聚酮合酶数据库初步构建及多烯类聚酮合酶系统发育分析
|
摘要
本文初步构建了聚酮类抗生素生物合成基因簇数据库,相比已有的两个聚酮合酶数据库,内容方面重点增加了聚酮合酶后修饰酶(主要包括糖基转移酶,糖基合成酶,甲基转移酶等)部分;功能方面,新建的数据库将具有更强的实用性,尤其是给系统发育分析研究带来了更多的方便,可以轻松的实现多序列下载、比对功能,还可以查阅相关的参考文献等,为组合生物合成新的聚酮类抗生素提供了一个良好的平台。
多烯大环内酯类抗生素是一类重要的抗真菌药物,具有相似的化学结构,生物合成基因簇也有很近的亲缘关系,因此本文选择多烯大环内酯类聚酮合酶作为研究对象,分别采用贝叶斯法、邻接法以及最大简约法三种建树方法,重点对酮基合成酶(ketosynthase, KS),酰基转移酶(acyltransferase, AT),酮基还原酶(ketoreductase,KR),脱水酶(dehydratase, DH)等结构域进行了系统发育分析。结果显示多烯大环内酯类抗生素不同结构部分对应的聚酮合酶具有不同的进化方式,而且有趣的是进化方式与该部分结构的功能以及化学结构的保守性相关。一方面,对抗生素活性以及选择性毒性有重要影响的化学结构部分,具有功能方面的保守性;对应的聚酮合酶来自一共同的祖先,具有序列上的保守性;这部分化学结构主要包括糖基化位点、羧基化位点以及半酮缩醇部分,具有结构方面的保守性。另一方面,多烯部分对应的聚酮合酶的主要进化方式为基因内部复制,复制数量的不同导致生成不同种类的,具有不同抗真菌活性的多烯大环内酯类抗生素。除此之外,我们也对多烯类抗生素存在多种结构类似物的原因进行了分析。
We have preliminarily constructed a new database for the polyketide antibiotic biosynthetic gene clusters. Compared with the existing two polyketide synthase databases, the new one mainly supplemented post polyketide synthase enzymes (including glycosyl transferase, glycosyl synthase, methyl transferase, etc) in the content aspect. As for the function of the new database, it will be more practical, especially for the phylogenetic analysis, it will provide more convenience, including downloading many sequences at the same time, multisequence alignment and corresponding reference index, etc. The new database will provide a good platform for combinatorial biosynthsis of new polyketide antibiotics
Polyene macrolide antibiotics are one group of important antifungal drugs, which have similar chemical structures and close evolutionary relationships of biosynthetic gene clusters, so we chose polyene macrolide polyketide synthase as reseach object and used Bayesian inference, Neighbor-joining and Maximum Parsimony method respectively to reconstruct the phylogenetic trees of domains KS, AT, KR, DH . The results indicated that polyketide synthases corresponding with different structural parts of polyene macrolide molecules have different modes of evolution. What’s more interesting is that the mode of polyketide synthase evolution is relevant to the conservativeness of the corresponding chemical structure and function. On the one hand, the chemical structures which are essential to the activity and selective toxicity are functional conservative; and the corresponding polyketide synthases whose sequences are conservative come from a common ancestor; the related chemical structures include glycosylated site, carboxylated site and hemiketal ring which are structurally coservative. On the other hand, the polyene region corresponding polyketide synthases evolved by intra-gene duplication, and the different number of duplications will lead to different kinds of polyene macrolide antibiotics which have different anfungal activities.Besides these, we also analyzed the reseaon why polyene macrolide antibiotics had so many structural analogs.
多烯大环内酯类抗生素是一类重要的抗真菌药物,具有相似的化学结构,生物合成基因簇也有很近的亲缘关系,因此本文选择多烯大环内酯类聚酮合酶作为研究对象,分别采用贝叶斯法、邻接法以及最大简约法三种建树方法,重点对酮基合成酶(ketosynthase, KS),酰基转移酶(acyltransferase, AT),酮基还原酶(ketoreductase,KR),脱水酶(dehydratase, DH)等结构域进行了系统发育分析。结果显示多烯大环内酯类抗生素不同结构部分对应的聚酮合酶具有不同的进化方式,而且有趣的是进化方式与该部分结构的功能以及化学结构的保守性相关。一方面,对抗生素活性以及选择性毒性有重要影响的化学结构部分,具有功能方面的保守性;对应的聚酮合酶来自一共同的祖先,具有序列上的保守性;这部分化学结构主要包括糖基化位点、羧基化位点以及半酮缩醇部分,具有结构方面的保守性。另一方面,多烯部分对应的聚酮合酶的主要进化方式为基因内部复制,复制数量的不同导致生成不同种类的,具有不同抗真菌活性的多烯大环内酯类抗生素。除此之外,我们也对多烯类抗生素存在多种结构类似物的原因进行了分析。
We have preliminarily constructed a new database for the polyketide antibiotic biosynthetic gene clusters. Compared with the existing two polyketide synthase databases, the new one mainly supplemented post polyketide synthase enzymes (including glycosyl transferase, glycosyl synthase, methyl transferase, etc) in the content aspect. As for the function of the new database, it will be more practical, especially for the phylogenetic analysis, it will provide more convenience, including downloading many sequences at the same time, multisequence alignment and corresponding reference index, etc. The new database will provide a good platform for combinatorial biosynthsis of new polyketide antibiotics
Polyene macrolide antibiotics are one group of important antifungal drugs, which have similar chemical structures and close evolutionary relationships of biosynthetic gene clusters, so we chose polyene macrolide polyketide synthase as reseach object and used Bayesian inference, Neighbor-joining and Maximum Parsimony method respectively to reconstruct the phylogenetic trees of domains KS, AT, KR, DH . The results indicated that polyketide synthases corresponding with different structural parts of polyene macrolide molecules have different modes of evolution. What’s more interesting is that the mode of polyketide synthase evolution is relevant to the conservativeness of the corresponding chemical structure and function. On the one hand, the chemical structures which are essential to the activity and selective toxicity are functional conservative; and the corresponding polyketide synthases whose sequences are conservative come from a common ancestor; the related chemical structures include glycosylated site, carboxylated site and hemiketal ring which are structurally coservative. On the other hand, the polyene region corresponding polyketide synthases evolved by intra-gene duplication, and the different number of duplications will lead to different kinds of polyene macrolide antibiotics which have different anfungal activities.Besides these, we also analyzed the reseaon why polyene macrolide antibiotics had so many structural analogs.
引文
[1] Omura S, Tanaka H. Production, structure, and antifungal activity of polyene macrolides. In: Omura S (ed) Macrolide antibiotics: chemistry, biology, and practice. Academic, 1984, 351–405
[2] Pontani DR, Sun D, Brown JW, et al.Inhibition of HIV replication by liposomal encapsulated amphotericin B. Antiviral Res., 1989, 11(3): 119-125
[3] Konopka K, Guo LS, Düzgünes N. Anti-HIV activity of amphotericin B-cholesteryl sulfate colloidal dispersion in vitro. Antiviral Res., 1999, 42(3): 197-209
[4] Waheed AA, Ablan SD, Mankowski MK et al. Inhibition of HIV-1 replication by amphotericin B methyester. J of biochem., 2006, 281(39): 28699-28711
[5] Cohen BE, Benaim G, Ruiz MC, et al. Increased calcium permeability is not responsible for the rapid lethal effects of amphotericin B on Leishmania sp. FEBS Lett., 1990, 259(2): 286-288
[6] Ali SA, Iqbal J, Nabeel, et al. Leishmanicidal activity of Nystatin (mycostatin): a potent polyene compound. Pak. Med. Assoc., 1997, 47: 246-248
[7] Valeriote F, Medoff G, Dieckman J. Potentiation of cytotoxicity of anticancer agents by several different polyene antibiotics. J Natl Cancer Inst, 1984, 72(2): 435-439
[8] Volpon L, Lancelin JM. Solution NMR structure of five representative glycosylated polyene macrolide antibiotics with a sterol-dependent antifungal activity. Eur. J. Biochem., 2002, 269: 4533–4454
[9] HAMILTON-MILLER J.M.T. Chemistry and biology of the polyene macrolide antibiotics. Bacteriol Rev., 1973, 37(3): 166-196
[10] Katz L. Manipulation of modular polyketide synthases. Chem Rev., 1997, 97(7): 2557- 2576
[11] Fjaervik E, Zotchev SB. Biosynthesis of the polyene macrolide antibiotic nystatin in Streptomyces noursei. Appl Microbiol Biotechnol., 2005, 67(4): 436-443
[12] de Kruijff B, Demel RA. Polyene antibiotic-sterol interactions in membranes of Acholeplasma laidlawii cells and lecithin liposomes. 3. Molecular structure of the polyene antibiotic-cholesterol complexes. Biochim Biophys Acta., 1974, 339(1): 57-70
[13] Teerlink T, de Kruijff B, Demel RA. The action of pimaricin, etruscomycin and amphotericin B on liposomes with varying sterol content. Biochim Biophys Acta.,1980, 599(2): 484-492
[14] Milhaud J. Permeabilizing action of filipin III on model membranes through a filipin-phospholipid binding. Biochim Biophys Acta., 1992, 1105(2): 307-318
[15] Baginski M, Resat H, McCammon JA. Molecular properties of amphotericin B membrane channel: a molecular dynamics simulation. Mol Pharmacol., 1997, 52(4): 560-570
[16] Zotchev SB. Polyene macrolide antibiotics and their applications in human therapy. Curr Med Chem., 2003, 10(3): 211-223
[17] Aszalos A, Bax A, Burlinson N, et al. Physico-chemical and microbiological comparison of nystatin, amphotericin A and amphotericin B, and structure of amphotericin A. J Antibiot ., 1985, 38(12): 1699-1713
[18] Kasumov KM, Borisova MP, Ermishkin LN, et al. How do ionic channel properties depend on the structure of polyene antibiotic molecules? Biochim Biophys Acta., 1979, 551(2): 229-237
[19] Cybulska B, Ziminski T, Borowski E, et al. The influence of electric charge of aromatic heptaene macrolide antibiotics on their activity on biological and lipidic model membranes. Mol Pharmacol., 1983, 24(2): 270-276
[20] Taylor AW, Costello BJ, Hunter PA, et al. Synthesis and antifungal selectivity of new derivatives of amphotericin B modified at the C-13 position. J Antibiot., 1993, 46(3): 486-493
[21] Bolard J, Legrand P, Heitz F, et al. One-sided action of amphotericin B on cholesterol-containing membranes is determined by its self-association in the medium. Biochemistry., 1991, 30(23): 5707-5715
[22] Barwicz J, Tancrède P. The effect of aggregation state of amphotericin-B on its interactions with cholesterol- or ergosterol-containing phosphatidylcholine monolayers. Chem Phys Lipids., 1997, 85(2):145-155
[23]刘志恒,姜成林主编,放线菌现代生物学与生物技术,科学出版社,2004
[24] Kira JW, Peter FL. Combinatorial biosynthesis of reduced polyketides. Nat Microbiol, 2005, 3: 925-936
[25]张致平主编,微生物药物学,化学工业出版社,2003
[26] Donadio S, Staver MJ, McAlpine JB, et al. Modular organization of genes required for complex polyketide biosynthesis. Science, 1991, 252: 675-679
[27] Bentley SD, Chater KF, Cerdeno-Tarraga AM, et al. Complete genome sequence of the model actinomycete Streptomyces coelicolor A3 (2). Nature, 2002, 417: 141-147
[28] Ikeda H, Ishikawa J, Hanamoto A, et al. Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis. Nat Biotechnol, 2003, 21(5): 526-531
[29] McDaniel R, Welch M, Hutchinson CR. Genetic approaches to polyketide antibiotics. Chem. Rev, 2005, 105: 543–558
[30] Chandran SS, Menzella HG, Carney JR, et al. Activating hybrid modular interfaces in synthetic polyketide synthases by cassette replacement of ketosynthase domains. Chem. Biol, 2006, 13: 469–474
[31] Murli S, Piagentini M, McDaniel R, et al. Identification of domains within megalomicin and erythromycin polyketide synthase modules responsible for differences in polyketide production levels in Escherichia coli. Biochemistry. 2004, 43(50): 15884-15890
[32] Desai RP, Leaf T, Hu Z, et al. Combining classical, genetic, and process strategies for improved precursor-directed production of 6-deoxyerythronolide B analogues. Biotechnol Prog, 2004, 20 (1): 38-43
[33] Denoya CD, Fedechko RW, Hafner EW, et al. A second branched-chain alpha-keto acid dehydrogenase gene cluster (bkdFGH) from Streptomyces avermitilis: its relationship to avermectin biosynthesis and the construction of a bkdF mutant suitable for the production of novel antiparasitic avermectins. J Bacteriol, 1995, 177(12): 3504-3511
[34] Yadav G, Gokhale RS, Mohanty D.SEARCHPKS: a program for detection and analysis of polyketide synthase domains. Nucleic Acids Res., 2003, 31(13): 3654-3658
[35] Tae H, Kong EB, Park K. ASMPKS: an analysis system for modular polyketide synthases. BMC Bioinformatics, 2007, 8: 327
[36]常青,周开亚。分子进化研究中系统发育树的重建。生物多样性,1998,6(1):55-62
[37] Saitou N, Nei M. The neighbor2joining method : A new method for reconstruction phylogenetic trees. Mol . Biol .Evol., 1987, 4: 406-425
[38] Nei M, Kumar S.分子进化与系统发育。北京:高等教育出版社,2002, 155-157
[39] Swofford D L ,Olsen GJ . Phylogeny reconstruction. In : Hillis D M , C Moritz (eds. ) , Molecular Systematics ,Sunderland : Sinauer Associates Inc., 1990, 411-501
[40] Swofford DL ,Olsen GJ ,Waddell PJ, et al. Phylogeny inference. In : Hillis D M , C Moritz , B K Mabel (eds. ), Molecular Systematics (Second edition). Sunderland : Sinauer Associates Inc., 1996, 407-510
[41] Ronquist F, Huelsenbeck JP. MrBayes 3: Bayesian phylogenetic inference under mixed models. Bioinformatics., 2003, 19(12): 1572-1574
[42] Tamura K, Dudley J, Nei M, Kumar S. MEGA4: Molecular evolutionary genetics analysis (MEGA) software version 4.0. Mol Biol Evol., 2007, 24(8): 1596-1569
[43] Caffrey P, Lynch S, Flood E, et al. Amphotericin biosynthesis in streptomyces nodosus:deductions from analysis of polyketide synthase and late genes. Chem Biol, 2001, 8(7): 712-723
[44] Sun Y, Zhou X, Dong H, et al. A complete gene cluster from Streptomyces nanchangensis NS3226 encoding biosynthesis of the polyether ionophore nanchangmycin. Chem Biol., 2003, 10(5): 431-441
[45] Brikun IA, Reeves AR, Cernota WH, et al. The erythromycin biosynthetic gene cluster of Aeromicrobium erythreum. J Ind Microbiol Biotechnol. 2004, 31(7): 335-344
[46] Rascher A, Hu Z, Buchanan GO, et al. Insights into the biosynthesis of the benzoquinone ansamycins geldanamycin and herbimycin, obtained by gene sequencing and disruption. Appl Environ Microbiol., 2005, 71(8): 4862-4871
[47] Gokhale RS, Khosla C. Role of linkers in communication between protein modules. Curr Opin Chem Biol, 2000, 4: 22-27
[48] Alekseyev VY, Liu CW, Cane DE, et al. Solution structure and proposed domain domain recognition interface of an acyl carrier protein domain from a modular polyketide synthase. Protein Sci., 2007, 16: 2093-2107
[49] Tang Y, Kim CY, Mathews II, et al. The 2.7-Angstrom crystal structure of a 194-kDa homodimeric fragment of the 6-deoxyerythronolide B synthase. Proc Natl Acad Sci, 2006, 103: 11124-11129
[50] Keatinge-Clay AT, Stroud RM. The structure of a ketoreductase determines the organization of the beta-carbon processing enzymes of modular polyketide synthases. Structure, 2006, 14: 737-748
[51] Tang Y, Chen AY, Kim CY, et al. Structural and mechanistic analysis of protein interactions in module 3 of the 6-deoxyerythronolide B synthase. Chemistry & Biology, 2007, 14: 931–943
[52] Liang D, Qiao J. Phylogenetic analysis of antibiotic glycosyltransferases. J Mol Evol., 2007, 64(3): 342-353
[53] Aparicio JF, Mendes MV, Antón N, et al. Polyene macrolide antibiotics biosynthesis. Curr Med Chem., 2004, 11(12): 1645-1656
[54] Campelo AB, Gil JA. The candicidin gene cluster from Streptomyces griseus IMRU 3570. Microbiology , 2002, 148: 51-59
[55] Omura S, Ikeda H, Ishikawa J, et al. Genome sequence of an industrial microorganism Streptomyces avermitilis: deducing the ability of producing secondary metabolites. Proc Natl Acad Sci., 2001, 98(21): 12215-12220
[56] Schwecke T, Aparicio JF, Molnár I, et al. The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin. Proc Natl Acad Sci., 1995, 92(17): 7839-7843
[57] Kodama JH, Borner T, Dittmann E. Natural biocombinatorics in the polyketide synthase genes of the actinobacterium streptomyces avermitilis. PLos Comput Biol, 2006, 2(10): e132
[58] Brautaset T, Sekurova ON, Sletta H, et al. 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
[59] Chen S, Huang X, Zhou X, et al. Organizational and mutational analysis of a complete FR-008/candicidin gene cluster encoding a structurally related polyene complex. Chem Biol., 2003, 10(11): 1065-1076
[60] Aparicio JF, Colina AJ, Ceballos E, et al. The biosynthetic gene cluster for the 26-membered ring polyene macrolide pimaricin. A new polyketide synthase organization encoded by two subclusters separated by functionalization genes. J Biol Chem., 1999, 274(15): 10133-10139
[61] Aparicio JF, Fouces R, Mendes MV, et al. A complex multienzyme system encoded by five polyketide synthase genes is involved in the biosynthesis of the 26-membered polyene macrolide pimaricin in Streptomyces natalensis. Chem Biol., 2000, 7(11): 895-905
[62] Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res., 1994, 22(22): 4673-4680
[63] Jones DT, Taylor WR, Thornton JM. The rapid generation of mutation data matrices from protein sequences. Comput Appl Biosci, 1992, 8(3): 275–282
[64] Page RD. TreeView: an application to display phylogenetic trees on personal computers.Comput Appl Biosci., 1996, 12(4): 357-358
[65] Jenke-Kodama H, Sandmann A, Müller R, et al. Evolutionary implications of bacterial polyketide synthases. Mol Biol Evol., 2005, 22(10): 2027-2039
[66] Caffrey P. Conserved Amino Acid Residues Correlating With Ketoreductase Stereospecificity in Modular Polyketide Synthases. ChemBioChem., 2003, 4: 649– 662
[67] Reid R, Piagentini M, Rodriguez E, et al. A model of structure and catalysis for ketoreductase domains in modular polyketide synthases. Biochemistry, 2003, 42, 72-79
[68] Aparicio JF, Caffrey P, Gil JA, et al. Polyene antibiotic biosynthesis gene clusters. Appl Microbiol Biotechnol., 2003, 61: 179–188
[69] Ginolhac A, Jarrin C, Robe P, et al. Type I polyketide synthases may have evolved through horizontal gene transfer. J Mol Evol. 2005, 60(6): 716-725
[70] Seco EM, Pérez-Zú?iga FJ, Rolón MS, et al. Starter unit choice determines the production of two tetraene macrolides, rimocidin and CE-108, in Streptomyces diastaticus var. 108. Chem Biol. 2004, 11(3): 357-366
[71] Ryu G, Choi WC, Hwang S, et al. Tetrin C, a new glycosylated polyene macrolide antibiotic produced by Streptomyces sp. GK9244. J Nat Prod., 1999, 62(6): 917-919
[72] Paquet V, Carreira EM. Significant improvement of antifungal activity of polyene macrolides by bisalkylation of the mycosamine. Org Lett., 2006, 8(9): 1807- 1809
[73] Carmody M, Murphy B, Byrne B, et al. Biosynthesis of amphotericin derivatives lacking exocyclic carboxyl groups. J Biol Chem., 2005, 280(41): 34420-34426
[74] Borgos SE, Tsan P, Sletta H, et al. Probing the structure-function relationship of polyene macrolides:engineered biosynthesis of soluble nystatin analogues. J Med Chem., 2006, 49(8): 2431-2439
[75] Gregory TR. The evolution of the genome. Peking: Science Press., 2007, 306-314
[2] Pontani DR, Sun D, Brown JW, et al.Inhibition of HIV replication by liposomal encapsulated amphotericin B. Antiviral Res., 1989, 11(3): 119-125
[3] Konopka K, Guo LS, Düzgünes N. Anti-HIV activity of amphotericin B-cholesteryl sulfate colloidal dispersion in vitro. Antiviral Res., 1999, 42(3): 197-209
[4] Waheed AA, Ablan SD, Mankowski MK et al. Inhibition of HIV-1 replication by amphotericin B methyester. J of biochem., 2006, 281(39): 28699-28711
[5] Cohen BE, Benaim G, Ruiz MC, et al. Increased calcium permeability is not responsible for the rapid lethal effects of amphotericin B on Leishmania sp. FEBS Lett., 1990, 259(2): 286-288
[6] Ali SA, Iqbal J, Nabeel, et al. Leishmanicidal activity of Nystatin (mycostatin): a potent polyene compound. Pak. Med. Assoc., 1997, 47: 246-248
[7] Valeriote F, Medoff G, Dieckman J. Potentiation of cytotoxicity of anticancer agents by several different polyene antibiotics. J Natl Cancer Inst, 1984, 72(2): 435-439
[8] Volpon L, Lancelin JM. Solution NMR structure of five representative glycosylated polyene macrolide antibiotics with a sterol-dependent antifungal activity. Eur. J. Biochem., 2002, 269: 4533–4454
[9] HAMILTON-MILLER J.M.T. Chemistry and biology of the polyene macrolide antibiotics. Bacteriol Rev., 1973, 37(3): 166-196
[10] Katz L. Manipulation of modular polyketide synthases. Chem Rev., 1997, 97(7): 2557- 2576
[11] Fjaervik E, Zotchev SB. Biosynthesis of the polyene macrolide antibiotic nystatin in Streptomyces noursei. Appl Microbiol Biotechnol., 2005, 67(4): 436-443
[12] de Kruijff B, Demel RA. Polyene antibiotic-sterol interactions in membranes of Acholeplasma laidlawii cells and lecithin liposomes. 3. Molecular structure of the polyene antibiotic-cholesterol complexes. Biochim Biophys Acta., 1974, 339(1): 57-70
[13] Teerlink T, de Kruijff B, Demel RA. The action of pimaricin, etruscomycin and amphotericin B on liposomes with varying sterol content. Biochim Biophys Acta.,1980, 599(2): 484-492
[14] Milhaud J. Permeabilizing action of filipin III on model membranes through a filipin-phospholipid binding. Biochim Biophys Acta., 1992, 1105(2): 307-318
[15] Baginski M, Resat H, McCammon JA. Molecular properties of amphotericin B membrane channel: a molecular dynamics simulation. Mol Pharmacol., 1997, 52(4): 560-570
[16] Zotchev SB. Polyene macrolide antibiotics and their applications in human therapy. Curr Med Chem., 2003, 10(3): 211-223
[17] Aszalos A, Bax A, Burlinson N, et al. Physico-chemical and microbiological comparison of nystatin, amphotericin A and amphotericin B, and structure of amphotericin A. J Antibiot ., 1985, 38(12): 1699-1713
[18] Kasumov KM, Borisova MP, Ermishkin LN, et al. How do ionic channel properties depend on the structure of polyene antibiotic molecules? Biochim Biophys Acta., 1979, 551(2): 229-237
[19] Cybulska B, Ziminski T, Borowski E, et al. The influence of electric charge of aromatic heptaene macrolide antibiotics on their activity on biological and lipidic model membranes. Mol Pharmacol., 1983, 24(2): 270-276
[20] Taylor AW, Costello BJ, Hunter PA, et al. Synthesis and antifungal selectivity of new derivatives of amphotericin B modified at the C-13 position. J Antibiot., 1993, 46(3): 486-493
[21] Bolard J, Legrand P, Heitz F, et al. One-sided action of amphotericin B on cholesterol-containing membranes is determined by its self-association in the medium. Biochemistry., 1991, 30(23): 5707-5715
[22] Barwicz J, Tancrède P. The effect of aggregation state of amphotericin-B on its interactions with cholesterol- or ergosterol-containing phosphatidylcholine monolayers. Chem Phys Lipids., 1997, 85(2):145-155
[23]刘志恒,姜成林主编,放线菌现代生物学与生物技术,科学出版社,2004
[24] Kira JW, Peter FL. Combinatorial biosynthesis of reduced polyketides. Nat Microbiol, 2005, 3: 925-936
[25]张致平主编,微生物药物学,化学工业出版社,2003
[26] Donadio S, Staver MJ, McAlpine JB, et al. Modular organization of genes required for complex polyketide biosynthesis. Science, 1991, 252: 675-679
[27] Bentley SD, Chater KF, Cerdeno-Tarraga AM, et al. Complete genome sequence of the model actinomycete Streptomyces coelicolor A3 (2). Nature, 2002, 417: 141-147
[28] Ikeda H, Ishikawa J, Hanamoto A, et al. Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis. Nat Biotechnol, 2003, 21(5): 526-531
[29] McDaniel R, Welch M, Hutchinson CR. Genetic approaches to polyketide antibiotics. Chem. Rev, 2005, 105: 543–558
[30] Chandran SS, Menzella HG, Carney JR, et al. Activating hybrid modular interfaces in synthetic polyketide synthases by cassette replacement of ketosynthase domains. Chem. Biol, 2006, 13: 469–474
[31] Murli S, Piagentini M, McDaniel R, et al. Identification of domains within megalomicin and erythromycin polyketide synthase modules responsible for differences in polyketide production levels in Escherichia coli. Biochemistry. 2004, 43(50): 15884-15890
[32] Desai RP, Leaf T, Hu Z, et al. Combining classical, genetic, and process strategies for improved precursor-directed production of 6-deoxyerythronolide B analogues. Biotechnol Prog, 2004, 20 (1): 38-43
[33] Denoya CD, Fedechko RW, Hafner EW, et al. A second branched-chain alpha-keto acid dehydrogenase gene cluster (bkdFGH) from Streptomyces avermitilis: its relationship to avermectin biosynthesis and the construction of a bkdF mutant suitable for the production of novel antiparasitic avermectins. J Bacteriol, 1995, 177(12): 3504-3511
[34] Yadav G, Gokhale RS, Mohanty D.SEARCHPKS: a program for detection and analysis of polyketide synthase domains. Nucleic Acids Res., 2003, 31(13): 3654-3658
[35] Tae H, Kong EB, Park K. ASMPKS: an analysis system for modular polyketide synthases. BMC Bioinformatics, 2007, 8: 327
[36]常青,周开亚。分子进化研究中系统发育树的重建。生物多样性,1998,6(1):55-62
[37] Saitou N, Nei M. The neighbor2joining method : A new method for reconstruction phylogenetic trees. Mol . Biol .Evol., 1987, 4: 406-425
[38] Nei M, Kumar S.分子进化与系统发育。北京:高等教育出版社,2002, 155-157
[39] Swofford D L ,Olsen GJ . Phylogeny reconstruction. In : Hillis D M , C Moritz (eds. ) , Molecular Systematics ,Sunderland : Sinauer Associates Inc., 1990, 411-501
[40] Swofford DL ,Olsen GJ ,Waddell PJ, et al. Phylogeny inference. In : Hillis D M , C Moritz , B K Mabel (eds. ), Molecular Systematics (Second edition). Sunderland : Sinauer Associates Inc., 1996, 407-510
[41] Ronquist F, Huelsenbeck JP. MrBayes 3: Bayesian phylogenetic inference under mixed models. Bioinformatics., 2003, 19(12): 1572-1574
[42] Tamura K, Dudley J, Nei M, Kumar S. MEGA4: Molecular evolutionary genetics analysis (MEGA) software version 4.0. Mol Biol Evol., 2007, 24(8): 1596-1569
[43] Caffrey P, Lynch S, Flood E, et al. Amphotericin biosynthesis in streptomyces nodosus:deductions from analysis of polyketide synthase and late genes. Chem Biol, 2001, 8(7): 712-723
[44] Sun Y, Zhou X, Dong H, et al. A complete gene cluster from Streptomyces nanchangensis NS3226 encoding biosynthesis of the polyether ionophore nanchangmycin. Chem Biol., 2003, 10(5): 431-441
[45] Brikun IA, Reeves AR, Cernota WH, et al. The erythromycin biosynthetic gene cluster of Aeromicrobium erythreum. J Ind Microbiol Biotechnol. 2004, 31(7): 335-344
[46] Rascher A, Hu Z, Buchanan GO, et al. Insights into the biosynthesis of the benzoquinone ansamycins geldanamycin and herbimycin, obtained by gene sequencing and disruption. Appl Environ Microbiol., 2005, 71(8): 4862-4871
[47] Gokhale RS, Khosla C. Role of linkers in communication between protein modules. Curr Opin Chem Biol, 2000, 4: 22-27
[48] Alekseyev VY, Liu CW, Cane DE, et al. Solution structure and proposed domain domain recognition interface of an acyl carrier protein domain from a modular polyketide synthase. Protein Sci., 2007, 16: 2093-2107
[49] Tang Y, Kim CY, Mathews II, et al. The 2.7-Angstrom crystal structure of a 194-kDa homodimeric fragment of the 6-deoxyerythronolide B synthase. Proc Natl Acad Sci, 2006, 103: 11124-11129
[50] Keatinge-Clay AT, Stroud RM. The structure of a ketoreductase determines the organization of the beta-carbon processing enzymes of modular polyketide synthases. Structure, 2006, 14: 737-748
[51] Tang Y, Chen AY, Kim CY, et al. Structural and mechanistic analysis of protein interactions in module 3 of the 6-deoxyerythronolide B synthase. Chemistry & Biology, 2007, 14: 931–943
[52] Liang D, Qiao J. Phylogenetic analysis of antibiotic glycosyltransferases. J Mol Evol., 2007, 64(3): 342-353
[53] Aparicio JF, Mendes MV, Antón N, et al. Polyene macrolide antibiotics biosynthesis. Curr Med Chem., 2004, 11(12): 1645-1656
[54] Campelo AB, Gil JA. The candicidin gene cluster from Streptomyces griseus IMRU 3570. Microbiology , 2002, 148: 51-59
[55] Omura S, Ikeda H, Ishikawa J, et al. Genome sequence of an industrial microorganism Streptomyces avermitilis: deducing the ability of producing secondary metabolites. Proc Natl Acad Sci., 2001, 98(21): 12215-12220
[56] Schwecke T, Aparicio JF, Molnár I, et al. The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin. Proc Natl Acad Sci., 1995, 92(17): 7839-7843
[57] Kodama JH, Borner T, Dittmann E. Natural biocombinatorics in the polyketide synthase genes of the actinobacterium streptomyces avermitilis. PLos Comput Biol, 2006, 2(10): e132
[58] Brautaset T, Sekurova ON, Sletta H, et al. 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
[59] Chen S, Huang X, Zhou X, et al. Organizational and mutational analysis of a complete FR-008/candicidin gene cluster encoding a structurally related polyene complex. Chem Biol., 2003, 10(11): 1065-1076
[60] Aparicio JF, Colina AJ, Ceballos E, et al. The biosynthetic gene cluster for the 26-membered ring polyene macrolide pimaricin. A new polyketide synthase organization encoded by two subclusters separated by functionalization genes. J Biol Chem., 1999, 274(15): 10133-10139
[61] Aparicio JF, Fouces R, Mendes MV, et al. A complex multienzyme system encoded by five polyketide synthase genes is involved in the biosynthesis of the 26-membered polyene macrolide pimaricin in Streptomyces natalensis. Chem Biol., 2000, 7(11): 895-905
[62] Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res., 1994, 22(22): 4673-4680
[63] Jones DT, Taylor WR, Thornton JM. The rapid generation of mutation data matrices from protein sequences. Comput Appl Biosci, 1992, 8(3): 275–282
[64] Page RD. TreeView: an application to display phylogenetic trees on personal computers.Comput Appl Biosci., 1996, 12(4): 357-358
[65] Jenke-Kodama H, Sandmann A, Müller R, et al. Evolutionary implications of bacterial polyketide synthases. Mol Biol Evol., 2005, 22(10): 2027-2039
[66] Caffrey P. Conserved Amino Acid Residues Correlating With Ketoreductase Stereospecificity in Modular Polyketide Synthases. ChemBioChem., 2003, 4: 649– 662
[67] Reid R, Piagentini M, Rodriguez E, et al. A model of structure and catalysis for ketoreductase domains in modular polyketide synthases. Biochemistry, 2003, 42, 72-79
[68] Aparicio JF, Caffrey P, Gil JA, et al. Polyene antibiotic biosynthesis gene clusters. Appl Microbiol Biotechnol., 2003, 61: 179–188
[69] Ginolhac A, Jarrin C, Robe P, et al. Type I polyketide synthases may have evolved through horizontal gene transfer. J Mol Evol. 2005, 60(6): 716-725
[70] Seco EM, Pérez-Zú?iga FJ, Rolón MS, et al. Starter unit choice determines the production of two tetraene macrolides, rimocidin and CE-108, in Streptomyces diastaticus var. 108. Chem Biol. 2004, 11(3): 357-366
[71] Ryu G, Choi WC, Hwang S, et al. Tetrin C, a new glycosylated polyene macrolide antibiotic produced by Streptomyces sp. GK9244. J Nat Prod., 1999, 62(6): 917-919
[72] Paquet V, Carreira EM. Significant improvement of antifungal activity of polyene macrolides by bisalkylation of the mycosamine. Org Lett., 2006, 8(9): 1807- 1809
[73] Carmody M, Murphy B, Byrne B, et al. Biosynthesis of amphotericin derivatives lacking exocyclic carboxyl groups. J Biol Chem., 2005, 280(41): 34420-34426
[74] Borgos SE, Tsan P, Sletta H, et al. Probing the structure-function relationship of polyene macrolides:engineered biosynthesis of soluble nystatin analogues. J Med Chem., 2006, 49(8): 2431-2439
[75] Gregory TR. The evolution of the genome. Peking: Science Press., 2007, 306-314