吸水链霉菌17997中格尔德霉素生物合成基因簇的研究
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摘要
吸水链霉菌17997(Streptomyces hygroscopicus 17997)是我所从中国土壤中分离得到的格尔德霉素(geldanamycin，GDM)产生菌。GDM属于苯安莎类抗生素。最先发现GDM具有抗原虫和抗肿瘤作用，最近我所的研究发现GDM还具有良好的抗病毒活性。国外的研究表明GDM的这些生物学活性是因为它能特异性地抑制热休克蛋白90的ATP／ADP结构域，下调多种Hsp90的靶蛋白功能所致，包括酪氨酸激酶、类固醇激素受体和转录因子等。GDM作为Hsp90的特异性抑制剂，成为在抗癌和抗病毒领域中非常有潜力的药物。但因为GDM肝毒性比较大，水溶性不好，所以寻找其低毒可溶性好的衍生物成为当今研究的主要目标。GDM的一种衍生物17—烯丙氨基—17—脱甲氧基GDM(17-AAG)正在美国进行Ⅱ期临床实验。
已知安莎类抗生素的生物合成是以3—氨基—5—羟基苯甲酸(AHBA)为起始单位，由Ⅰ型聚酮合酶(PKS)催化顺序加上乙二酸，丙二酸或者甲氧基丙二酸等延伸单位，在酰胺合酶参与下形成聚酮体骨架，然后再进行后续的加工(post PKS modification)。在对GDM生物合成基因簇的研究中，本实验室在S．hygroscopicus 17997中曾发现了苯醌型和萘醌型两种AHBA生物合成基因和与之连锁的两个PKS基因簇，但其中未包括GDM的后修饰基因。本研究根据GDM的后修饰基因—氨甲酰基转移酶基因(gdmN)的保守序列设计PCR引物，在S．hygroscopicus 17997基因组中扩增出了732bp的基因片段，通过测序和同源比较，证实该基因片段与S．hygroscopicus NRRL 3602的gdmN有94％的同源性。利用该基因片段的引物，进行菌落PCR筛选S．hygroscopicus 17997的基因组文库，获得了6个阳性克隆，并利用732bp的PCR产物作为探针对阳性克隆进行Southern blot验证和定位。选择CT-4阳性柯斯质粒进行亚克隆测序，将测得的28.356kb DNA序列进行BLAST和ORF分析，证实与公布的S．hygroscopicus NRRL3602 GDM生物合成基因的部分序列基本一致。CT-4柯斯质粒克隆中外源序列可能包括12个基因：与gdmA3基因同源的PKS基因、酰胺合酶基因(gdmF)、单加氧酶基因(gdmM)、氨甲酰基转移酶基因(gdmN)、与甲氧基丙二酰—酰基携带蛋白合成相关的5个基因(gdmH、I、J、K和G)、LuxR家族的转录调节基因(gdmRⅡ)、氨基
Geldanamycin (GDM), produced by the Streptomyces hygroscopicus 17997 which was isolated from China soil by our institute reseacher. GDM, belonging to the benzenenoid ansamycin, possess antitumor and antiprotozoon activity and recently, was discovered that it shows antivirus bioactivity. Extensive research have vertified that GDM can bind specifically to the ATP/ADP domain of heat shock protein 90 (Hsp90), thus down-regulate target proteins including tyrosine kinases, steroid receptors, transcription factors et al. As a specific inhibitor of Hsp90, GDM became a potential promising antitumor and antivirus medicine. To overcome the hypatotoxicity and poor solubility of GDM, the main research work was focused on finding its less toxic and more soluble derivatives. One of its derivatives, 17-AAG, is now in clinical trial (phase II) in United States. It was known that the biosynthesis of ansamycins involves the assembly 3-amino-5-hydroxybenzoic acid (AHBA) as starter unit, followed by the sequential addition of extender units such as acetate, malonate, and methoxymalonate to form a polyketide backbone catalyzed by type I polyketide synthsase (PKS), which then undergoes further downstream processing.
During studies on the geldanamycin biosynthetic genes from Streptomyces hygroscopicus 17997, two possible separate AHBA biosynthetic gene clusters and two sets of PKS genes were found in our lab. But the involvement of these genes in the GDM biosynthesis was not identified, and the post-PKS modification genes were absent yet. In this study conserved sequences of one of possible post-PKS modification gene, the carbamoyltransferase gene (gdmN) in GDM biosynthesis were used to design the primers, by which a 732bp gene fragment was amplified from the Streptomyces hygroscopicus 17997 genome DNA. This gene fragment was sequenced and found it has identity of 94% with the gdmN of Streptomyces hygroscopicus NRRL 3602. Through the colony-PCR by the primers screening, six positive cosmid clones were identified from the Streptomyces hygroscopicus 17997 genomic library. The CT-4 cosmid was sub-cloned and sequenced. The 28.356kb foreign gene sequence of the CT-4 cosmid shows high identity with the known GDM biosynthesis gene cluster of Streptomyces hygroscopicus NRRL 3602 based on BLAST analysis. 12 possible ORFs were identified from the CT-4 cosmid including PKS gene
已知安莎类抗生素的生物合成是以3—氨基—5—羟基苯甲酸(AHBA)为起始单位，由Ⅰ型聚酮合酶(PKS)催化顺序加上乙二酸，丙二酸或者甲氧基丙二酸等延伸单位，在酰胺合酶参与下形成聚酮体骨架，然后再进行后续的加工(post PKS modification)。在对GDM生物合成基因簇的研究中，本实验室在S．hygroscopicus 17997中曾发现了苯醌型和萘醌型两种AHBA生物合成基因和与之连锁的两个PKS基因簇，但其中未包括GDM的后修饰基因。本研究根据GDM的后修饰基因—氨甲酰基转移酶基因(gdmN)的保守序列设计PCR引物，在S．hygroscopicus 17997基因组中扩增出了732bp的基因片段，通过测序和同源比较，证实该基因片段与S．hygroscopicus NRRL 3602的gdmN有94％的同源性。利用该基因片段的引物，进行菌落PCR筛选S．hygroscopicus 17997的基因组文库，获得了6个阳性克隆，并利用732bp的PCR产物作为探针对阳性克隆进行Southern blot验证和定位。选择CT-4阳性柯斯质粒进行亚克隆测序，将测得的28.356kb DNA序列进行BLAST和ORF分析，证实与公布的S．hygroscopicus NRRL3602 GDM生物合成基因的部分序列基本一致。CT-4柯斯质粒克隆中外源序列可能包括12个基因：与gdmA3基因同源的PKS基因、酰胺合酶基因(gdmF)、单加氧酶基因(gdmM)、氨甲酰基转移酶基因(gdmN)、与甲氧基丙二酰—酰基携带蛋白合成相关的5个基因(gdmH、I、J、K和G)、LuxR家族的转录调节基因(gdmRⅡ)、氨基
Geldanamycin (GDM), produced by the Streptomyces hygroscopicus 17997 which was isolated from China soil by our institute reseacher. GDM, belonging to the benzenenoid ansamycin, possess antitumor and antiprotozoon activity and recently, was discovered that it shows antivirus bioactivity. Extensive research have vertified that GDM can bind specifically to the ATP/ADP domain of heat shock protein 90 (Hsp90), thus down-regulate target proteins including tyrosine kinases, steroid receptors, transcription factors et al. As a specific inhibitor of Hsp90, GDM became a potential promising antitumor and antivirus medicine. To overcome the hypatotoxicity and poor solubility of GDM, the main research work was focused on finding its less toxic and more soluble derivatives. One of its derivatives, 17-AAG, is now in clinical trial (phase II) in United States. It was known that the biosynthesis of ansamycins involves the assembly 3-amino-5-hydroxybenzoic acid (AHBA) as starter unit, followed by the sequential addition of extender units such as acetate, malonate, and methoxymalonate to form a polyketide backbone catalyzed by type I polyketide synthsase (PKS), which then undergoes further downstream processing.
During studies on the geldanamycin biosynthetic genes from Streptomyces hygroscopicus 17997, two possible separate AHBA biosynthetic gene clusters and two sets of PKS genes were found in our lab. But the involvement of these genes in the GDM biosynthesis was not identified, and the post-PKS modification genes were absent yet. In this study conserved sequences of one of possible post-PKS modification gene, the carbamoyltransferase gene (gdmN) in GDM biosynthesis were used to design the primers, by which a 732bp gene fragment was amplified from the Streptomyces hygroscopicus 17997 genome DNA. This gene fragment was sequenced and found it has identity of 94% with the gdmN of Streptomyces hygroscopicus NRRL 3602. Through the colony-PCR by the primers screening, six positive cosmid clones were identified from the Streptomyces hygroscopicus 17997 genomic library. The CT-4 cosmid was sub-cloned and sequenced. The 28.356kb foreign gene sequence of the CT-4 cosmid shows high identity with the known GDM biosynthesis gene cluster of Streptomyces hygroscopicus NRRL 3602 based on BLAST analysis. 12 possible ORFs were identified from the CT-4 cosmid including PKS gene
引文
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34. August PR, Tang L, Yoon YJ, Ning S, Muller R, Yu TW, Taylor M, Hoffmann D, Kim CG, Zhang X, Hutchinson CR, Floss HG. Biosynthesis of the ansamycin antibiotic rifamycin: deductions from the molecular analysis of the rif biosynthetic gene cluster of Amycolatopsis mediterranei S699. Chem Biol. 1998 Feb; 5(2): 69-79
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40. Pereda A, Summers RG, Stassi DL, Ruan X, Katz L. The loading domain of the erythromycin polyketide synthase is not essential for erythromycin biosynthesis in Saccharopolyspora erythraea. Microbiology. 1998 Feb; 144 ( Pt 2): 543-53
41. Long PF, Wilkinson CJ, Bisang CP, Cortes J, Dunster N, Oliynyk M, McCormick E, McArthur H, Mendez C, Salas JA, Staunton J, Leadlay PF. Engineering specificity of starter unit selection by the erythromycin-producing polyketide synthase. Mol Microbiol. 2002 Mar; 43(5): 1215-25
42. Marsden AF, Wilkinson B, Cortes J, Dunster NJ, Staunton J, Leadlay PF. Engineering broader specificity into an antibiotic-producing polyketide synthase. Science. 1998 Jan 9; 279(5348): 199-202
43. Tang L, Yoon YJ, Choi CY, Hutchinson CR. Characterization of the enzymatic domains in the modular polyketide synthase involved in rifamycin B biosynthesis by Amycolatopsis mediterranei. Gene. 1998 Aug 31; 216(2): 255-65
44. Haydock, S.F., et al., & Leadlay, P.F. (1995). Divergent sequencemotifs correlated with the substrate specificity of (methyl) malonyl-CoA: acyl carrier protein transacylase domains in modular polyketide synthases. FEBS Lett. 374, 246-248
45. McDaniel R, Thamchaipenet A, Gustafsson C, et al. Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel "unnatural" natural products. Proc Natl Acad Sci USA, 1999, 96:1846 -1851
46. Rodriguez E, McDaniel R. Combinatorial biosynthesis of antimicrobials and other natural products. Curr Opin Microbiol. 2001 Oct; 4(5): 526-34. Review
47. Allen IW, Ritchie DA. Cloning and analysis of DNA sequences from Streptomyces hygroscopicus encoding geldanamycin biosynthesis. Mol Gen Genet. 1994 Jun 3; 243(5): 593-9
48. Rascher A, Hu Z, Viswanathan N, Schirmer A, Reid R, Nierman WC, Lewis M, Hutchinson CR, Cloning and Characterization of a Gene Cluster for Geldanamycin Production in Streptomyces Hygroscopicus NRRL 3602. FEMS Microbiology Letters, 2003,218:223-230
49. Patel K, Piagentini M, Rascher A, Tian ZQ, Buchanan GO, Regentin R, Hu Z, Hutchinson CR, McDaniel R. Engineered Biosynthesis of Geldanamycin Analogs for Hsp90 Inhibition Chemistry & Biology, 2004,11:1625-1633
50. Hong YS, Lee D, Kim W, Jeong JK, Kim CG, Sohng JK, Lee JH, Paik SG, Lee JJ. Inactivation of the carbamoyltransferase gene refines post-polyketide synthase modification steps in the biosynthesis of the antitumor agent geldanamycin. J Am Chem Soc. 2004 Sep 15; 126(36): 11142-11143
51. Lee D, Lee K, Cai XF, Dat NT, Boovanahalli SK, Lee M, Shin JC, Kim W, Jeong JK, Lee JS, Lee CH, Lee JH, Hong YS, Lee JJ. Biosynthesis of the heat-shock protein 90 inhibitor geldanamycin: new insight into the formation of the benzoquinone moiety. Chembiochem. 2006 Feb; 7(2): 246-248
52. Rascher A, Hu Z, Buchanan GO, Reid R, Hutchinson CR. Insights into the biosynthesis of the benzoquinone ansamycins geldanamycin and herbimycin, obtained by gene sequencing and disruption. Appl Environ Microbiol. 2005 Aug; 71(8): 4862-4871
53. Patel K, Piagentini M, Rascher A, Tian ZQ, Buchanan GO, Regentin R, Hu Z, Hutchinson CR, McDaniel R. Engineered biosynthesis of geldanamycin analogs for Hsp90 inhibition. Chem Biol. 2004 Dec; 11(12): 1625-1633
54. Tudor G, Gutierrez P, Aguilera-Gutierrez A, Sausville EA. Cytotoxicity and apoptosis of benzoquinones: redox cycling, cytochrome c release, and BAD protein expression. Biochem Pharmacol. 2003 Apr 1; 65(7): 1061-1075
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