

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