Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Recent advances in the biosynthesis of nucleoside antibiotics

Abstract

Nucleoside antibiotics are a diverse class of natural products with promising biomedical activities. These compounds contain a saccharide core and a nucleobase. Despite the large number of nucleoside antibiotics that have been reported, biosynthetic studies on these compounds have been limited compared with those on other types of natural products such as polyketides, peptides, and terpenoids. Due to recent advances in genome sequencing technology, the biosynthesis of nucleoside antibiotics has rapidly been clarified. This review covering 2009–2019 focuses on recent advances in the biosynthesis of nucleoside antibiotics.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. 1.

    Isono K. Nucleoside antibiotics: structure, biological activity, and biosynthesis. J Antibiot. 1988;41:1711–39.

    CAS  PubMed  Google Scholar 

  2. 2.

    Takatsuki A, Kohno K, Tamura G. Inhibition of biosynthesis of polyisoprenol sugars in chick embryo microsomes by tunicamycin. Agric Biol Chem. 1975;39:2089–91.

    CAS  Google Scholar 

  3. 3.

    Suzuki S, Isono K, Nagatsu J, Mizutani T, Kawashima Y, Mizuno T. A new antibiotic, polyoxin A. J Antibiot. 1965;18:131.

    CAS  PubMed  Google Scholar 

  4. 4.

    Serpi M, Ferrari V, Pertusati F. Nucleoside derived antibiotics to fight microbial drug resistance: new utilities for an established class of drugs? J Med Chem. 2016;59:10343–82.

    CAS  PubMed  Google Scholar 

  5. 5.

    Sato T, Hirasawa K, Uzawa J, Inaba T, Isono K. Biosynthesis of octosyl acid A: incorporation of C-13 labeled glucose. Tetrahedron Lett. 1979;20:3441–4.

    Google Scholar 

  6. 6.

    Chen W, Qu D, Zhai L, Tao M, Wang Y, Lin S, et al. Characterization of the polyoxin biosynthetic gene cluster from Streptomyces cacaoi and engineered production of polyoxin H. J Biol Chem. 2009;284:10627–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Lilla EA, Yokoyama K. Carbon extension in peptidylnucleoside biosynthesis by radical SAM enzymes. Nat Chem Biol. 2016;12:905–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    He N, Wu P, Lei Y, Xu B, Zhu X, Xu G, et al. Construction of an octosyl acid backbone catalyzed by a radical S-adenosylmethionine enzyme and a phosphatase in the biosynthesis of high-carbon sugar nucleoside antibiotics. Chem Sci. 2016;8:444–51.

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Binter A, Oberdorfer G, Hofzumahaus S, Nerstheimer S, Altenbacher G, Gruber K, et al. Characterization of the PLP-dependent aminotransferase NikK from Streptomyces tendae and its putative role in nikkomycin biosynthesis. FEBS J. 2011;278:4122–35.

    CAS  PubMed  Google Scholar 

  10. 10.

    Isono K, Crain PF, McCloskey JA. Isolation and structure of octosyl acids. Anhydrooctose uronic acid nucleosides. J Am Chem Soc. 1975;97:943–5.

    CAS  Google Scholar 

  11. 11.

    Hong H, Samborskyy M, Zhou Y, Leadlay PF. C-nucleoside formation in the biosynthesis of the antifungal malayamycin A. Cell Chem Biol. 2019;26:493–501.

    CAS  PubMed  Google Scholar 

  12. 12.

    Isono K, Uramoto M, Kusakabe H, Kimura K, Izaki K, Nelson CC, et al. Liposidomycins: novel nucleoside antibiotics which inhibit bacterial peptidoglycan synthesis. J Antibiot. 1985;38:1617–21.

    CAS  PubMed  Google Scholar 

  13. 13.

    Brandish PE, Kimura K, Inukai M, Southgate R, Lonsdale JT, Bugg TDH. Modes of action of tunicamycin, liposidomycin B, and mureidomycin A: Inhibition of phospho-N-acetylmuramyl-pentapeptide translocase from Escherichia coli. Antimicrob Agents Chemother. 1996;40:1640–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Igarashi M, Takahashi Y, Shitara T, Nakamura H, Naganawa H, Miyake T, et al. Caprazamycins, novel lipo-nucleoside antibiotics, from Streptomyces sp. II. Structure Elucidation of Caprazamycins. J Antibiot. 2005;58:327–37.

    CAS  PubMed  Google Scholar 

  15. 15.

    Takahashi Y, Igarashi M, Miyake T, Soutome H, Ishikawa K, Komatsuki Y, et al. Novel semisynthetic antibiotics from caprazamycins A-G: Caprazene derivatives and their antibacterial activity. J Antibiot. 2013;66:171–8.

    CAS  PubMed  Google Scholar 

  16. 16.

    Kaysser L, Lutsch L, Siebenberg S, Wemakor E, Kammerer B, Gust B. Identification and manipulation of the caprazamycin gene cluster lead to new simplified liponucleoside antibiotics and give insights into the biosynthetic pathway. J Biol Chem. 2009;284:14987–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Kaysser L, Siebenberg S, Kammerer B, Gust B. Analysis of the liposidomycin gene cluster leads to the identification of new caprazamycin derivatives. ChemBioChem. 2010;11:191–6.

    CAS  PubMed  Google Scholar 

  18. 18.

    Funabashi M, Baba S, Nonaka K, Hosobuchi M, Fujita Y, Shibata T, et al. The biosynthesis of liposidomycin-like A-90289 antibiotics featuring a new type of sulfotransferase. ChemBioChem. 2009;11:184–90.

    Google Scholar 

  19. 19.

    Funabashi M, Baba S, Nonaka K, Hosobuchi M, Fujita Y, Shibata T, et al. Characterization of LipL as a non-heme, Fe(II)-dependent α-ketoglutarate: UMP dioxygenase that generates uridine-5′-aldehyde during A-90289 biosynthesis. J Biol Chem. 2011;286:7885–92.

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Barnard-Britson S, Chi X, Nonaka K, Spork AP, Tibrewal N, Goswami A, et al. Amalgamation of nucleosides and amino acids in antibiotic biosynthesis: Discovery of an l -threonine: Uridine-5′-aldehyde transaldolase. J Am Chem Soc. 2012;134:18514–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Chi X, Pahari P, Nonaka K, Van Lanen SG. Biosynthetic origin and mechanism of formation of the aminoribosyl moiety of peptidyl nucleoside antibiotics. J Am Chem Soc. 2011;133:14452–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Cheng L, Chen W, Zhai L, Xu D, Huang T, Lin S, et al. Identification of the gene cluster involved in muraymycin biosynthesis from Streptomyces sp. NRRL 30471. Mol Biosyst. 2011;7:920–7.

    CAS  PubMed  Google Scholar 

  23. 23.

    Huang Y, Liu X, Cui Z, Wiegmann D, Niro G, Ducho C, et al. Pyridoxal-5′-phosphate as an oxygenase cofactor: discovery of a carboxamide-forming, α-amino acid monooxygenase-decarboxylase. Proc Natl Acad Sci. 2018;115:974–9.

    CAS  PubMed  Google Scholar 

  24. 24.

    Hiratsuka T, Suzuki H, Kariya R, Seo T, Minami A, Oikawa H. Biosynthesis of the structurally unique polycyclopropanated polyketide-nucleoside hybrid jawsamycin (FR-900848). Angew Chem Int Ed. 2014;53:5423–6.

    CAS  Google Scholar 

  25. 25.

    Funabashi M, Baba S, Takatsu T, Kizuka M, Ohata Y, Tanaka M, et al. Structure-based gene targeting discovery of sphaerimicin, a bacterial translocase I inhibitor. Angew Chem Int Ed. 2013;52:11607–11.

    CAS  Google Scholar 

  26. 26.

    Winn M, Goss RJM, Kimura KI, Bugg TDH. Antimicrobial nucleoside antibiotics targeting cell wall assembly: Recent advances in structure-function studies and nucleoside biosynthesis. Nat Prod Rep. 2010;27:279–304.

    CAS  PubMed  Google Scholar 

  27. 27.

    Rackham EJ, Grüschow S, Ragab AE, Dickens S, Goss RJM. Pacidamycin biosynthesis: Identification and heterologous expression of the first uridyl peptide antibiotic gene cluster. ChemBioChem. 2010;11:1700–9.

    CAS  PubMed  Google Scholar 

  28. 28.

    Zhang W, Ostash B, Walsh CT. Identification of the biosynthetic gene cluster for the pacidamycin group of peptidyl nucleoside antibiotics. Proc Natl Acad Sci. 2010;107:16828–33.

    CAS  PubMed  Google Scholar 

  29. 29.

    Zhang W, Ntai I, Bolla ML, Malcolmson SJ, Kahne D, Kelleher NL, et al. Nine enzymes are required for assembly of the pacidamycin group of peptidyl nucleoside antibiotics. J Am Chem Soc. 2011;133:5240–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Ragab AE, Grüschow S, Tromans DR, Goss RJM. Biogenesis of the unique 4′,5′-dehydronucleoside of the uridyl peptide antibiotic pacidamycin. J Am Chem Soc. 2011;133:15288–91.

    CAS  PubMed  Google Scholar 

  31. 31.

    Michailidou F, Chung CW, Brown MJB, Bent AF, Naismith JH, Leavens WJ, et al. Pac13 is a small, monomeric dehydratase that mediates the formation of the 3′-deoxy nucleoside of pacidamycins. Angew Chem Int Ed. 2017;56:12492–7.

    CAS  Google Scholar 

  32. 32.

    Takatsuki A, Arima K, Tamura G. Tunicamycin, a new antibiotic. I Isolation and characterization of tunicamycin. J Antibiot. 1971;24:215–23.

    CAS  PubMed  Google Scholar 

  33. 33.

    Tsvetanova BC, Kiemle DJ, Price NPJ. Biosynthesis of tunicamycin and metabolic origin of the 11-carbon dialdose sugar, tunicamine. J Biol Chem. 2002;277:35289–96.

    CAS  PubMed  Google Scholar 

  34. 34.

    Wyszynski FJ, Hesketh AR, Bibb MJ, Davis BG. Dissecting tunicamycin biosynthesis by genome mining: Cloning and heterologous expression of a minimal gene cluster. Chem Sci. 2010;1:581–9.

    CAS  Google Scholar 

  35. 35.

    Vior NM, Bibb MJ, Royer SF, Davis BG, Widdick D, Gomez-Escribano JP, et al. Analysis of the tunicamycin biosynthetic gene cluster of Streptomyces chartreusis reveals new insights into tunicamycin production and immunity. Antimicrob Agents Chemother. 2018;62:e00130-18.

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Chen W, Qu D, Zhai L, Tao M, Wang Y, Lin S, et al. Characterization of the tunicamycin gene cluster unveiling unique steps involved in its biosynthesis. Protein Cell. 2010;1:1093–105.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Wyszynski FJ, Lee SS, Yabe T, Wang H, Gomez-Escribano JP, Bibb MJ, et al. Biosynthesis of the tunicamycin antibiotics proceeds via unique exo-glycal intermediates. Nat Chem. 2012;4:539–46.

    CAS  PubMed  Google Scholar 

  38. 38.

    Murakami R, Fujita Y, Kizuka M, Kagawa T, Muramatsu Y, Miyakoshi S, et al. A-94964, a novel inhibitor of bacterial translocase I, produced by Streptomyces sp. SANK 60404. I. Taxonomy, isolation and biological activity. J Antibiot. 2008;61:537–44.

    CAS  PubMed  Google Scholar 

  39. 39.

    Shiraishi T, Nishiyama M, Kuzuyama T. Biosynthesis of the uridine-derived nucleoside antibiotic A-94964: Identification and characterization of the biosynthetic gene cluster provide insight into the biosynthetic pathway. Org Biomol Chem. 2018;17:461–6.

    Google Scholar 

  40. 40.

    Arai M, Haneishi T, Kitahara N, Enokita R, Kawakubo K, Kondo Y. Herbicidin A and B, two new antibiotics with herbicidal activity. I. Producing organism and biological activities. J Antibiot. 1976;29:863–9.

    CAS  PubMed  Google Scholar 

  41. 41.

    Hamill RL, Hoehn MM. A9145, a new adenine-containing antifungal antibiotic. I. Discovery and isolation. J Antibiot. 1973;26:463–5.

    CAS  Google Scholar 

  42. 42.

    Lin GM, Romo AJ, Liem PH, Chen Z, Liu HW. Identification and interrogation of the herbicidin biosynthetic gene cluster: first insight into the biosynthesis of a rare undecose nucleoside antibiotic. J Am Chem Soc. 2017;139:16450–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Malina H, Tempete C, Robert-Gero M. Biosynthesis of sinefungin by cell-free extract of Streptomyces incarnatus NRRL 8089. J Antibiot. 1987;40:505–11.

    CAS  PubMed  Google Scholar 

  44. 44.

    Parry RJ, Arzu IY, Ju S, Baker BJ. Biosynthesis of sinefungin: on the mode of incorporation of L-Ornithine. J Am Chem Soc. 1989;111:8981–2.

    CAS  Google Scholar 

  45. 45.

    Cone MC, Yin X, Grochowski LL, Parker MR, Zabriskie TM. The blasticidin S biosynthesis gene cluster from Streptomyces griseochromogenes: sequence analysis, organization, and initial characterization. ChemBioChem. 2003;4:821–8.

    CAS  PubMed  Google Scholar 

  46. 46.

    Deng Z, Zabriskie TM, He X, Li L, Wu J. Analysis of the mildiomycin biosynthesis gene cluster in Streptoverticillum remofaciens ZJU5119 and characterization of MilC, a Hydroxymethyl cytosyl-glucuronic acid synthase. ChemBioChem. 2012;13:1613–21.

    PubMed  Google Scholar 

  47. 47.

    Niu G, Li L, Wei J, Tan H. Cloning, heterologous expression, and characterization of the gene cluster required for gougerotin biosynthesis. Chem Biol. 2013;20:34–44.

    CAS  PubMed  Google Scholar 

  48. 48.

    Liu Y, Gong R, Liu X, Zhang P, Zhang Q, Cai YS, et al. Discovery and characterization of the tubercidin biosynthetic pathway from Streptomyces tubercidicus NBRC 13090. Microb Cell Fact. 2018;17:1–10.

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Kudo F, Tsunoda T, Takashima M, Eguchi T. Five-membered cyclitol phosphate formation by a myo-inositol phosphate synthase orthologue in the biosynthesis of the carbocyclic nucleoside antibiotic aristeromycin. ChemBioChem. 2016;17:2143–8.

    CAS  PubMed  Google Scholar 

  50. 50.

    Xu G, Kong L, Gong R, Xu L, Gao Y, Jiang M, et al. Coordinated biosynthesis of the purine nucleoside antibiotics. Appl Environ Microbiol. 2018;84:1–16.

    Google Scholar 

  51. 51.

    Ushimaru R, Liu H. Biosynthetic origin of the atypical stereochemistry in the thioheptose core of albomycin nucleoside antibiotics. J Am Chem Soc. 2019;141:2211–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Kang WJ, Pan HX, Wang S, Yu B, Hua H, Tang GL. Identification of the amipurimycin gene cluster yields insight into the biosynthesis of C9 sugar nucleoside antibiotics. Org Lett. 2019;21:3148–52.

    CAS  PubMed  Google Scholar 

  53. 53.

    Romo AJ, Shiraishi T, Ikeuchi H, Lin G-M, Geng Y, Lee Y-H, et al. The amipurimycin and miharamycin biosynthetic gene clusters: unraveling the origins of 2-aminopurinyl peptidyl nucleoside antibiotics. J Am Chem Soc. 2019;141:14152–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Palmu K, Rosenqvist P, Thapa K, Ilina Y, Siitonen V, Baral B, et al. Discovery of the showdomycin gene cluster from Streptomyces showdoensis ATCC 15227 yields insight into the biosynthetic logic of C-nucleoside antibiotics. ACS Chem Biol. 2017;12:1472–7.

    CAS  PubMed  Google Scholar 

  55. 55.

    Oja T, Niiranen L, Sandalova T, Klika KD, Niemi J, Mäntsälä P, et al. Structural basis for C-ribosylation in the alnumycin A biosynthetic pathway. Proc Natl Acad Sci. 2013;110:1291–6.

    CAS  PubMed  Google Scholar 

  56. 56.

    Ko Y, Wang SA, Ogasawara Y, Ruszczycky MW, Liu HW. Identification and characterization of enzymes catalyzing pyrazolopyrimidine formation in the biosynthesis of formycin A. Org Lett. 2017;19:1426–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Wang S-A, Ko Y, Zeng J, Geng Y, Ren D, Ogasawara Y, et al. Identification of the formycin A biosynthetic gene cluster from Streptomyces kaniharaensis illustrates the interplay between biological pyrazolopyrimidine formation and de Novo purine biosynthesis. J Am Chem Soc. 2019;141:6127–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Dumitru RV, Ragsdale SW. Mechanism of 4-(β-D-ribofuranosyl)aminobenzene 5′-phosphate synthase, a key enzyme in the methanopterin biosynthetic pathway. J Biol Chem. 2004;279:39389–95.

    CAS  PubMed  Google Scholar 

  59. 59.

    White RH. The conversion of a phenol to an aniline occurs in the biochemical formation of the 1-(4-aminophenyl)-1-deoxy-D-ribitol moiety in methanopterin. Biochemistry. 2011;50:6041–52.

    CAS  PubMed  Google Scholar 

  60. 60.

    Ochi K, Yashima S, Eguchi Y, Matsushita K. Biosynthesis of formycin. Incorporation and distribution of 13C-, 14C-, and 15N-labeled compounds into formycin. J Biol Chem. 1979;254:8819–24.

    CAS  PubMed  Google Scholar 

  61. 61.

    Matsuda K, Tomita T, Shin-ya K, Wakimoto T, Kuzuyama T, Nishiyama M. Discovery of unprecedented hydrazine-forming machinery in bacteria. J Am Chem Soc. 2018;140:9083–6.

    CAS  PubMed  Google Scholar 

  62. 62.

    Matsuda K, Hasebe F, Shiwa Y, Kanesaki Y, Tomita T, Yoshikawa H, et al. Genome mining of amino group carrier protein-mediated machinery: Discovery and biosynthetic characterization of a natural product with unique hydrazone unit. ACS Chem Biol. 2017;12:124–31.

    CAS  PubMed  Google Scholar 

  63. 63.

    Maffioli SI, Zhang Y, Degen D, Carzaniga T, Del Gatto G, Serina S, et al. Antibacterial nucleoside-analog inhibitor of bacterial RNA polymerase. Cell. 2017;169:1240–48.e23.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Sosio M, Gaspari E, Iorio M, Pessina S, Medema MH, Bernasconi A, et al. Analysis of the pseudouridimycin biosynthetic pathway provides insights into the formation of C-nucleoside antibiotics. Cell Chem Biol. 2018;25:540–9.e4.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work is supported by a grant from JSPS KAKENHI (16H06453 to TK).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Tomohisa Kuzuyama.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

This study is dedicated to Dr Kiyoshi Isono with respect to his long-standing contribution to the study of nucleoside antibiotics.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shiraishi, T., Kuzuyama, T. Recent advances in the biosynthesis of nucleoside antibiotics. J Antibiot 72, 913–923 (2019). https://doi.org/10.1038/s41429-019-0236-2

Download citation

Further reading

Search

Quick links