Advertisement

Applied Microbiology and Biotechnology

, Volume 102, Issue 5, pp 2225–2234 | Cite as

Genomic-driven discovery of an amidinohydrolase involved in the biosynthesis of mediomycin A

Applied genetics and molecular biotechnology

Abstract

Clethramycin (1) and mediomycin A (2) belong to the linear polyene polyketide (LPP) family of antibiotics that exhibit potent antifungal activity. Structural similarities exist between 1 and 2, except that 2 contains an amino moiety substituted for the guanidino moiety. Herein, the draft genome sequence of Streptomyces mediocidicus ATCC23936, a strain which produces both 1 and 2, was obtained through de novo sequencing. Bioinformatic analysis of the genome revealed a clethramycin (cle) gene cluster that contained 25 open reading frames (orfs). However, amidinohydrolase for 2 formation was not found in the cle gene cluster. Further genomic analysis revealed an amidinohydrolase MedX, which can hydrolyse the guanidino form (1) into the amino form (2) via heterologous co-expression of the cle cluster in Streptomyces lividans or by in vitro catalysis. These results also suggest the feasibility of engineering novel LPPs for drug discovery by manipulating the biosynthetic machinery of S. mediocidicus.

Keywords

Biosynthesis Clethramycin Mediomycin A Amidinohydrolase Linear polyene polyketides (LPPs) 

Notes

Acknowledgements

We thank Dr. Mei Ge, Shanghai Laiyi Center for Biopharmaceuticals R & D, for providing S. mediocidicus ATCC23936.

Funding information

This work was supported by grants from Tianjin science and technology plan projects (no. 16YFZCSY01000).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical statement

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

253_2017_8729_MOESM1_ESM.pdf (489 kb)
ESM 1 (PDF 489 kb)

References

  1. Banskota AH, Mcalpine JD, Ibrahim A, Aouidate M, Piraee M, Alarco AM, Farnet CM, Zazopoulos E (2006) Genomic analyses lead to novel secondary metabolites. Part 3. ECO-0501, a novel antibacterial of a new class. J Antibiot 59(9):533–542.  https://doi.org/10.1038/ja.2006.74 CrossRefPubMedGoogle Scholar
  2. Cai P, Kong F, Fink P, Ruppen ME, Williamson RT, Keiko T (2007) Polyene antibiotics from Streptomyces mediocidicus. J Nat Prod 70(2):215–219.  https://doi.org/10.1021/np060542f CrossRefPubMedGoogle Scholar
  3. Chandra A, Nair MG (1995) Azalomycin F complex from Streptomyces hygroscopicus, MSU/MN-4-75B. J Antibiot 48(8):896–898.  https://doi.org/10.7164/antibiotics.48.896 CrossRefPubMedGoogle Scholar
  4. Chen S, Wu Q, Shen Q, Wang H (2015) Progress in understanding the genetic information and biosynthetic pathways behind Amycolatopsis antibiotics, with implications for the continued discovery of novel drugs. Chembiochem 17:119–128CrossRefPubMedGoogle Scholar
  5. Dowling DP, Di CL, Gennadios HA, Christianson DW (2008) Evolution of the arginase fold and functional diversity. Cell Mol Life Sci 65(13):2039–2055.  https://doi.org/10.1007/s00018-008-7554-z CrossRefPubMedPubMedCentralGoogle Scholar
  6. Elkins JM, Clifton IJ, Hernández H, Doan LX, Robinson CV, Schofield CJ, Hewitson KS (2002) Oligomeric structure of proclavaminic acid amidino hydrolase: evolution of a hydrolytic enzyme in clavulanic acid biosynthesis. Biochem J 366(2):423–434.  https://doi.org/10.1042/bj20020125 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Frank J, Dékány G, Pelczer I, ApSimon JW (1987) The composition of primycin. Tetrahedron Lett 28(24):2759–2762.  https://doi.org/10.1016/S0040-4039(00)96202-6 CrossRefGoogle Scholar
  8. Furumai T, Yamakawa T, Yoshida R, Igarashi Y (2003) Clethramycin, a new inhibitor of pollen tube growth with antifungal activity from Streptomyces hygroscopicus TP-A0623. I. Screening, taxonomy, fermentation, isolation and biological properties. J Antibiot 56(8):700–704.  https://doi.org/10.7164/antibiotics.56.700 CrossRefPubMedGoogle Scholar
  9. Gust B, Challis GL, Fowler K, Kieser T, Chater KF (2003) PCR-targeted Streptomyces gene replacement identifies a protein domain needed for biosynthesis of the sesquiterpene soil odor geosmin. Proc Natl Acad Sci U S A 100(4):1541–1546.  https://doi.org/10.1073/pnas.0337542100 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Hong H, Samborskyy M, Lindner F, Leadlay PF (2016) An amidinohydrolase provides the missing link in the biosynthesis of amino marginolactone antibiotics. Angew Chem Int Ed Engl 55(3):1118–1123.  https://doi.org/10.1002/anie.201509300 CrossRefPubMedGoogle Scholar
  11. Hornung A, Bertazzo M, Dziarnowski A, Schneider K, Welzel K, Wohlert SE, Holzenkämpfer M, Nicholson GJ, Bechthold A, Süssmuth RD (2007) A genomic screening approach to the structure-guided identification of drug candidates from natural sources. Chembiochem 8(7):757–766.  https://doi.org/10.1002/cbic.200600375 CrossRefPubMedGoogle Scholar
  12. Igarashi Y, Iwashita T, Fujita T, Naoki H, Yamakawa T, Yoshida R, Furuma T (2003) Clethramycin, a new inhibitor of pollen tube growth with antifungal activity from Streptomyces hygroscopicus TP-A0623. II. Physico-chemical properties and structure determination. J Antibiot 56(8):705–708.  https://doi.org/10.7164/antibiotics.56.705 CrossRefPubMedGoogle Scholar
  13. Kusserow K, Tam G (2017) Complete genome sequence of Actinomadura parvosata subsp. kistnae, a rich source of novel natural product (bio-)chemistry. J Genomics 5:75–76.  https://doi.org/10.7150/jgen.19673 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Lee SJ, Kim DJ, Kim HS, Lee BI, Yoon HJ, Yoon JY, Kim KH, Jang JY, Im HN, An DR (2011) Crystal structures of Pseudomonas aeruginosa guanidinobutyrase and guanidinopropionase, members of the ureohydrolase superfamily. J Struct Biol 175(3):329–338.  https://doi.org/10.1016/j.jsb.2011.05.002 CrossRefPubMedGoogle Scholar
  15. Liu W, Min M, Xue Y, Nan L, Wang S, Chen Y (2013a) The C-terminal extended serine residue is absolutely required in nosiheptide maturation. Chembiochem 14(5):573–576.  https://doi.org/10.1002/cbic.201200681 CrossRefPubMedGoogle Scholar
  16. Liu W, Xue Y, Ma M, Wang S, Liu N, Chen Y (2013b) Multiple oxidative routes towards the maturation of nosiheptide. Chembiochem 14(13):1544–1547.  https://doi.org/10.1002/cbic.201300427 CrossRefPubMedGoogle Scholar
  17. Mcalpine JB, Bachmann BO, Piraee M, Tremblay S, Alarco AM, Zazopoulos E, Farnet CM (2005) Microbial genomics as a guide to drug discovery and structural elucidation: ECO-02301, a novel antifungal agent, as an example. J Nat Prod 68(4):493–496.  https://doi.org/10.1021/np0401664 CrossRefPubMedGoogle Scholar
  18. Nei M, Kumar S (2000) Molecular evolution and phylogenetics. Oxford University Press, USAGoogle Scholar
  19. Park HB, Perez CE, Barber KW, Rinehart J, Crawford JM (2017) Genome mining unearths a hybrid nonribosomal peptide synthetase-like-pteridine synthase biosynthetic gene cluster. elife 6:e25229PubMedPubMedCentralGoogle Scholar
  20. Saitou N, Nei M (1987) The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol 4(4):406–425PubMedGoogle Scholar
  21. Sbaraini N, Andreis FC, Thompson CE, Guedes RLM, Junges Â, Campos T, Staats CC, Vainstein MH, Vasconcelos ATRD, Schrank A (2017) Genome-wide analysis of secondary metabolite gene clusters in ophiostoma ulmi and ophiostoma novo-ulmi reveals a fujikurin-like gene cluster with a putative role in infection. Front Microbiol 8:1063.  https://doi.org/10.3389/fmicb.2017.01063 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Stephan H, Kempter C, Metzger JW, Jung G, Potterat O, Pfefferle C, Fiedler H (1996) Kanchanamycins, new polyol macrolide antibiotics produced by Streptomyces olivaceus Tü 4018. J Antibiot 49(8):765–769.  https://doi.org/10.7164/antibiotics.49.765 CrossRefPubMedGoogle Scholar
  23. Tamura K, Dudley J, Nei M, Kumar S (2007) MEGA4: molecular evolutionary genetics analysis (MEGA) software version 4.0. Mol Biol Evol 24(8):1596–1599.  https://doi.org/10.1093/molbev/msm092 CrossRefPubMedGoogle Scholar
  24. Zhang L, Hashimoto T, Qin B, Hashimoto J, Kozone I, Kawahara T, Okada M, Awakawa T, Ito T, Asakawa Y, Ueki M, Takahashi S, Osada H, Wakimoto T, Ikeda H, Shin-Ya K, Abe I (2017) Characterization of giant modular PKSs provides insight into genetic mechanism for structural diversification of aminopolyol polyketides. Angew Chem Int Ed Engl 56(7):1740–1745.  https://doi.org/10.1002/anie.201611371 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Physiology and Pathophysiology, School of Basic Medical SciencesTianjin Medical UniversityTianjinChina
  2. 2.Department of Pathogen Biology, School of Basic Medical SciencesTianjin Medical UniversityTianjinChina

Personalised recommendations