Abstract
This mini-review is centered on genetic aspects of biosynthesis of landomycins (La), a family of angucycline polyketides. From the very discovery in the 1990s, La were noted for unusual structure and potent anticancer properties. La are produced by a few actinobacteria that belong to genus Streptomyces. Biochemical logic behind the production of La aglycon and glycoside halves and effects of La on mammalian cells have been thoroughly reviewed in 2009–2012. Yet, the genetic diversity of La biosynthetic gene clusters (BGCs) and regulation of their production were not properly reviewed since discovery of La. Here, we aim to fill this gap by focusing on three interrelated topics. First, organization of known La BGCs is compared. Second, up-to-date scheme of biosynthetic pathway to landomycin A (LaA), the biggest (by molar weight) member of La family, is succinctly outlined. Third, we describe genetic and nutritional factors that influence La production and export. A summary of the practical utility of the gained knowledge and future directions to study La biosynthesis conclude this mini-review.
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References
Baig I, Kharel M, Kobylyanskyy A, Zhu L, Rebets Y, Ostash B, Luzhetskyy A, Bechthold A, Fedorenko VA, Rohr J (2006) On the acceptor substrate of C-glycosyltransferase UrdGT2: three prejadomycin C-glycosides from an engineered mutant of Streptomyces globisporus 1912 ΔlndE(urdGT2). Angew Chem Int Ed Engl 45(46):7842–7846. https://doi.org/10.1002/anie.200603176
Dutko L, Rebets Y, Ostash B, Luzhetskyy A, Bechthold A, Nakamura T, Fedorenko V (2006) A putative proteinase gene is involved in regulation of landomycin E biosynthesis in Streptomyces globisporus 1912. FEMS Microbiol Lett 255(2):280–285. https://doi.org/10.1111/j.1574-6968.2005.00085.x
Erb A, Krauth C, Luzhetskyy A, Bechthold A (2009) Differences in the substrate specificity of glycosyltransferases involved in landomycins A and E biosynthesis. Appl Microbiol Biotechnol 83(6):1067–1076. https://doi.org/10.1007/s00253-009-1993-9
Fedorenko V, Basiliya L, Pankevych K, Dubitska L, Ostash B, Luzhetskyy A, Gromyko O, Krugel H (2000) Genetic control of antitumor antibiotics-polyketides biosynthesis by actinomycetes. Bull Inst Agr Microbiol (Ukr) 8:27–31
Feng Z, Kallifidas D, Brady SF (2011) Functional analysis of environmental DNA-derived type II polyketide synthases reveals structurally diverse secondary metabolites. Proc Natl Acad Sci U S A 108(31):12629–12634. https://doi.org/10.1073/pnas.1103921108
Gessner A, Heitzler T, Zhang S, Klaus C, Murillo R, Zhao H, Vanner S, Zechel DL, Bechthold A (2015) Changing biosynthetic profiles by expressing bldA in Streptomyces strains. Chembiochem 16(15):2244–2252. https://doi.org/10.1002/cbic.201500297
Gromyko O, Rebets Y, Ostash B, Luzhetskyy A, Fukuhara M, Bechthold A, Nakamura T, Fedorenko V (2004) Generation of Streptomyces globisporus SMY622 strain with increased landomycin E production and it’s initial characterization. J Antibiot 57(6):383–389. https://doi.org/10.7164/antibiotics.57.383
Henkel T, Rohr J, Beale JM, Schwenen L (1990) Landomycins, new angucycline antibiotics from Streptomyces sp. I. Structural studies on landomycins A-D. J Antibiot 43(5):492–503. https://doi.org/10.7164/antibiotics.43.492
Horbal L, Fedorenko V, Bechthold A, Luzhetskyy A (2013) A transposon-based strategy to identify the regulatory gene network responsible for landomycin E biosynthesis. FEMS Microbiol Lett 342(2):138–146. https://doi.org/10.1111/1574-6968.12117
Kharel MK, Pahari P, Lian H, Rohr J (2010) Enzymatic total synthesis of rabelomycin, an angucycline group antibiotic. Org Lett 12(12):2814–2817. https://doi.org/10.1021/ol1009009
Kharel MK, Pahari P, Shepherd MD, Tibrewal N, Nybo SE, Shaaban KA, Rohr J (2012a) Angucyclines: biosynthesis, mode-of-action, new natural products, and synthesis. Nat Prod Rep 29(2):264–325. https://doi.org/10.1039/c1np00068c
Kharel MK, Pahari P, Shaaban KA, Wang G, Morris C, Rohr J (2012b) Elucidation of post-PKS tailoring steps involved in landomycin biosynthesis. Org Biomol Chem 10(21):4256–4265. https://doi.org/10.1039/c2ob07171a
Korynevska A, Heffeter P, Matselyukh B, Elbling L, Micksche M, Stoika R, Berger W (2007) Mechanisms underlying the anticancer activities of the angucycline landomycin E. Biochem Pharmacol 74(12):1713–1726. https://doi.org/10.1016/j.bcp.2007.08.026
Krauth C, Fedoryshyn M, Schleberger C, Luzhetskyy A, Bechthold A (2009) Engineering a function into a glycosyltransferase. Chem Biol 16(1):28–35. https://doi.org/10.1016/j.chembiol.2008.12.003
Lavrinchuk B, Kotenko KA, Golembiovs’ka SL, Matseliukh BP (2011) Obtaining and characteristic of Streptomyces globisporus 1912 mutants with high biosynthesis of landomycin E. Mikrobiol Z (Ukr) 73(6):31–35
Lehka LV, Panchuk RR, Berger W, Rohr J, Stoika RS (2015) The role of reactive oxygen species in tumor cells apoptosis induced by landomycin A. Ukr Biochem J 87(5):72–82. https://doi.org/10.15407/ubj87.05.072
Luzhetskyy A, Liu T, Fedoryshyn M, Ostash B, Fedorenko V, Rohr J, Bechthold A (2004) Function of lanGT3, a glycosyltransferase gene involved in landomycin A biosynthesis. Chembiochem 5(11):1567–1570. https://doi.org/10.1002/cbic.200400123
Luzhetskyy A, Taguchi T, Fedoryshyn M, Dürr C, Wohlert SE, Novikov V, Bechthold A (2005a) LanGT2 catalyzes the first glycosylation step during landomycin A biosynthesis. Chembiochem 6(8):1406–1410. https://doi.org/10.1002/cbic.200500018
Luzhetskyy A, Fedoryshyn M, Dürr C, Taguchi T, Novikov V, Bechthold A (2005b) Iteratively acting glycosyltransferases involved in the hexasaccharide biosynthesis of landomycin A. Chem Biol 12(7):725–729. https://doi.org/10.1016/j.chembiol.2005.05.008
Matselyukh B, Mohammadipanah F, Laatsch H, Rohr J, Efremenkova O, Khilya V (2015) N-methylphenylalanyl-dehydrobutyrine diketopiperazine, an A-factor mimic that restores antibiotic biosynthesis and morphogenesis in Streptomyces globisporus 1912-B2 and Streptomyces griseus 1439. J Antibiot 68(1):9–14. https://doi.org/10.1038/ja.2014.86
Matselyukh BP, Polishchuk LV, Lukyanchuk VV, Golembiovska SL, Lavrenchuk VY (2016) Sequences of landomycin E and carotenoid biosynthetic gene clusters, and molecular structure of transcriptional regulator of Streptomyces globisporus 1912. Mikrobiol Z 78(6):60–70
Myronovskyi M, Brötz E, Rosenkränzer B, Manderscheid N, Tokovenko B, Rebets Y, Luzhetskyy A (2016) Generation of new compounds through unbalanced transcription of landomycin A cluster. Appl Microbiol Biotechnol 100(21):9175–9186. https://doi.org/10.1007/s00253-016-7721-3
Ostash B, Rebets Y, Yuskevich V, Luzhetskyy A, Tkachenko V, Fedorenko V (2003) Targeted disruption of Streptomyces globisporus lndF and lndL cyclase genes involved in landomycin E biosynthesis. Folia Microbiol (Praha) 48(4):484–488. https://doi.org/10.1007/BF02931329
Ostash B, Rix U, Rix LL, Liu T, Lombo F, Luzhetskyy A, Gromyko O, Wang C, Braña AF, Méndez C, Salas JA, Fedorenko V, Rohr J (2004) Generation of new landomycins by combinatorial biosynthetic manipulation of the LndGT4 gene of the landomycin E cluster in S. globisporus. Chem Biol 11(4):547–555. https://doi.org/10.1016/j.chembiol.2004.03.011
Ostash B, Kozarevska I, Fedorenko V (2005) Generation of landomycin D-producing strain Streptomyces globisporus LD3. Folia Microbiol (Praha) 50(1):19–23. https://doi.org/10.1007/BF02931289
Ostash I, Ostash B, Walker S, Fedorenko V (2007) Proton-dependent transporter gene lndJ confers resistance to landomycin E in Streptomyces globisporus. Genetika 43(8):1032–1037. https://doi.org/10.1134/S1022795407080030
Ostash I, Ostash B, Luzhetskyy A, Bechthold A, Walker S, Fedorenko V (2008a) Coordination of export and glycosylation of landomycins in Streptomyces cyanogenus S136. FEMS Microbiol Lett 285(2):195–202. https://doi.org/10.1111/j.1574-6968.2008.01225.x
Ostash I, Rebets Y, Ostash B, Kobylyanskyy A, Myronovskyy M, Nakamura T, Walker S, Fedorenko V (2008b) An ABC transporter encoding gene lndW confers resistance to landomycin E. Arch Microbiol 190(1):105–109. https://doi.org/10.1007/s00203-008-0367-5
Ostash B, Korynevska A, Stoika R, Fedorenko V (2009) Chemistry and biology of landomycins, an expanding family of polyketide natural products. Mini-Rev Med Chem 9(9):1040–1051. https://doi.org/10.2174/138955709788922593
Ostash B, Ostash I, Zhu L, Kharel MK, Luzhetskiĭ A, Bechthold A, Walker S, Rohr J, Fedorenko V (2010) Properties of lanK-based regulatory circuit involved in landomycin biosynthesis in Streptomyces cyanogenus S136. Genetika 46(5):604–609. https://doi.org/10.1134/S1022795410050030
Ostash B, Rebets Y, Myronovskyy M, Tsypik O, Ostash I, Kulachkovskyy O, Datsyuk Y, Nakamura T, Walker S, Fedorenko V (2011) Identification and characterization of the Streptomyces globisporus 1912 regulatory gene lndYR that affects sporulation and antibiotic production. Microbiology 157(Pt 4):1240–1249. https://doi.org/10.1099/mic.0.045088-0
Paananen P, Patrikainen P, Kallio P, Mäntsälä P, Niemi J, Niiranen L, Metsä-Ketelä M (2013) Structural and functional analysis of angucycline C-6 ketoreductase LanV involved in landomycin biosynthesis. Biochemistry 52(31):5304–5314. https://doi.org/10.1021/bi400712q
Panchuk RR, Lehka LV, Terenzi A, Matselyukh BP, Rohr J, Jha AK, Downey T, Kril IJ, Herbacek I, van Schoonhoven S, Heffeter P, Stoika RS, Berger W (2017) Rapid generation of hydrogen peroxide contributes to the complex cell death induction by the angucycline antibiotic landomycin E. Free Radic Biol Med 106:134–147. https://doi.org/10.1016/j.freeradbiomed.2017.02.024
Rebets Y, Ostash B, Luzhetskyy A, Hoffmeister D, Brana A, Mendez C, Salas JA, Bechthold A, Fedorenko V (2003a) Production of landomycins in Streptomyces globisporus 1912 and S. cyanogenus S136 is regulated by genes encoding putative transcriptional activators. FEMS Microbiol Lett 222(1):149–153. https://doi.org/10.1016/S0378-1097(03)00258-1
Rebets YU, Ostash B, Gromyko O, Mik U, Basiliya L, Fedorenko V (2003b) Resistance of recombinant Streptomyces albus Cest114 and Streptomyces globisporus 1912 strains to landomycin E. Visnyk Lviv Univ (Biol Ser) 33:47–54
Rebets Y, Ostash B, Luzhetskyy A, Kushnir S, Fukuhara M, Bechthold A, Nashimoto M, Nakamura T, Fedorenko V (2005) DNA-binding activity of LndI protein and temporal expression of the gene that upregulates landomycin E production in Streptomyces globisporus 1912. Microbiology 151(Pt 1):281–290. https://doi.org/10.1099/mic.0.27244-0
Rebets YV, Ostash BO, Fukuhara M, Nakamura T, Fedorenko VO (2006) Expression of the regulatory protein LndI for landomycin E production in Streptomyces globisporus 1912 is controlled by the availability of tRNA for the rare UUA codon. FEMS Microbiol Lett 256(1):30–37. https://doi.org/10.1111/j.1574-6968.2005.00087.x
Rebets Y, Dutko L, Ostash B, Luzhetskyy A, Kulachkovskyy O, Yamaguchi T, Nakamura T, Bechthold A, Fedorenko V (2008) Function of lanI in regulation of landomycin a biosynthesis in Streptomyces cyanogenus S136 and cross-complementation studies with Streptomyces antibiotic regulatory proteins encoding genes. Arch Microbiol 189(2):111–120. https://doi.org/10.1007/s00203-007-0299-5
Rohr J, Wohlert SE, Oelkers C, Kirschning A, Ries M (1997) Biosynthetic short activation of the 2,3,6-trideoxysugar L-rhodinose. Chem Commun 10:973–974. https://doi.org/10.1039/A702125I
Shaaban KA, Stamatkin C, Damodaran C, Rohr J (2011) 11-Deoxylandomycinone and landomycins X-Z, new cytotoxic angucyclin(on)es from a Streptomyces cyanogenus K62 mutant strain. J Antibiot 64(1):141–150. https://doi.org/10.1038/ja.2010.121
Tam HK, Härle J, Gerhardt S, Rohr J, Wang G, Thorson JS, Bigot A, Lutterbeck M, Seiche W, Breit B, Bechthold A, Einsle O (2015) Structural characterization of O- and C-glycosylating variants of the landomycin glycosyltransferase LanGT2. Angew Chem Int Ed Engl 54(9):2811–2815. https://doi.org/10.1002/anie.201409792
Tsypik O, Ostash B, Rebets’Iu, Fedorenko V (2013) Characterization of Streptomyces globisporus 1912 lnd cluster region containing lndY, lndYR, lndW2 and lndW genes. Tsitol Genet (Ukr.) 47(1):11–16. https://doi.org/10.3103/S0095452713010106
von Mulert U, Luzhetskyy A, Hofmann C, Mayer A, Bechthold A (2004) Expression of the landomycin biosynthetic gene cluster in a PKS mutant of Streptomyces fradiae is dependent on the coexpression of a putative transcriptional activator gene. FEMS Microbiol Lett 230(1):91–97. https://doi.org/10.1016/S0378-1097(03)00861-9
Westrich L, Domann S, Faust B, Bedford D, Hopwood DA, Bechthold A (1999) Cloning and characterization of a gene cluster from Streptomyces cyanogenus S136 probably involved in landomycin biosynthesis. FEMS Microbiol Lett 170(2):381–387. https://doi.org/10.1111/j.1574-6968.1999.tb13398.x
Yushchuk O, Ostash I, Vlasiuk I, Gren T, Luzhetskyy A, Kalinowski J, Fedorenko V, Ostash B (2018) Heterologous AdpA transcription factors enhance landomycin production in Streptomyces cyanogenus S136 under a broad range of growth conditions. Appl Microbiol Biotechnol 102(19):8419–8428. https://doi.org/10.1007/s00253-018-9249-1
Zhu L, Ostash B, Rix U, Nur-E-Alam M, Mayers A, Luzhetskyy A, Mendez C, Salas JA, Bechthold A, Fedorenko V, Rohr J (2005) Identification of the function of gene lndM2 encoding a bifunctional oxygenase-reductase involved in the biosynthesis of the antitumor antibiotic landomycin E by Streptomyces globisporus 1912 supports the originally assigned structure for landomycinone. J Org Chem 70(2):631–638. https://doi.org/10.1021/jo0483623
Zhu L, Luzhetskyy A, Luzhetska M, Mattingly C, Adams V, Bechthold A, Rohr J (2007) Generation of new landomycins with altered saccharide patterns through over-expression of the glycosyltransferase gene lanGT3 in the biosynthetic gene cluster of landomycin A in Streptomyces cyanogenus S-136. Chembiochem 8(1):83–88. https://doi.org/10.1002/cbic.200600360
Acknowledgements
We thank all current and former members of Fedorenko group (Lviv University) who contributed to the studies of La. We also sincerely apologize to everyone who contributed to studies of La, and whose works were not cited due to page constraints.
Funding
This work was supported by grants of Ministry of Education and Science of Ukraine M/26-2018 and Bg-41Nr (to B.O.).
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Yushchuk, O., Kharel, M., Ostash, I. et al. Landomycin biosynthesis and its regulation in Streptomyces. Appl Microbiol Biotechnol 103, 1659–1665 (2019). https://doi.org/10.1007/s00253-018-09601-1
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DOI: https://doi.org/10.1007/s00253-018-09601-1