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Acyltransferase that catalyses the condensation of polyketide and peptide moieties of goadvionin hybrid lipopeptides


Fusions of fatty acids and peptides expand the structural diversity of natural products; however, polyketide/ribosomally synthesized and post-translationally modified peptides (PK/RiPPs) hybrid lipopeptides are relatively rare. Here we report a family of PK/RiPPs called goadvionins, which inhibit the growth of Gram-positive bacteria, and an acyltransferase, GdvG, which catalyses the condensation of the PK and RiPP moieties. Goadvionin comprises a trimethylammonio 32-carbon acyl chain and an eight-residue RiPP with an avionin structure. The positions of six hydroxyl groups and one double bond in the very-long acyl chain were determined by radical-induced dissociation tandem mass spectrometry, which collides radical ion species to generate C–C bond cleavage fragments. GdvG belongs to the Gcn5-related N-acetyltransferase superfamily. Unlike conventional acyltransferases, GdvG transfers a very long acyl chain that is tethered to an acyl carrier protein to the N-terminal amino group of the RiPP moiety. gdvG homologues flanked by PK/fatty acid and RiPP biosynthesis genes are widely distributed in microbial species, suggesting that acyltransferase-catalysed condensation of PKs and RiPPs is a general strategy in biosynthesis of similar lipopeptides.

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Fig. 1: Goadvionin biosynthesis gene cluster.
Fig. 2: Characterization of products biosynthesized by the gdv cluster.
Fig. 3: Proposed goadvionin biosynthesis pathway.
Fig. 4: Chemical structures of goadvionins and goadpeptins.
Fig. 5: In vitro reconstitution of acyl transfer catalysed by GdvG.
Fig. 6: Putative secondary metabolite biosynthesis gene clusters containing gdvG homologues are widely distributed in microorganism genomes.

Data availability

All relevant data are included in the manuscript and the Supplementary Information. The nucleotide sequence of the gdv cluster has been deposited in the DDBJ with accession number LC481990.


  1. Baltz, R. H., Miao, V. & Wrigley, S. K. Natural products to drugs: daptomycin and related lipopeptide antibiotics. Nat. Prod. Rep. 22, 717–741 (2005).

    CAS  Article  Google Scholar 

  2. Arima, K., Kakinuma, A. & Tamura, G. Surfactin, a crystalline peptidelipid surfactant produced by Bacillus subtilis: isolation, characterization and its inhibition of fibrin clot formation. Biochem. Biophys. Res. Commun. 31, 488–494 (1968).

    CAS  Article  Google Scholar 

  3. Choi, S. K. et al. Identification of a polymyxin synthetase gene cluster of Paenibacillus polymyxa and heterologous expression of the gene in Bacillus subtilis. J Bacteriol. 191, 3350–3358 (2009).

    CAS  Article  Google Scholar 

  4. Marahiel, M. A. Protein templates for the biosynthesis of peptide antibiotics. Chem. Biol. 4, 561–567 (1997).

    CAS  Article  Google Scholar 

  5. Duitman, E. H. et al. The mycosubtilin synthetase of Bacillus subtilis ATCC6633: a multifunctional hybrid between a peptide synthetase, an amino transferase, and a fatty acid synthase. Proc. Natl Acad. Sci. USA 96, 13294–13299 (1999).

    CAS  Article  Google Scholar 

  6. Wiebach, V. et al. The anti-staphylococcal lipolanthines are ribosomally synthesized lipopeptides. Nat. Chem. Biol. 14, 652–654 (2018).

    CAS  Article  Google Scholar 

  7. Aszodi, J., Carniato, D., Le Beller, D., Lesquame, G. & Quernin, M.-H. New bicyclic lipopeptide, preparation and use as antimicrobial agent. European Union patent EP15306065 (2015).

  8. Favrot, L., Blanchard, J. S. & Vergnolle, O. Bacterial GCN5-related N-acetyltransferases: from resistance to regulation. Biochemistry 55, 989–1002 (2016).

    CAS  Article  Google Scholar 

  9. Onaka, H., Nakaho, M., Hayashi, K., Igarashi, Y. & Furumai, T. Cloning and characterization of the goadsporin biosynthetic gene cluster from Streptomyces sp. TP-A0584. Microbiology 151, 3923–3933 (2005).

    CAS  Article  Google Scholar 

  10. Ozaki, T. et al. Dissection of goadsporin biosynthesis by in vitro reconstitution leading to designer analogues expressed in vivo. Nat. Commun. 8, 14207 (2017).

    CAS  Article  Google Scholar 

  11. Kupke, T., Stevanovic, S., Sahl, H. G. & Gotz, F. Purification and characterization of EpiD, a flavoprotein involved in the biosynthesis of the lantibiotic epidermin. J. Bacteriol. 174, 5354–5361 (1992).

    CAS  Article  Google Scholar 

  12. Müller, W. M., Schmiederer, T., Ensle, P. & Süssmuth, R. D. In vitro biosynthesis of the prepeptide of type-III lantibiotic labyrinthopeptin A2 including formation of a C-C bond as a post-translational modification. Angew. Chem. Int. Ed. 49, 2436–2440 (2010).

    Article  Google Scholar 

  13. Blin, K. et al. antiSMASH 5.0: Updates to the secondary metabolite genome mining pipeline. Nucleic Acids Res. 47, gkz310 (2019).

  14. Kihara, A. Very long-chain fatty acids: elongation, physiology and related disorders. J. Biochem. 152, 387–395 (2012).

    CAS  Article  Google Scholar 

  15. Wyche, T. P., Hou, Y. P., Vazquez-Rivera, E., Braun, D. & Bugni, T. S. Peptidolipins B-F, antibacterial lipopeptides from an ascidian-derived Nocardia sp. J. Nat. Prod. 75, 735–740 (2012).

    CAS  Article  Google Scholar 

  16. Ekroos, K. et al. Charting molecular composition of phosphatidylcholines by fatty acid scanning and ion trap MS3 fragmentation. J. Lipid Res. 44, 2181–2192 (2003).

    CAS  Article  Google Scholar 

  17. Takahashi, H. et al. Hydrogen attachment/abstraction dissociation (HAD) of gas-phase peptide ions for tandem mass spectrometry. Anal. Chem. 88, 3810–3816 (2016).

    CAS  Article  Google Scholar 

  18. Takahashi, H. et al. Structural analysis of phospholipid using hydrogen abstraction dissociation and oxygen attachment dissociation in tandem mass spectrometry. Anal. Chem. 90, 7230–7238 (2018).

    CAS  Article  Google Scholar 

  19. Noike, M. et al. A peptide ligase and the ribosome cooperate to synthesize the peptide pheganomycin. Nat. Chem. Biol. 11, 71–76 (2015).

    CAS  Article  Google Scholar 

  20. Chooi, Y. H. & Tang, Y. Adding the lipo to lipopeptides: do more with less. Chem. Biol. 17, 791–793 (2010).

    CAS  Article  Google Scholar 

  21. Cosmina, P. et al. Sequence and analysis of the genetic locus responsible for surfactin synthesis in Bacillus subtilis. Mol. Microbiol. 8, 821–831 (1993).

    CAS  Article  Google Scholar 

  22. Kraas, F. I., Helmetag, V., Wittmann, M., Strieker, M. & Marahiel, M. A. Functional dissection of surfactin synthetase initiation module reveals insights into the mechanism of lipoinitiation. Chem. Biol. 17, 872–880 (2010).

    CAS  Article  Google Scholar 

  23. Towler, D. A. et al. Myristoyl Coa-protein N-myristoyltransferase activities from rat-liver and yeast possess overlapping yet distinct peptide substrate specificities. J. Biol. Chem. 263, 1784–1790 (1988).

    CAS  Article  Google Scholar 

  24. Van Wagoner, R. M. & Clardy, J. FeeM, an N-acyl amino acid synthase from an uncultured soil microbe: structure, mechanism, and acyl carrier protein binding. Structure 14, 1425–1435 (2006).

    Article  Google Scholar 

  25. Hiratsuka, T. et al. Biosynthesis of the structurally unique polycyclopropanated polyketide-nucleoside hybrid jawsamycin (FR-900848). Angew. Chem. Int. Ed. 53, 5423–5426 (2014).

    CAS  Article  Google Scholar 

  26. Gu, L. et al. GNAT-like strategy for polyketide chain initiation. Science 318, 970–974 (2007).

    CAS  Article  Google Scholar 

  27. Forouhar, F. et al. Structural and functional evidence for Bacillus subtilis PaiA as a novel N1-spermidine/spermine acetyltransferase. J Biol. Chem. 280, 40328–40336 (2005).

    CAS  Article  Google Scholar 

  28. Peddie, V. et al. Cytotoxic glycosylated fatty acid amides from a Stelletta sp. marine sponge. J. Nat. Prod. 78, 2808–2813 (2015).

    CAS  Article  Google Scholar 

  29. Nakao, Y., Maki, T., Matsunaga, S., van Soest, R. W. M. & Fusetani, N. Penarolide sulfates A(1) and A(2), new α-glucosidase inhibitors from a marine sponge Penares sp. Tetrahedron 56, 8977–8987 (2000).

    CAS  Article  Google Scholar 

  30. Takada, K. et al. Schulzeines A-C, new α-glucosidase inhibitors from the marine sponge Penares schulzei. J. Am. Chem. Soc. 126, 187–193 (2004).

    CAS  Article  Google Scholar 

  31. Konno, K., Shirahama, H. & Matsumoto, T. Clithioneine, an amino-acid betaine from Clitocybe acromelalga. Phytochemistry 23, 1003–1006 (1984).

    CAS  Article  Google Scholar 

  32. Ghosal, S. & Srivastava, R. S. Structure of erysophorine: a new quaternary alkaloid of Erythrina arborescens. Phytochemistry 13, 2603–2605 (1974).

    CAS  Article  Google Scholar 

  33. Parkinson, E. I. et al. Discovery of the tyrobetaine natural products and their biosynthetic gene cluster via metabologenomics. ACS Chem. Biol. 13, 1029–1037 (2018).

    CAS  Article  Google Scholar 

  34. Smith, T. E. et al. Accessing chemical diversity from the uncultivated symbionts of small marine animals. Nat. Chem. Biol. 14, 179–185 (2018).

    CAS  Article  Google Scholar 

  35. Julien, B., Tian, Z. Q., Reid, R. & Reeves, C. D. Analysis of the ambruticin and jerangolid gene clusters of Sorangium cellulosum reveals unusual mechanisms of polyketide biosynthesis. Chem. Biol. 13, 1277–1286 (2006).

    CAS  Article  Google Scholar 

  36. Matsuo, Y., Ishida, R., Matsumoto, T., Tatewaki, M. & Suzuki, M. Yendolipin, a novel lipobetaine with an inhibitory activity toward morphogenesis in a foliaceous green alga Monostroma oxyspermum. Tetrahedron 53, 869–876 (1997).

    CAS  Article  Google Scholar 

  37. Onaka, H., Taniguchi, S., Ikeda, H., Igarashi, Y. & Furumai, T. pTOYAMAcos, pTYM18, and pTYM19, actinomycete Escherichia coli integrating vectors for heterologous gene expression. J. Antibiot. (Tokyo) 56, 950–956 (2003).

    CAS  Article  Google Scholar 

  38. Ishikawa, J. & Hotta, K. FramePlot: a new implementation of the frame analysis for predicting protein-coding regions in bacterial DNA with a high G + C content. FEMS Microbiol. Lett. 174, 251–253 (1999).

    CAS  Article  Google Scholar 

  39. Komatsu, M. et al. Engineered Streptomyces avermitilis host for heterologous expression of biosynthetic gene cluster for secondary metabolites. ACS Synth. Biol. 2, 384–396 (2013).

    CAS  Article  Google Scholar 

  40. Onaka, H., Tabata, H., Igarashi, Y., Sato, Y. & Furumai, T. Goadsporin, a chemical substance which promotes secondary metabolism and morphogenesis in streptomycetes. I. Purification and characterization. J. Antibiot. (Tokyo) 54, 1036–1044 (2001).

    CAS  Article  Google Scholar 

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This research was supported in part by a grant-in-aid from the IFO, Institute for Fermentation, Osaka (to H.O., S.A. and T. Ozaki), Amano Enzyme (to H.O and S.A), JSPS KAKENHI grant-in-aid for Young Scientists B (no. 26850044 to S.A.), JSPS KAKENHI grant-in-aid for Scientific Research on Innovative Areas (no. JP16H06444) and the JSPS A3 Foresight Program (to H.O., S.A. and Y.K.). We thank D. Du and T. Tsunoda for assistance with the in vitro assays, S. Kawano for assistance with genetic work, D. Asakawa for HAD-MS/MS data analysis, M. Wada and Y. Shimabukuro for HAD-MS/MS development, and Y. Ohnishi and S. Iwamoto for valuable comments on the manuscript.

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Authors and Affiliations



R.K. and Y.K. performed in vitro assays. T. Ozaki, T. Ono, S.A. and H.O. performed genome mining and bioinformatic analyses. S.H., H.T., Y.S., T. Ono, Kazuya Teramoto, Kanae Teramoto, Koichi Tanaka and I.A. determined chemical structures. R.K., S.H., H.T., Y.K., S.A., Koichi Tanaka and H.O. analysed the data. S.H., Y.K., and H.O. wrote the paper.

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Correspondence to Hiroyasu Onaka.

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Supplementary Information

Supplementary Figs. 1–56, Methods and Tables 1–16.

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Kozakai, R., Ono, T., Hoshino, S. et al. Acyltransferase that catalyses the condensation of polyketide and peptide moieties of goadvionin hybrid lipopeptides. Nat. Chem. 12, 869–877 (2020).

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