Browse > Article

Characterization and Culture Optimization of Regiospecific Cyclosporin Hydroxylation in Rare Actinomycetes Species  

PARK, NAM-SIL (Department of Biotechnology, Inha University)
MYEONG, JI-SEON (Department of Biotechnology, Inha University)
PARK, HYUN-JOO (Song Won Envichem Inc.)
HAN, KYU-BOEM (Hanson Biotech Co., Ltd. 201 IACRI, Han Nam University)
KIM, SANG-NYUN (LG Household and HealthCare, R&D Park)
KIM, EUNG-SOO (Department of Biotechnology, Inha University)
Publication Information
Journal of Microbiology and Biotechnology / v.15, no.1, 2005 , pp. 188-191 More about this Journal
Abstract
Abstract Cyclosporins are a family of clinically-important immunosuppressive cyclic peptides produced by Tolypocladium inflatum. The structural modification of cyclosporins via hydroxylation at various positions of N-methyl leucines in cyclosporin A leads to a dramatic change of their bioactive spectra. Among over 100 soil actinomycetes screened, two actinomycetes species, Sebekia benihana and Pseudonocardia autotrophica, were identified to contain superior cyclosporin A hydroxylation activities. A HPLC-based cyclosporin A hydroxylation assay revealed that each strain possesses distinctive hydroxylation specificity and regiospecificity; mono-hydroxylation at the 4th N-methyl leucine of cyclosporin A by S. benihana, and di-hydroxylations at both 4th and 9th N-methyl leucines of cyclosporin A by P. autotrophica. The conversion yields for cyclosporin A hydroxylation by both S. benihana and P. autotrophica were significantly improved from less than 10% and 18% up to 58% and 45%, respectively, in the optimized culture containing molybdenum with 0.05 g/l of cyclosporin A concentration. An ancymidol-specific inhibition of cyclosporin hydroxylation also suggested that the regiospecific cyclosporin hydroxylation might be catalyzed by a putative cytochrome P450 mono-oxygenase enzyme.
Keywords
Cyclosporin; hydroxylation; actinomycetes; bioconversion;
Citations & Related Records

Times Cited By Web Of Science : 8  (Related Records In Web of Science)
연도 인용수 순위
  • Reference
1 Kendrew, S. G., D. A. Hopwood, and E. N. Marsh. 1997. Identification of a monooxygenase from Streptomyces coelicotor A3(2) involved in biosynthesis of actinorhodin: Purification and characterization of the recombinant enzyme. J. Bacteriol. 179: 4305- 4310   DOI   PUBMED
2 Kim, C.-Y., H.-J. Park, and E.-S. Kim. 2003. Heterologous expression of hybrid type II polyketide synthase system in Streptomyces species. J. Microbiol. Biotechnol. 13: 819- 822
3 Sewing, K. E., U. Christians, K. Kohlhaw, H. Radeke, S. Strohmeyer, R. Kownatzki, J. Budniak, R. Schottmann, J. S. Bleck, V. M. Almeida, et al. 1990. Biologic activity of cyclosporine metabolites. Transplant. Proc. 22: 1129- 1134
4 Streblow, D. N., M. Kitabwalla, M. Malkovsky, and C. D. Pauza. 1998. Cyclophilin a modulates processing of human immunodeficiency virus type 1 p55Gag: Mechanism for antiviral effects of cyclosporin A. Virology 245: 197- 202   DOI   ScienceOn
5 Hozurni, Y., T. Irnaizurni, and S. Kondo. 1994. Effect of cyclosporin on hair-existing area of nude mice. J. Dermatol. Sci. 7: 33- 38   DOI   PUBMED
6 Settaf, A., J. Gugenheim, M. K. Lahlou, M. Gigou, M. Capron-Laudereau, B. Charpentier, M. Reynes, F. Lokiec, and H. Bismuth. 1989. Cyclosporin, toxicity and efficacy in rejection of liver allografts in the rat. J. Chir. 126: 431- 437
7 White, D. J., A. M. Plumb, G. Pawelec, and G. Brons. 1979. Cyclosporin A: An immunosuppressive agent preferentially active against proliferating T cells. Transplantation 27: 55-58   DOI   PUBMED   ScienceOn
8 Wenger, R. M. 1990. Structures of cyclosporine and its metabolites. Transplant. Proc. 22: 1104- 1108
9 Perkins, M. E., T. W. Wu, and S. M. Le Blancq. 1998. Cyclosporin analogs inhibit in vitro growth of Cryptosporidium parvum. Antimicrob. Agents Chemother. 42: 843- 848   PUBMED
10 Kim, C.-Y., H.-J. Park, Y. J. Yoon, H.-Y. Kang, and E.-S. Kim. 2004. Stimulation of actinorhodin production by Streptomyces lividans with a chromosomally-integrated antibiotic regulatory gene afsR2. J. Microbiol. Biotechnol. 14: 1089- 1092
11 Zhao, D. X., M. Beran, J. Kozova, and Z. Rehacek. 1991. Formation of cyclosporins by Tolypocladium inflatum. Folia Microbiol. 36: 549- 556   DOI   ScienceOn
12 Liu, W. T., K. Marat, Y. Ren, R. T. Eng, and P. Y. Wong. 1998. Structural characterization of two novel oxidative derivatives of cyclosporine generated by a chemical method. Clin. Biochem. 31: 173-180   DOI   ScienceOn
13 Korea Patent 10-2000-0067585
14 Moussaif, M., P. Jacques, P. Schaarwachter, H. Budzikiewicz, and P. Thonart. 1997. Cyclosporin C is the main antifungal compound produced by Acremonium luzulae. Appl. Environ. Microbiol. 63: 1739- 1743   PUBMED
15 Kuhnt, M., F. Bitsch, J. France, H. Hofmann, J. J. Sanglier, and R. Traber. 1996. Microbial biotransformation products of cyclosporin A. J. Antibiot. 49: 781- 787   DOI   ScienceOn
16 Copeland, K. R., J. A. Thliveris, and R. W. Yatscoff. 1990. Toxicity of cyclosporine metabolites. Ther. Drug Manit. 12: 525- 532   DOI   ScienceOn
17 Cifkova, R. and H. Hallen. 2001. Cyclosporin-induced hypertension. J. Hypertens. 19: 2283- 2285   DOI   ScienceOn
18 Jung, W.-S., E.-S. Kim. H.-Y. Kang, C.-Y. Choi, D. H. Sherman, and Y. J. Yoon. 2003. Site-directed mutagenesis on putative macrolactone ring size determinant in the hybrid pikromycin-tylosin polyketide synthase. J. Microbiol. Biotechnol. 13: 823- 827
19 Maurer, G., H. R. Loosli, E. Schreier, and B. Keller. 1984. Disposition of cyclosporine in several animal species and man. I. Structural elucidation of its metabolites. Drug. Metab. Dispos. 12: 120- 126   PUBMED
20 Yamamoto, S. and R. Kato. 1994. Hair growth-stimulating effects of cyclosporin A and FK506, potent immunosuppressants. J. Dermatol. Sci. 7: 47- 54   DOI   PUBMED
21 Tongpim, S. and M. A. Pickard. 1999. Cometabolic oxidation of phenanthrene to phenanthrene trans-9, 10-dihydrodiol by Mycobacterium strain Sl growing on anthracene in the presence of phenanthrene. Can. J. Microbiol. 45: 369- 376   DOI   ScienceOn
22 Kim, S.-N., H.-J. Ahn, M.-K. Kim, J.-I. Kim, J.-H. Kim, C.-W. Lee, M.-H. Lee, C.-D. Kim, H.-S. Cho, H.-S. Kim, M.-H. Jung, and S.-J. Kim. 2003. Nonimmunosuppressive [gamma-hydroxy-methylleucine4] cyclosporin A, hair growth stimulator and external composition for skin using the same USP 6521595.