Article Search
닫기

Microbiology and Biotechnology Letters

보문(Article)

View PDF

Molecular and Cellular Microbiology (MCM)  |  Microbial Genetics, Physiology and Metabolism

Microbiol. Biotechnol. Lett. 2021; 49(3): 458-465

https://doi.org/10.48022/mbl.2104.04014

Received: April 25, 2021; Revised: May 13, 2021; Accepted: May 14, 2021

Archangium gephyra 의 tubulysin 생합성 유전자 분석

Analysis of Tubulysin Biosynthetic Genes in Archangium gephyra

Juo Choi1,2, Taejoon Park1, Daun Kang2, Jeongju Lee2, Yungpil Kim2, Pilgoo Lee2, Gregory J. Y. Chung2, and Kyungyun Cho1*

1Department of Biotechnology, Hoseo University, Asan 31499, Republic of Korea 2MECOX CureMed Co., Seoul 06744, Republic of Korea

Correspondence to :
Kyungyun Cho,      kycho@hoseo.edu

Tubulysins are a group of bioactive secondary metabolites from myxobacteria exhibiting strong anticancer activity against various cancer cell lines. In this study, we describe the identification of putative tubulysin biosynthetic gene clusters (tubA~tubF) in the genome sequences of two tubulysin-producing myxobacterial strains, Archangium gephyra MEHO_002 and MEHO_004. The inactivation of the putative tubulysin biosynthetic genes resulted in a tubulysin-production defect. The DNA sequences of the A. gephyra MEHO_002 and MEHO_004 tubulysin biosynthetic genes were 97% identical, and the amino acid sequences of the encoded proteins shared a similarity of 97−100%. The nucleotide sequences of the tubulysin biosynthetic gene clusters in MEHO_002 and MEHO_004 were 86% identical to that in Cystobacter sp. SBCb004 known as a tubulysin-producing myxobacterium, and the organization of the clusters was identical except for the lack of a tubZ gene in the clusters in MEHO_002 and MEHO_004. The amino acid sequences of the proteins encoded by each gene were 88-97% similar to those encoded by SBCb004, and the domain compositions of the proteins were also identical.

Keywords: Archangium gephyra, tubulysin, myxobacteria, secondary metabolite

Graphical Abstract


  1. Etienne-Manneville S. 2010. From signaling pathways to microtubule dynamics: the key players. Curr. Opin. Cell Biol. 22:104-111.
    Pubmed
  2. Risinger AL, Giles FJ, Mooberry SL. 2009. Microtubule dynamics as a target in oncology. Cancer Treat Rev. 35: 255-261.
    Pubmed KoreaMed
  3. Sasse F, Steinmetz H, Heil J, Hőfle G, Reichenbach H. 2000. Tubulysins, new cytostatic peptides from myxobacteria acting on microtubuli. Production, isolation, physico-chemical and biological properties. J. Antibiot. 53: 879-885.
    Pubmed
  4. Khalil MW, Sasse F, Lünsdorf H, Elnakady YA, Reichenbach H. 2006. Mechanism of action of tubulysin, an antimitotic peptide from myxobacteria. ChemBioChem 7: 678-683.
    Pubmed
  5. Chai Y, Pistorius D, Ullrich A, Weissman KJ, Kazmaier U, Műller R. 2010. Discovery of 23 natural tubulysins from Angiococcus disciformis An d48 and Cystobacter SBCb004. Chem. Biol. 17:296-309.
    Pubmed
  6. Steinmetz H, Glaser N, Herdtweck E, Sasse F, Reichenbach H, Hőfle G. 2004. Isolation, crystal and solution structure determination, and biosynthesis of tubulysins - powerful inhibitors of tubulin polymerization from myxobacteria. Angew. Chem. Int. Ed. 43: 4888-4892.
    Pubmed
  7. Dömling A, Richter W. 2005. Myxobacterial epothilones and tubulysins as promising anticancer agents. Mol. Divers. 9: 141147.
    Pubmed
  8. Kaur G, Hollingshead M, Holbeck S, Schauer-Vukasinovic V, Camalier RF, Domling A, et al. 2006. Biological evaluation of tubulysin A: a potential anticancer and antiangiogenic natural product. Biochem. J. 396: 235-242.
    Pubmed KoreaMed
  9. Murray BC, Peterson MT, Fecik RA. 2015. Chemistry and biology of tubulysins: antimitotic tetrapeptides with activity against drug resistant cancers. Nat. Prod. Rep. 32: 654-662.
    Pubmed
  10. Reddy JA, Dorton R, Bloomfield A, Nelson M, Dircksen C, Vetzel M, et al. 2018. Pre-clinical evaluation of EC1456, a folatetubulysin anti-cancer therapeutic. Sci. Rep. 8: 8943.
    Pubmed KoreaMed
  11. Szigetvari NM, Dhawan D, Ramos-Vara JA, Leamon CP, Klein PJ, Ruple AA, et al. 2018. Phase I/II clinical trial of the targeted chemotherapeutic drug, folate-tubulysin, in dogs with naturallyoccurring invasive urothelial carcinoma. Oncotarget 9: 3704237053.
    Pubmed KoreaMed
  12. Courter JR, Joseph Z, Hamilton JZ, Hendrick NR, Zaval M, Waight AB, et al. 2020. Structure-activity relationships of tubulysin analogues. Bioorg. Med. Chem. Lett. 30: 127241.
    Pubmed
  13. Sandmann A, Sasse F, Müller R. 2004. Identification and analysis of the core biosynthetic machinery of tubulysin, a potent cytotoxin with potential anticancer activity. Chem. Biol. 11:1071-1079.
    Pubmed
  14. Hyun H, Choi J, Kang D, Kim Y, Lee P, Chung GJY, et al. 2021. Screening of myxobacteria carrying tubulysin biosynthetic genes. Microbiol. Biotechnol. Lett. 49: 32-38.
  15. Shin H, Youn J, An D, Cho K. 2013. Production of antimicrobial substances by strains of myxobacteria Corallococcus and Myxococcus. Kor. J. Microbiol. Biotechnol. 41: 44-51.
  16. Lee B, Lee C, Cho K. 2003. Isolation of dispersed mutants from wild myxobacteria. Kor. J. Microbiol. Biotechnol. 31: 342-347.
  17. Sambrook J, Fritsch EF, Maniatis T. 1989. Molecular Cloning: a Laboratory Manual, 2nd ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, N.Y., USA.
  18. Blin K, Shaw S, Steinke K, Villebro R, Ziemert N, Lee SY, et al. 2019. antiSMASH 5.0: updates to the secondary metabolite genome mining pipeline. Nucleic Acids Res. 47: W81-W87.
    Pubmed KoreaMed
  19. Johnson M, Zaretskaya I, Raytselis Y, Mereshuk Y, McGinnis S, Madden TL. 2008. NCBI BLAST: a better web interface. Nucleic Acids Res. 36: W5-W9.
    Pubmed KoreaMed
  20. Marchler-Bauer A, Derbyshire MK, Gonzales NR, Lu S, Chitsaz F, Geer LY, et al. 2015. CDD: NCBI's conserved domain database. Nucleic Acids Res. 43: D222-D226.
    Pubmed KoreaMed
  21. Shimkets LJ. 1986. Correlation of energy-dependent cell cohesion with social motility in Myxococcus xanthus. J. Bacteriol. 166: 837-841.
    Pubmed KoreaMed
  22. Chai Y, Shan S, Weissman KJ, Hu S, Zhang Y, Műller R. 2012. Heterologous expression and genetic engineering of the tubulysin biosynthetic gene cluster using Red/ET recombineering and inactivation mutagenesis. Chem. Biol. 19: 361-371.
    Pubmed
  23. Ullrich A, Chai Y, Pistorius D, Elnakady YA, Herrmann JE, Weissman KJ, et al. 2009. Pretubulysin, a potent and chemically accessible tubulysin precursor from Angiococcus disciformis. Angew. Chem. Int. Ed. Engl. 48: 4422-4425.
    Pubmed
  24. Selva E, Gastaldo L, Saddler GS, Toppo G, Ferrari P, Carniti G, et al. 1996. Antibiotics A21459 A and B, new inhibitors of bacterial protein synthesis. I. Taxonomy, isolation and characterization. J. Antibiot. 49: 145-149.
    Pubmed
  25. Sasse F, Steinmetz H, Schupp T, Petersen F, Memmert K, Hofmann H, et al. 2002. Argyrins, immunosuppressive cyclic peptides from myxobacteria. I. Production, isolation, physicochemical and biological properties. J. Antibiot. 55: 543-551.
    Pubmed

Starts of Metrics

Share this article on :

  • mail

Related articles in MBL

Most KeyWord ?

What is Most Keyword?

  • It is most registrated keyword in articles at this journal during for 2 years.