Biopolym. Cell. 2002; 18(6):467-477.
Огляди
Створення продуцентів нових полікетидних антибіотиків методами генетичної інженерії
1Осташ Б. О., 1Федоренко В. О.
  1. Львівський національний університет імені Івана Франка
    вул. Грушевського, 4, Львів, Україна, 79005

Abstract

Зроблено огляд сучасних експериментальних даних в галузі вивчення біосинтезу полікетидів – однієї з найбільших груп природних сполук, що проявляють широкий спектр цінних біологічних властивостей. Розуміння генетичних та біохімічних аспектів полікетидного синтезу дозволяє створити рекомбінантні штами мікроорганізмів, що продукують нові сполуки з передбачуваною структурою. Описано основні методи генетичного «дизайну» нових полікетидних сполук, наведено приклади геноінженерного конструювання продуцентів промислово важливих полікетидних ан­тибіотиків.

References

[1] Pfeifer BA, Khosla C. Biosynthesis of polyketides in heterologous hosts. Microbiol Mol Biol Rev. 2001;65(1):106-18. PubMed PMID: 8561459.
[2] Hutchinson CR, Fujii I. Polyketide synthase gene manipulation: a structure-function approach in engineering novel antibiotics. Annu Rev Microbiol. 1995;49:201-38.
[3] O'Hagan D. Biosynthesis of fatty acid and polyketide metabolites. Nat Prod Rep. 1993;10(6):593-624.
[4] Krohn K, Rohr J. Angucyclines: Total syntheses, new structures, and biosynthetic studies of an emerging new class of antibiotics. Topics in Current Chemistry. 1997;127–95.
[5] Hwang CK, Kim HS, Hong YS, Kim YH, Hong SK, Kim SJ, Lee JJ. Expression of Streptomyces peucetius genes for doxorubicin resistance and aklavinone 11-hydroxylase in Streptomyces galilaeus ATCC 31133 and production of a hybrid aclacinomycin. Antimicrob Agents Chemother. 1995;39(7):1616-20.
[6] Kramer PJ, Zawada RJX, McDaniel R, Hutchinson CR, Hopwood DA, Khosla C. Rational Design and Engineered Biosynthesis of a Novel 18-Carbon Aromatic Polyketide. J Am Chem Soc. 1997;119(4):635–9.
[7] Lewis K. Multidrug resistance pumps in bacteria: variations on a theme. Trends Biochem Sci. 1994;19(3):119-23.
[8] Rohr J, Thiericke R. Angucycline group antibiotics. Nat Prod Rep. 1992;9(2):103-7.
[9] Bisang C, Long PF, Cort?s J, Westcott J, Crosby J, Matharu AL, Cox RJ, Simpson TJ, Staunton J, Leadlay PF. A chain initiation factor common to both modular and aromatic polyketide synthases. Nature. 1999;401(6752):502-5.
[10] Hopwood DA. Forty years of genetics with Streptomyces: from in vivo through in vitro to in silico. Microbiology. 1999;145 (Pt 9):2183-202.
[11] Staunton J, Wilkinson B. Biosynthesis of Erythromycin and Rapamycin. Chem Rev. 1997;97(7):2611-2630.
[12] Rangan VS, Joshi AK, Smith S. Mapping the functional topology of the animal fatty acid synthase by mutant complementation in vitro. Biochemistry. 2001;40(36):10792-9.
[13] Hopwood DA. Genetic Contributions to Understanding Polyketide Synthases. Chem Rev. 1997;97(7):2465-2498.
[14] Hutchinson CR, Decker H, Madduri K, Otten SL, Tang L. Genetic control of polyketide biosynthesis in the genus Streptomyces. Antonie Van Leeuwenhoek. 1993-1994;64(2):165-76.
[15] Funa N, Ohnishi Y, Fujii I, Shibuya M, Ebizuka Y, Horinouchi S. A new pathway for polyketide synthesis in microorganisms. Nature. 1999;400(6747):897-9.
[16] Wu N, Tsuji SY, Cane DE, Khosla C. Assessing the Balance between Protein?Protein Interactions and Enzyme?Substrate Interactions in the Channeling of Intermediates between Polyketide Synthase Modules. J Am Chem Soc. 2001;123(27):6465–74.
[17] Gokhale RS, Tsuji SY, Cane DE, Khosla C. Dissecting and exploiting intermodular communication in polyketide synthases. Science. 1999;284(5413):482-5.
[18] Tsuji SY, Wu N, Khosla C. Intermodular communication in polyketide synthases: comparing the role of protein-protein interactions to those in other multidomain proteins. Biochemistry. 2001;40(8):2317-25.
[19] Gaisser S, B?hm GA, Cort?s J, Leadlay PF. Analysis of seven genes from the eryAI-eryK region of the erythromycin biosynthetic gene cluster in Saccharopolyspora erythraea. Mol Gen Genet. 1997;256(3):239-51.
[20] Salah-Bey K, Doumith M, Michel JM, Haydock S, Cort?s J, Leadlay PF, Raynal MC. Targeted gene inactivation for the elucidation of deoxysugar biosynthesis in the erythromycin producer Saccharopolyspora erythraea. Mol Gen Genet. 1998;257(5):542-53.
[21] Suwa M, Sugino H, Sasaoka A, Mori E, Fujii S, Shinkawa H, Nimi O, Kinashi H. Identification of two polyketide synthase gene clusters on the linear plasmid pSLA2-L in Streptomyces rochei. Gene. 2000;246(1-2):123-31.
[22] Kwon H-J, Smith WC, Xiang L, Shen B. Cloning and heterologous expression of the macrotetrolide biosynthetic gene cluster revealed anovel polyketide synthase that lacks an acyl carrier protein. J Am Chem Soc. 2001;123(14):3385–6.
[23] Yu TW, Shen Y, Doi-Katayama Y, Tang L, Park C, Moore BS, Richard Hutchinson C, Floss HG. Direct evidence that the rifamycin polyketide synthase assembles polyketide chains processively. Proc Natl Acad Sci U S A. 1999;96(16):9051-6.
[24] Brautaset T, Sekurova ON, Sletta H, Ellingsen TE, Str?m AR, Valla S, Zotchev SB. Biosynthesis of the polyene antifungal antibiotic nystatin in Streptomyces noursei ATCC 11455: analysis of the gene cluster and deduction of the biosynthetic pathway. Chem Biol. 2000;7(6):395-403.
[25] Pfeifer BA, Admiraal SJ, Gramajo H, Cane DE, Khosla C. Biosynthesis of complex polyketides in a metabolically engineered strain of E. coli. Science. 2001;291(5509):1790-2.
[26] Tsoi CJ, Khosla C. Combinatorial biosynthesis of 'unnatural' natural products: the polyketide example. Chem Biol. 1995;2(6):355-62.
[27] Hutchinson CR. Microbial polyketide synthases: more and more prolific. Proc Natl Acad Sci U S A. 1999;96(7):3336-8.
[28] Khosla C, Gokhale RS, Jacobsen JR, Cane DE. Tolerance and specificity of polyketide synthases. Annu Rev Biochem. 1999;68:219-53.
[29] Shen B, Hutchinson CR. Deciphering the mechanism for the assembly of aromatic polyketides by a bacterial polyketide synthase. Proc Natl Acad Sci U S A. 1996;93(13):6600-4.
[30] Shen B, Summers RG, Wendt-Pienkowski E, Hutchinson CR. The Streptomyces glaucescens tcmKL polyketide synthase and tcmN polyketide cyclase genes govern the size and shape of aromatic polyketides. J Am Chem Soc. 1995;117(26):6811–21.
[31] Bao W, Sheldon PJ, Wendt-Pienkowski E, Hutchinson CR. The Streptomyces peucetius dpsC gene determines the choice of starter unit in biosynthesis of the daunorubicin polyketide. J Bacteriol. 1999;181(15):4690-5.
[32] Zawada RJ, Khosla C. Domain analysis of the molecular recognition features of aromatic polyketide synthase subunits. J Biol Chem. 1997;272(26):16184-8.
[33] Dreier J, Khosla C. Mechanistic analysis of a type II polyketide synthase. Role of conserved residues in the beta-ketoacyl synthase-chain length factor heterodimer. Biochemistry. 2000;39(8):2088-95.
[34] McDaniel R, Ebert-Khosla S, Hopwood DA, Khosla C. Rational design of aromatic polyketide natural products by recombinant assembly of enzymatic subunits. Nature. 1995;375(6532):549-54.
[35] Meurer G, Gerlitz M, Wendt-Pienkowski E, Vining LC, Rohr J, Hutchinson CR. Iterative type II polyketide synthases, cyclases and ketoreductases exhibit context-dependent behavior in the biosynthesis of linear and angular decapolyketides. Chem Biol. 1997;4(6):433-43.
[36] McDaniel R, Hutchinson CR, Khosla C. Engineered biosynthesis of novel polyketides: analysis of tcmN function in tetracenomycin biosynthesis. J Am Chem Soc. 1995;117(26):6805–10.
[37] Hutchinson CR. Biosynthetic studies of daunorubicin and tetracenomycin C. Chem Rev. 1997;97(7):2525-2536.
[38] Bentley R, Bennett JW. Constructing polyketides: from collie to combinatorial biosynthesis. Annu Rev Microbiol. 1999;53:411-46.
[39] Ostash BO, Pankevych BO, Luzhetskiy AM, Basiliya LI, Gromyko OM, Kruegel H, Fedorenko VO. Studying of genes involved in landomycin E biosynthesis by Streptomyces globisporus 1912. 12th Int Symp Biol Actinomycete. Vancouver, 2001: 133.
[40] McDaniel R, Thamchaipenet A, Gustafsson C, Fu H, Betlach M, Ashley G. Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel "unnatural" natural products. Proc Natl Acad Sci U S A. 1999;96(5):1846-51.
[41] Hertweck C. The multiplasmid approach: a new perspective for combinatorial biosynthesis. Chembiochem. 2000;1(2):103-6.
[42] Tang L, McDaniel R. Construction of desosamine containing polyketide libraries using a glycosyltransferase with broad substrate specificity. Chem Biol. 2001;8(6):547-55.
[43] Shen Y, Yoon P, Yu TW, Floss HG, Hopwood D, Moore BS. Ectopic expression of the minimal whiE polyketide synthase generates a library of aromatic polyketides of diverse sizes and shapes. Proc Natl Acad Sci U S A. 1999;96(7):3622-7.
[44] Fern?ndez-Moreno MA, Carb? L, Cuesta T, Vall?n C, Malpartida F. A silent ABC transporter isolated from Streptomyces rochei F20 induces multidrug resistance. J Bacteriol. 1998;180(16):4017-23.
[45] K?nzel E, Wohlert S-E, Beninga C, Haag S, Decker H, Hutchinson CR, et al. Tetracenomycin M, a novel Ggenetically engineered tetracenomycin resulting from a combination of mithramycin and tetracenomycin biosynthetic genes. Chem Eur J. 1997;3(10):1675–8.
[46] Kirsching A, Bechthold A, Rohr J. Chemical and biochemical aspects of deoxysugars and deoxysugar oligosaccharides. Top Curr Chem. 1997; 188: 1-84.
[47] Salas JA, M?ndez C. Genetic manipulation of antitumor-agent biosynthesis to produce novel drugs. Trends Biotechnol. 1998;16(11):475-82.
[48] Niemi J, Ylihonko K, Hakala J, P?rssinen R, Kopio A, M?nts?l? P. Hybrid anthracycline antibiotics: production of new anthracyclines by cloned genes from Streptomyces purpurascens in Streptomyces galilaeus. Microbiology. 1994;140 ( Pt 6):1351-8.
[49] Betlach MC, Kealey JT, Ashley GW, McDaniel R. Characterization of the macrolide P-450 hydroxylase from Streptomyces venezuelae which converts narbomycin to picromycin. Biochemistry. 1998;37(42):14937-42.
[50] Brukner P, Sterner O, Bailey JE, Minos W. Production of novel hybrid polyketides by heterologous expression of the naphtocyclinone aromatase and hydroxylase genes from Streptomyces arenae II Proc. of the 11t h Int. Symp. on Biol, of Actinomycetes (Crete, Greece, October 24-28 1999). Sissi- Heraklion, 1999: 85.
[51] Kantola J, Kunnari T, Hautala A, Hakala J, Ylihonko K, M?nts?l? P. Elucidation of anthracyclinone biosynthesis by stepwise cloning of genes for anthracyclines from three different Streptomyces spp. Microbiology. 2000;146 (Pt 1):155-63.
[52] Quir?s LM, Carbajo RJ, Bra?a AF, Salas JA. Glycosylation of macrolide antibiotics. Purification and kinetic studies of a macrolide glycosyltransferase from Streptomyces antibioticus. J Biol Chem. 2000;275(16):11713-20.
[53] Gaisser S, Doumith M, Olano C. In vivo expression of glycosyltransferases in Saccharopolyspora erythraea II Proc. of the 11t h Int Symp Biol, of Actinomycetes (Crete, Greece, October 24-28 1999). Sissi-Heraklion, 1999: 186.
[54] Gaisser S, Leadlay PF. Sugaring the pill by design. Nat Biotechnol. 1998;16(1):19-20.
[55] Patallo EP, Blanco G, Fischer C, Brana AF, Rohr J, Mendez C, Salas JA. Deoxysugar methylation during biosynthesis of the antitumor polyketide elloramycin by Streptomyces olivaceus. Characterization of three methyltransferase genes. J Biol Chem. 2001;276(22):18765-74.
[56] Fedorenko VO, Basilia LI, Pankevitch KO, Dubytska LP, Ostash BO, Luzhetskiy AM, Gromyko OM, Kryugel G. Genetic control of antitumor antibiotic polyketide biosynthesis by actinomycetes. Bull Inst S-Kh Mikrobiol. 2000; (8):27-31.