Skip to main content
Log in

Discovery of caerulomycin/collismycin-type 2,2′-bipyridine natural products in the genomic era

  • Natural Products - Mini Review
  • Published:
Journal of Industrial Microbiology & Biotechnology

Abstract

2,2′-Bipyridine (2,2′-BP) is the unique molecular scaffold of the bioactive natural products represented by caerulomycins (CAEs) and collismycins (COLs). CAEs and COLs are highly similar in the chemical structures in which their 2,2′-BP cores typically contain a di- or tri-substituted ring A and an unmodified ring B. Here, we summarize the CAE and COL-type 2,2′-BP natural products known or hypothesized to date: (1) isolated using methods traditional for natural product characterization, (2) created by engineering the biosynthetic pathways of CAEs or COLs, and (3) predicted upon bioinformatics-guided genome mining. The identification of these CAE and COL-type 2,2′-BP natural products not only demonstrates the development of research techniques and methods in the field of natural product chemistry but also reflects the general interest in the discovery of CAE and COL-type 2,2′-BP natural products.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

References

  1. Atkinson HJ, Morris JH, Ferrin TE, Babbitt PC (2009) Using sequence similarity networks for visualization of relationships across diverse protein superfamilies. PLoS One 4. https://doi.org/10.1371/journal.pone.0004345

    Article  Google Scholar 

  2. Bruntner C, Bormann C (1998) The Streptomyces tendae Tu901 l-lysine 2-aminotransferase catalyzes the initial reaction in nikkomycin D biosynthesis. Eur J Biochem 254:347–355. https://doi.org/10.1046/j.1432-1327.1998.2540347.x

    Article  CAS  PubMed  Google Scholar 

  3. Chatterjee DK, Raether W, Iyer N, Ganguli BN (1984) Caerulomycin, an antifungal antibiotic with marked in vitro and in vivo activity against Entamoeba histolytica. Z Parasitenkd 70:569–573. https://doi.org/10.1007/bf00926587

    Article  CAS  PubMed  Google Scholar 

  4. Chen M, Liu J, Duan P, Li M, Liu W (2017) Biosynthesis and molecular engineering of templated natural products. Natl Sci Rev 4:553–575. https://doi.org/10.1093/nsr/nww045

    Article  CAS  Google Scholar 

  5. Chen M, Pang B, Du Y-N, Zhang Y-P, Liu W (2017) Characterization of the metallo-dependent amidohydrolases responsible for “auxiliary” leucinyl removal in the biosynthesis of 2,2′-bipyridine antibiotics. Synth Syst Biotechnol 2:137–146. https://doi.org/10.1016/j.synbio.2017.07.002

    Article  PubMed  PubMed Central  Google Scholar 

  6. Chen M, Zhang Y, Du Y, Zhao Q, Zhang Q, Wu J, Liu W (2017) Enzymatic competition and cooperation branch the caerulomycin biosynthetic pathway toward different 2,2′-bipyridine members. Org Biomol Chem 15:5472–5475. https://doi.org/10.1039/c7ob01284e

    Article  CAS  PubMed  Google Scholar 

  7. Cragg GM, Newman DJ (2013) Natural products: a continuing source of novel drug leads. Biochim Biophys Acta-Gen Subj 1830:3670–3695. https://doi.org/10.1016/j.bbagen.2013.02.008

    Article  CAS  Google Scholar 

  8. Divekar PV, Read G, Vining LC (1967) Caerulomycin A new antibiotic from Streptomyces caeruleus baldacci. 2 structure. Can J Chem 45:1215–1223. https://doi.org/10.1139/v67-201

    Article  CAS  Google Scholar 

  9. Fu P, Liu P, Li X, Wang Y, Wang S, Hong K, Zhu W (2011) Cyclic bipyridine glycosides from the marine-derived actinomycete Actinoalloteichus cyanogriseus WH1-2216-6. Org Lett 13:5948–5951. https://doi.org/10.1021/ol202245s

    Article  CAS  PubMed  Google Scholar 

  10. Fu P, Wang S, Hong K, Li X, Liu P, Wang Y, Zhu W (2011) Cytotoxic bipyridines from the marine-derived actinomycete Actinoalloteichus cyanogriseus WH1-2216-6. J Nat Prod 74:1751–1756. https://doi.org/10.1021/np200258h

    Article  CAS  PubMed  Google Scholar 

  11. Fu P, Zhu Y, Mei X, Wang Y, Jia H, Zhang C, Zhu W (2014) Acyclic congeners from Actinoalloteichus cyanogriseus provide insights into cyclic bipyridine glycoside formation. Org Lett 16:4264–4267. https://doi.org/10.1021/ol5019757

    Article  CAS  PubMed  Google Scholar 

  12. Funk A, Divekar PV (1959) Caerulomycin, a new antibiotic from Streptomyces caeruleus baldacci. 1. Production, isolation, assay, and biological properties. Can J Microbiol 5:317–321. https://doi.org/10.1139/m59-039

    Article  CAS  PubMed  Google Scholar 

  13. Garcia I, Vior NM, Brana AF, Gonzalez-Sabin J, Rohr J, Moris F, Mendez C, Salas JA (2012) Elucidating the biosynthetic pathway for the polyketide-nonribosomal peptide collismycin A: mechanism for formation of the 2,2′-bipyridyl ring. Chem Biol 19:399–413. https://doi.org/10.1016/j.chembiol.2012.01.014

    Article  CAS  PubMed  Google Scholar 

  14. Garcia I, Vior NM, Gonzalez-Sabin J, Brana AF, Rohr J, Moris F, Mendez C, Salas JA (2013) Engineering the biosynthesis of the polyketide-nonribosomal peptide collismycin A for generation of analogs with neuroprotective activity. Chem Biol 20:1022–1032. https://doi.org/10.1016/j.chembiol.2013.06.014

    Article  CAS  PubMed  Google Scholar 

  15. Gerlt JA (2017) Genomic enzymology: web tools for leveraging protein family sequence-function space and genome context to discover novel functions. Biochem 56:4293–4308. https://doi.org/10.1021/acs.biochem.7b00614

    Article  CAS  Google Scholar 

  16. Gerlt JA, Bouvier JT, Davidson DB, Imker HJ, Sadkhin B, Slater DR, Whalen KL (2015) Enzyme function initiative-enzyme similarity tool (EFI-EST): a web tool for generating protein sequence similarity networks. BBA-Proteins Proteom 1854:1019–1037. https://doi.org/10.1016/j.bbapap.2015.04.015

    Article  CAS  Google Scholar 

  17. Gomi S, Amano S, Sato E, Miyadoh S, Kodama Y (1994) Novel antibiotics SF2738A, SF2738B and SF2738C, and their analogs produced by Streptomyces sp. J Antibiot 47:1385–1394. https://doi.org/10.7164/antibiotics.47.1385

    Article  CAS  PubMed  Google Scholar 

  18. Hapke M, Brandt L, Luetzen A (2008) Versatile tools in the construction of substituted 2,2′-bipyridines-cross-coupling reactions with tin, zinc and boron compounds. Chem Soc Rev 37:2782–2797. https://doi.org/10.1039/b810973g

    Article  CAS  PubMed  Google Scholar 

  19. Kaes C, Katz A, Hosseini MW (2000) Bipyridine: the most widely used ligand. A review of molecules comprising at least two 2,2′-bipyridine units. Chem Rev 100:3553–3590. https://doi.org/10.1021/cr990376z

    Article  CAS  PubMed  Google Scholar 

  20. Lin Z, Chen D, Liu W (2016) Biosynthesis-based artificial evolution of microbial natural products. Sci China Chem 59:1175–1187. https://doi.org/10.1007/s11426-016-0062-x

    Article  CAS  Google Scholar 

  21. Martinez Gil A, Egea P, Medina Padilla M, Palomero E, Perez Baz J, Fernandez Chimeno R, Medarde Fernandez A, Canedo Hernandez L, Romero Millan F, Castro Morera A, Alonso Cascon M, Sanchez Quesada J (2010) Use of collismycin and derivatives thereof as oxidative stress inhibitors. United States Patent US20100048635

  22. McInnes AG, Smith DG, Walter JA, Vining LC, Wright JLC (1979) Biosynthesis of caerulomycin-A in Streptomyces caeruleus. Incorporation of C-14-labeled and C-13-labeled precursors and analyses of labeling patterns by C-13 NMR. Can J Chem 57:3200–3204. https://doi.org/10.1139/v79-524

    Article  CAS  Google Scholar 

  23. McInnes AG, Smith DG, Walter JA, Wright JLC, Vining LC, Arsenault GP (1978) Caerulomycin-D, a novel glycosidic derivative of 3,4-dihydroxy-2,2′-dipyridyl 6-aldoxime from Streptomyces caeruleus. Can J Chem 56:1836–1842. https://doi.org/10.1139/v78-298

    Article  CAS  Google Scholar 

  24. McInnes AG, Smith DG, Wright JLC, Vining LC (1977) Caerulomycins-B and caerulomycin-C, new 2,2′-dipyridyl derivatives from Streptomyces caeruleus. Can J Chem 55:4159–4165. https://doi.org/10.1139/v77-589

    Article  CAS  Google Scholar 

  25. Namwat W, Kinoshita H, Nihira T (2002) Identification by heterologous expression and gene disruption of VisA as l-lysine 2-aminotransferase essential for virginiamycin S biosynthesis in Streptomyces virginiae. J Bacteriol 184:4811–4818. https://doi.org/10.1128/jb.184.17.4811-4818.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Qu X, Pang B, Zhang Z, Chen M, Wu Z, Zhao Q, Zhang Q, Wang Y, Liu Y, Liu W (2012) Caerulomycins and collismycins share a common paradigm for 2,2′-bipyridine biosynthesis via an unusual hybrid polyketide-peptide assembly logic. J Am Chem Soc 134:9038–9041. https://doi.org/10.1021/ja3016457

    Article  CAS  PubMed  Google Scholar 

  27. Rudolf JD, Yan X, Shen B (2016) Genome neighborhood network reveals insights into enediyne biosynthesis and facilitates prediction and prioritization for discovery. J Ind Microbiol Biotechnol 43:261–276. https://doi.org/10.1007/s10295-015-1671-0

    Article  CAS  PubMed  Google Scholar 

  28. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504. https://doi.org/10.1101/gr.1239303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shindo K, Yamagishi Y, Okada Y, Kawai H (1994) Collismycin-A and collismycin-B, novel nonsteroidal inhibitors of dexamethasone-glucocorticoid receptor-binding. J Antibiot 47:1072–1074. https://doi.org/10.7164/antibiotics.47.1072

    Article  CAS  PubMed  Google Scholar 

  30. Singla AK, Agrewala JN, Vohra RM, Singh JR (2007) Use of bipyridine compound ‘caerulomycin A’ derivatives and analogs thereof as immunosuppressive agents. European Patent EP1942889

  31. Stadler M, Bauch F, Henkel T, Muhlbauer A, Muller H, Spaltmann F, Weber K (2001) Antifungal actinomycete metabolites discovered in a differential cell-based screening using a recombinant TOPO1 deletion mutant strain. Arch Pharm 334:143–147. https://doi.org/10.1002/1521-4184(200105)334:5%3c143:aid-ardp143%3e3.0.co;2-b

    Article  CAS  Google Scholar 

  32. Suzuki H, Ohnishi Y, Horinouchi S (2007) GriC and GriD constitute a carboxylic acid reductase involved in grixazone biosynthesis in Streptomyces griseus. J Antibiot 60:380–387. https://doi.org/10.1038/ja.2007.52

    Article  CAS  PubMed  Google Scholar 

  33. Tsuge N, Furihata K, Shin-Ya K, Hayakawa Y, Seto H (1999) Novel antibiotics pyrisulfoxin A and B produced by Streptomyces californicus. J Antibiot 52:505–507. https://doi.org/10.7164/antibiotics.52.505

    Article  CAS  PubMed  Google Scholar 

  34. Velasquez JE, van der Donk WA (2011) Genome mining for ribosomally synthesized natural products. Curr Opin Chem Biol 15:11–21. https://doi.org/10.1016/j.cbpa.2010.10.027

    Article  CAS  PubMed  Google Scholar 

  35. Vining LC, McInnes AG, McCulloch AW, Smith DG, Walter JA (1988) The biosynthesis of caerulomycins in Streptomyces caeruleus. Isolation of a new caerulomycin and incorporation of picolinic-acid and glycerol into caerulomycin-A. Can J Chem 66:191–194. https://doi.org/10.1139/v88-031

    Article  CAS  Google Scholar 

  36. Zhao S, Sakai A, Zhang X, Vetting MW, Kumar R, Hillerich B, San Francisco B, Solbiati J, Steeves A, Brown S, Akiva E, Barber A, Seidel RD, Babbitt PC, Almo SC, Gerlt JA, Jacobson MP (2014) Prediction and characterization of enzymatic activities guided by sequence similarity and genome neighborhood networks. Elife 3. https://doi.org/10.7554/elife.03275

    Article  Google Scholar 

  37. Zhu Y, Fu P, Lin Q, Zhang G, Zhang H, Li S, Ju J, Zhu W, Zhang C (2012) Identification of caerulomycin A gene cluster implicates a tailoring amidohydrolase. Org Lett 14:2666–2669. https://doi.org/10.1021/ol300589r

    Article  CAS  PubMed  Google Scholar 

  38. Zhu Y, Picard M-E, Zhang Q, Barma J, Despres XM, Mei X, Zhang L, Duvignaud J-B, Couture M, Zhu W, Shi R, Zhang C (2016) Flavoenzyme CrmK-mediated substrate recycling in caerulomycin biosynthesis. Chem Sci 7:4867–4874. https://doi.org/10.1039/c6sc00771f

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhu Y, Xu J, Mei X, Feng Z, Zhang L, Zhang Q, Zhang G, Zhu W, Liu J, Zhang C (2016) Biochemical and structural insights into the aminotransferase CrmG in caerulomycin biosynthesis. ACS Chem Biol 11:943–952. https://doi.org/10.1021/acschembio.5b00984

    Article  CAS  PubMed  Google Scholar 

  40. Zhu Y, Zhang Q, Li S, Lin Q, Fu P, Zhang G, Zhang H, Shi R, Zhu W, Zhang C (2013) Insights into caerulomycin A biosynthesis: a two-component monooxygenase CrmH-catalyzed oxime formation. J Am Chem Soc 135:18750–18753. https://doi.org/10.1021/ja410513g

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by Grants from the National Natural Science Foundation of China (21472231, 21520102004, 31430005, and 21750004), Chinese Academy of Sciences (SQYZDJ-SSW-SLH1037 and XDB20020200), Science and Technology Commission of Shanghai Municipality (17JC1405100 and 15JC1400400), the National Mega-project for Innovative Drugs (2018ZX09711001-006-010), and Youth Innovation Promotion Association of the Chinese Academy of Sciences (2017303).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Wen Liu.

Additional information

This article is part of the Special Issue “Natural Product Discovery and Development in the Genomic Era 2019”.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, D., Zhao, Q. & Liu, W. Discovery of caerulomycin/collismycin-type 2,2′-bipyridine natural products in the genomic era. J Ind Microbiol Biotechnol 46, 459–468 (2019). https://doi.org/10.1007/s10295-018-2092-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10295-018-2092-7

Keywords

Navigation