Fostriecin生物合成相关基因功能的研究
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摘要
福司曲星(Fostriecin, FST)是由链霉菌Streptomyces pulveraceus产生的一种磷酸酯类聚酮化合物,具有良好的抗肿瘤活性。FST的生物合成是由Ⅰ型聚酮合酶催化形成,其后经过一系列后修饰加工反应,如：羟基化、磷酸化等。目前,对FST的研究主要针对其生物活性及化学合成方面。不同链霉菌遗传转化体系建立的难易程度不同,FST产生菌的遗传转化体系较难建立,至今未见FST产生菌遗传转化体系和生物合成机制的相关报道。
本研究建立并优化了FST产生菌S. pulveraceus的遗传转化体系；通过基因阻断失活,确定了FST生物合成后修饰基因的功能；初步确定了FST生物合成的PKS后修饰途径。具体研究结果及结论如下：
(1)利用接合转移方法建立并优化了FST产生菌S. pulveraceus的遗传转化体系。最适宜的转化条件为：以孢子悬液作为受体菌,50℃热激10min,涂布于添加终浓度为5%甘氨酸的MS培养基,培养18h后,用终浓度为20μg/mL的阿伯拉霉素和25μg/mL的萘啶酮酸覆盖。
(2)对Red/ET重组系统的电转体系进行优化,提高了同源重组效率。具体的参数为：电转时加入500ng外源线性DNA,制备感受态细胞时大肠杆菌培养至OD600值为0.4～0.6,感受态细胞的终浓度为0.7×107个/μL,添加的L-阿拉伯糖终浓度为20mmol/L,诱导3h。
(3)根据FST基因簇上与其生物合成相关的基因序列进行BLAST同源比对分析,发现FST生物合成基因簇含有5个主要后修饰基因,被命名为fosG、fosJ、fosK、fosH和fosM。为了研究它们各自的功能,通过基因阻断试验对基因进行失活。与野生型菌株相比,fosG阻断变株不再产化合物PD113271,以FST为主要产物；fosJ阻断变株产生五种新衍生物(1-5)；.fosH阻断变株产生两种新衍生物(6,7)；fosK阻断变株产生两种新衍生物(8,PD113270)；而fosM基因缺失突变株只产生一种新衍生物(9)。经质谱和核磁对新衍生物的结构进行解析,初步证实了这5个后修饰基因的功能。fosG、 fosJ、fosK编码细胞色素P450单氧化酶,属于羟化酶,分别修饰FST C-4、C-8及C-18位的羟基化；FosH属于磷酸激酶家族成员,参与FST C-9位的磷酸化；fosM基因负责脱去C-3位丙二酸酯形成FST C2, C3位之间的不饱和双键。
(4)通过基因互补试验,确定基因缺失突变株的代谢产物不是由其它因素影响的。以pSET153-tsr为出发质粒,连入目的基因构建基因回复载体,分别转入相应的基因阻断突变株中,得到回复菌株。对其进行摇瓶发酵,HPLC分析显示：基因在其阻断变株中获得表达,fosJ～fosM回复菌株重新合成FST, fosG回复菌株重新积累到化合物PD113271。
(5)多数聚酮化合物的结构中包含一个或多个双键,这些双键是由PKS模块中酮还原酶-脱水酶(KR-DH)双结构域催化形成,但FST PKS最后一个模块缺少DH结构域,无法形成内酯环的不饱和双键。通过对fosM基因功能的研究,发现该不饱和双键的形成不依赖于PKS模块脱水酶(DH)结构域,由后修饰基因fosM完成。FST生物合成的整个PKS后修饰过程均伴随着C-3位丙二酸酯结构进行,只有当FosK催化形成C-18位羟基后,FosM才发挥功能作为FST合成的最后一步脱去丙二酸形成不饱和内酯。
(6)根据5个后修饰基因阻断试验得到的一系列衍生物结构分析,初步确定了FST生物合成的PKS后修饰途径。带有丙二酸酯结构的化合物4经FosJ羟化,加载C-8位羟基,形成化合物6。再先后经FosH和FosK作用,在C-9位进行磷酸化,C-18位进行羟基化,形成化合物8和9。FosM最后发挥作用,脱去丙二酸,形成C2-C3位间的双键,完成FST的生物合成。FosG是在FST合成后才开始执行它的功能,形成C-4位带羟基的FST即化合物PD113271。
Fostriecin (FST) is a phosphate ester polyketide produced by Streptomyces pulveraceus with promising antitumor activity. FST is synthesized by a modular FST polyketide synthase (PKS) and a series of post-PKS modifying reactions, including hydroxylation, phosphorylation and so on. Recently, the studies on FST mainly exist in biological activity and chemical synthesis. It has not been reported on the FST biosynthetic mechanism. In this study, we established and optimized genomic transfer system for FST producer S. pulveraceus, delineated the functions of post-PKS modification genes by gene knockout inactivation, and elucidated the pathway for post-PKS modification in FST biosynthesis. The main results and conclusions are listed as follows:
(1) We established and optimized gemonic transfer system for FST producer S. pulveraceus by conjugal transfer method. The optimal conditions were spore suspension as conjugation recipients, Ms agar medium with5%glycin,50℃heat shock10min and flooding apramycin (20μg/mL) and nalidixic acid (25μg/mL) after18h.
(2) To enhance the electrotransformation efficiency, we optimized electrotransformation system of Red/ET recombination system. The optimal electrotansformation parameters as follows:500ng foreign DNA, OD600for E. coli reaches0.4-0.6, competent cell concentration is0.7×107/μL, and final concentration of L-alabinose is20mmol/L, inducing3h.
(3) The BLAST analysis of the FST biosynthetic gene cluster revealed that it includes five genes putatively involved in post-PKS modifications, named fosG, fosH, fosJ, fosK and fosM. To elucidate the functions of these genes, we inactivated their functions by gene knockout experiments. Compared with wild-type strain, fosG disrupted strain failed to produce PD113271and accumulated FST as the major product; fosJ disrupted strain accumulated five new FST analogues,1-5; fosH and fosK disrupted strains accumulated two new FST analogues,6,7and8, PD113270, respectively; fosM disrupted strains only accumulated one new FST analogue,9. Structures of these new derivatives were identified through mass and'H NMR spectroscopic analysis. On the basis of the structures of these compounds, we verified the functions of these post-PKS modification genes. FosG-, fosJ-and fosK-encoded cytochrome P450monooxygenases belonged to hydroxylases, are responsible for C-4C-8and C-18hydroxylation, respectively. FosH encoded phosphokinase are involved in C-9phosphorylation. FosM might be the crucial enzyme involved in formation of double bond at C2-C3in FST biosynthesis.
(4) Genetic complementations to the mutant strains were subsequently carried out to confirm the metabolites were not influenced by other factors. All target genes were amplified and inserted into pSET153-tsr to yield gene complemented vectors. Then these complemented plasmids were introduced into the corresponding mutant strains by conjugation. When cultured these complemented strains, HPLC analysis suggested that all target genes could be expressed in the corresponding mutant strains. We observed that FST was accumulated by fosJ～fosM complementations and PD113271was restored with fosG complementation.
(5) Many poliketides contain one or more double bonds in their structures that are generated by ketoreductase-dehydratase (KR-DH) domains within the PKS modules. It is unable to form the unsaturated double bond of the lactone ring due to the lack of a cognate DH domain in the FST PKS terminal module. Through the determination of function offosM gene, we found that the formation of an unsaturated double bond is dependent upon FosM, not a DH domain in the module PKS. All the post-PKS modification steps in FST biosynthesis can occur with the polyketide chain bearing a malonyl ester at the C-3position. FosM is responsible for the formal elimination of malonate to generate the unsaturated lactone in FST biosynthesis only when the C-18hydroxylation catalyzed by FosK is completed.
(6) According to the chemical structures of a series of new analogues achieved from the five post-PKS modification gene disruption experiments, we elucidated the pathway for post-PKS modifications in FST biosynthesis. The malonylated compound4, liberated from PKS elongation by TE, was catalyzed by FosJ to form compound6. Then, FosH and FosK could catalyze the phosphorylation at C-9and hydroxylation at C-18to create the malonylated compound8and9, respectively. Finally, FosM performs its function on elimination of malonic acid and formation of double bond between C-2and C-3. When the biosynthesis of FST is completed, FosG starts to play its role in C4-hydroxylation of FST to afford PD113271.
本研究建立并优化了FST产生菌S. pulveraceus的遗传转化体系；通过基因阻断失活,确定了FST生物合成后修饰基因的功能；初步确定了FST生物合成的PKS后修饰途径。具体研究结果及结论如下：
(1)利用接合转移方法建立并优化了FST产生菌S. pulveraceus的遗传转化体系。最适宜的转化条件为：以孢子悬液作为受体菌,50℃热激10min,涂布于添加终浓度为5%甘氨酸的MS培养基,培养18h后,用终浓度为20μg/mL的阿伯拉霉素和25μg/mL的萘啶酮酸覆盖。
(2)对Red/ET重组系统的电转体系进行优化,提高了同源重组效率。具体的参数为：电转时加入500ng外源线性DNA,制备感受态细胞时大肠杆菌培养至OD600值为0.4～0.6,感受态细胞的终浓度为0.7×107个/μL,添加的L-阿拉伯糖终浓度为20mmol/L,诱导3h。
(3)根据FST基因簇上与其生物合成相关的基因序列进行BLAST同源比对分析,发现FST生物合成基因簇含有5个主要后修饰基因,被命名为fosG、fosJ、fosK、fosH和fosM。为了研究它们各自的功能,通过基因阻断试验对基因进行失活。与野生型菌株相比,fosG阻断变株不再产化合物PD113271,以FST为主要产物；fosJ阻断变株产生五种新衍生物(1-5)；.fosH阻断变株产生两种新衍生物(6,7)；fosK阻断变株产生两种新衍生物(8,PD113270)；而fosM基因缺失突变株只产生一种新衍生物(9)。经质谱和核磁对新衍生物的结构进行解析,初步证实了这5个后修饰基因的功能。fosG、 fosJ、fosK编码细胞色素P450单氧化酶,属于羟化酶,分别修饰FST C-4、C-8及C-18位的羟基化；FosH属于磷酸激酶家族成员,参与FST C-9位的磷酸化；fosM基因负责脱去C-3位丙二酸酯形成FST C2, C3位之间的不饱和双键。
(4)通过基因互补试验,确定基因缺失突变株的代谢产物不是由其它因素影响的。以pSET153-tsr为出发质粒,连入目的基因构建基因回复载体,分别转入相应的基因阻断突变株中,得到回复菌株。对其进行摇瓶发酵,HPLC分析显示：基因在其阻断变株中获得表达,fosJ～fosM回复菌株重新合成FST, fosG回复菌株重新积累到化合物PD113271。
(5)多数聚酮化合物的结构中包含一个或多个双键,这些双键是由PKS模块中酮还原酶-脱水酶(KR-DH)双结构域催化形成,但FST PKS最后一个模块缺少DH结构域,无法形成内酯环的不饱和双键。通过对fosM基因功能的研究,发现该不饱和双键的形成不依赖于PKS模块脱水酶(DH)结构域,由后修饰基因fosM完成。FST生物合成的整个PKS后修饰过程均伴随着C-3位丙二酸酯结构进行,只有当FosK催化形成C-18位羟基后,FosM才发挥功能作为FST合成的最后一步脱去丙二酸形成不饱和内酯。
(6)根据5个后修饰基因阻断试验得到的一系列衍生物结构分析,初步确定了FST生物合成的PKS后修饰途径。带有丙二酸酯结构的化合物4经FosJ羟化,加载C-8位羟基,形成化合物6。再先后经FosH和FosK作用,在C-9位进行磷酸化,C-18位进行羟基化,形成化合物8和9。FosM最后发挥作用,脱去丙二酸,形成C2-C3位间的双键,完成FST的生物合成。FosG是在FST合成后才开始执行它的功能,形成C-4位带羟基的FST即化合物PD113271。
Fostriecin (FST) is a phosphate ester polyketide produced by Streptomyces pulveraceus with promising antitumor activity. FST is synthesized by a modular FST polyketide synthase (PKS) and a series of post-PKS modifying reactions, including hydroxylation, phosphorylation and so on. Recently, the studies on FST mainly exist in biological activity and chemical synthesis. It has not been reported on the FST biosynthetic mechanism. In this study, we established and optimized genomic transfer system for FST producer S. pulveraceus, delineated the functions of post-PKS modification genes by gene knockout inactivation, and elucidated the pathway for post-PKS modification in FST biosynthesis. The main results and conclusions are listed as follows:
(1) We established and optimized gemonic transfer system for FST producer S. pulveraceus by conjugal transfer method. The optimal conditions were spore suspension as conjugation recipients, Ms agar medium with5%glycin,50℃heat shock10min and flooding apramycin (20μg/mL) and nalidixic acid (25μg/mL) after18h.
(2) To enhance the electrotransformation efficiency, we optimized electrotransformation system of Red/ET recombination system. The optimal electrotansformation parameters as follows:500ng foreign DNA, OD600for E. coli reaches0.4-0.6, competent cell concentration is0.7×107/μL, and final concentration of L-alabinose is20mmol/L, inducing3h.
(3) The BLAST analysis of the FST biosynthetic gene cluster revealed that it includes five genes putatively involved in post-PKS modifications, named fosG, fosH, fosJ, fosK and fosM. To elucidate the functions of these genes, we inactivated their functions by gene knockout experiments. Compared with wild-type strain, fosG disrupted strain failed to produce PD113271and accumulated FST as the major product; fosJ disrupted strain accumulated five new FST analogues,1-5; fosH and fosK disrupted strains accumulated two new FST analogues,6,7and8, PD113270, respectively; fosM disrupted strains only accumulated one new FST analogue,9. Structures of these new derivatives were identified through mass and'H NMR spectroscopic analysis. On the basis of the structures of these compounds, we verified the functions of these post-PKS modification genes. FosG-, fosJ-and fosK-encoded cytochrome P450monooxygenases belonged to hydroxylases, are responsible for C-4C-8and C-18hydroxylation, respectively. FosH encoded phosphokinase are involved in C-9phosphorylation. FosM might be the crucial enzyme involved in formation of double bond at C2-C3in FST biosynthesis.
(4) Genetic complementations to the mutant strains were subsequently carried out to confirm the metabolites were not influenced by other factors. All target genes were amplified and inserted into pSET153-tsr to yield gene complemented vectors. Then these complemented plasmids were introduced into the corresponding mutant strains by conjugation. When cultured these complemented strains, HPLC analysis suggested that all target genes could be expressed in the corresponding mutant strains. We observed that FST was accumulated by fosJ～fosM complementations and PD113271was restored with fosG complementation.
(5) Many poliketides contain one or more double bonds in their structures that are generated by ketoreductase-dehydratase (KR-DH) domains within the PKS modules. It is unable to form the unsaturated double bond of the lactone ring due to the lack of a cognate DH domain in the FST PKS terminal module. Through the determination of function offosM gene, we found that the formation of an unsaturated double bond is dependent upon FosM, not a DH domain in the module PKS. All the post-PKS modification steps in FST biosynthesis can occur with the polyketide chain bearing a malonyl ester at the C-3position. FosM is responsible for the formal elimination of malonate to generate the unsaturated lactone in FST biosynthesis only when the C-18hydroxylation catalyzed by FosK is completed.
(6) According to the chemical structures of a series of new analogues achieved from the five post-PKS modification gene disruption experiments, we elucidated the pathway for post-PKS modifications in FST biosynthesis. The malonylated compound4, liberated from PKS elongation by TE, was catalyzed by FosJ to form compound6. Then, FosH and FosK could catalyze the phosphorylation at C-9and hydroxylation at C-18to create the malonylated compound8and9, respectively. Finally, FosM performs its function on elimination of malonic acid and formation of double bond between C-2and C-3. When the biosynthesis of FST is completed, FosG starts to play its role in C4-hydroxylation of FST to afford PD113271.
引文
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