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Discovery of acylsulfenic acid-featuring natural product sulfenicin and characterization of its biosynthesis

Nature Chemistry volume 17, pages 1011–1019 (2025)Cite this article

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Abstract

Life’s organic molecules are built with diverse functional groups that enable various importance biological functions. As such, the discovery of unique functional groups in nature can expand our understanding of the natural world. Here we report the genome-aided discovery of sulfenicin, a polyketide–non-ribosomal peptide hybrid natural product from a marine Streptomyces bacterium bearing a unique acylsulfenic acid functionality. Through a series of heterologous biosynthesis, functional genetics and enzymatic reconstitution experiments, we show that this previously described synthetic functional group is biologically assembled by a set of enzymes from both primary and secondary metabolism, including a flavin-dependent S-hydroxylase that hydroxylates the sulfur atom of a thiocarboxylic acid. Although public databases so far include no parallel for the sulfenicin biosynthetic gene cluster, enzymes catalysing the production of acylsulfenic acid are widely distributed in bacterial genomes, implying that this labile functional group may similarly have a broad distribution among specialized metabolites.

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Fig. 1: An acylsulfenic acid functional group in NPs.
Fig. 2: Heterologous expression of the taa BGC and structural characterization of a thiazole acylsulfenic acid.
Fig. 3: In vivo deletion of genes in M1152_taa to probe biosynthetic function.
Fig. 4: In vitro reconstitution of acylsulfenic acid-synthesizing enzymes.
Fig. 5: Analysis and characterization of TaaH.
Fig. 6: Phylogenetic and sequence similarity networking analysis of TaaH.

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Data availability

The X-ray crystallographic coordinate for 1-Cu(II) reported in this study has been deposited at the Cambridge Crystallographic Data Centre (CCDC), under the CCDC number 2387232. These data can be obtained free of charge from the CCDC at www.ccdc.cam.ac.uk/data_request/cif. The genome sequence data of Streptomyces sp. CNT360 is available on JGI at https://genome.jgi.doe.gov (project ID 1016045). Experimental data supporting the conclusions of this study are available within the article and its Supplementary Information. Source data containing accession numbers and information of proteins used for SSN analysis are provided. Source data are provided with this paper.

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Acknowledgements

This work was supported by National Institutes of Health grants 1R35GM150565 (to J.L.), R01GM085770 (to B.S.M.) and F32GM129960 (to T.d.R.), as well as a National Science Foundation grant 2239561 (to J.L.). We thank P. Jensen (University of California San Diego (UCSD)) and the Fijian government for access to strain Streptomyces sp. CNT360 under material transfer agreement 9D00CF1B-436F-4687-A75E-F483ED5B3181. We acknowledge M. Walla of the University of South Carolina (USC) Mass Spectrometry Facility for assistance in acquiring HRMS and HRMS/MS data; P. J. Pellechia and T. Johnson from USC NMR Facility, and B. M. Duggan from UCSD NMR Facility for help with acquiring NMR data; M. D. Smith from USC X-Ray Diffraction Facility for acquiring X-ray crystallography data; T. Sawa from Kumamoto University for providing 34S-labelled l-cysteine; as well as J. Riffle, D. V. Peryshkov and K. D. Shimizu from USC, K.-S. Ju from The Ohio State University, Y. Kudo from Tohoku University, M. S. Cushman from Purdue University, and Q. Wu from Yale University for helpful discussions.

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Author notes

  1. Hongbin Zou

    Present address: Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

  2. Tristan de Rond

    Present address: School of Chemical Sciences, University of Auckland, Auckland, New Zealand

  3. Takayoshi Awakawa

    Present address: RIKEN Center for Sustainable Resource Science, Wako, Japan

  4. These authors contributed equally: Dan Xue, Hongbin Zou.

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA

    Dan Xue, Yanping Qiu, Michael D. Madden, Mingming Xu, Xiaoying Lian, Conor Pulliam, Ethan A. Older, Lukuan Hou, Andrew Campbell & Jie Li

  2. Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, San Diego, CA, USA

    Hongbin Zou, Tristan de Rond, Takayoshi Awakawa & Bradley S. Moore

  3. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA

    Wei Lv

  4. Campus Chemical Instrument Center, The Ohio State University, Columbus, OH, USA

    Chunhua Yuan

  5. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, CA, USA

    Bradley S. Moore

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Contributions

D.X., H.Z., B.S.M. and J.L. designed the research. D.X., H.Z., Y.Q., W.L., M.D.M., M.X., X.L., C.P., E.A.O., L.H., A.C., T.d.R., T.A. and C.Y. performed the research. All authors analysed the data and discussed results. All authors participated in preparing the paper.

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Supplementary information

Supplementary Information

Supplementary Notes, Figs. 1–49, Tables 1–11 and unprocessed gels.

Supplementary Data 1

Source Data for Supplementary Fig. 44.

Supplementary Data 2

Source Data for Supplementary Fig. 47b.

Supplementary Data 3

Source Data for Supplementary Fig. 48.

Supplementary Data 4

Coordinates for 1-Cu(II).

Supplementary Data 5

Crystallographic data for 1-Cu(II) (CCDC 2387232).

Source data

Source Data Fig. 2

Source data for UV and IR spectra in Fig. 2c.

Source Data Fig. 5

Statistical source data for kinetic analysis in Fig. 5a.

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Xue, D., Zou, H., Qiu, Y. et al. Discovery of acylsulfenic acid-featuring natural product sulfenicin and characterization of its biosynthesis. Nat. Chem. 17, 1011–1019 (2025). https://doi.org/10.1038/s41557-025-01833-9

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