抗肿瘤抗生素阿嗪霉素B和氯丝菌素的生物合成研究
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摘要
阿嗪霉素B(Azinomycin B)又叫嗜癌霉素A,是1954年由日本科学家从Streptomyces sahachiroi的发酵产物中分离得到的一种有良好的体内抗肿瘤活性和潜在的体外细胞毒活性的天然化合物。后来又从另外一种链霉菌Streptomyces griseofuscus的发酵产物中也分离得到了Azinomycin B的其它结构类似物(Azinomycins),Azinomycins的结构非常独特,含有一个奈甲酸单元,一个环氧丙烷结构,还有现知化合物中独一无二的氮杂双环(1-azabicyclo[3.1.0]-hexane ring)结构。其中Azinomycin B的活性最好,抗肿瘤活性与临床应用的丝裂霉素相当。机理是通过环氧丙烷和氮丙啶烷基化DNA的嘌呤碱基,形成链间交联,从而起到抑制细胞增殖的作用。Azinomycin B结构的不稳定性,限制了其开发利用,利用化学方法改造其结构成本高昂,组合生物合成的方法可以高效低成本的产生活性更好,结构更稳定的Azinomycin B的类似物。
利用Ⅰ型重复使用聚酮合成酶(iterative typeⅠpolyketides, iPKS)的保守序列,设计兼并性引物,PCR扩增到Ⅰ型重复使用聚酮合成酶的DNA片段,并以之为探针筛选Azinomycin B的产生菌Streptomyces sahachiroi NRR2485的Cosmid基因组文库,克隆到了基因组上约60kb的DNA序列,生物信息学分析显示其为Azinomycin B的生物合成基因簇,包含39个开放阅读框。通过在异源宿主Streptomyces albus中单独表达aziB,得到产物5-甲基萘甲酸,共表达aziB,aziB1,aziB2得到产物3-甲氧基-5-甲基萘甲酸,从而证明了克隆的DNA序列包含Azinomycin B的生物合成基因簇。通过同源重组的方法对ORF 36进行了基因中断后,还能检测到Azinomycin B的产生。从而确定了Azinomycin B的生物合成基因簇的边界。
氯丝菌素(Chlorothricin,CHL)是一个产生于S.antibioticus DSM40725的螺环乙酰乙酸内酯家族抗生素,该家族天然产物具有广泛生物活性(包括抗感染、抗肿瘤、抗疟和胆固醇合成抑制等),以Ⅰ型聚酮合成酶基因片段作为探针,结合染色体步移的方法克隆了S.antibioticus DSM 40725染色体上122 kb左右的完整CHL生物合成基因簇。发现在其中chlBl编码的是一个Ⅰ型重复使用聚酮合成酶。Azinomycin B生物合成基因簇中的aziB编码的也是一个Ⅰ型重复使用聚酮合成酶。ChlB1和AziB1组织结构相同,蛋白序列同源性高,但是ChlB1催化合成单环芳香化合物6-甲基水杨酸,而AziB催化合成双环的5-甲基萘甲酸。以ChlB1和AziB为对象研究Ⅰ型重复使用聚酮合成酶的催化机制,对ChlB1和AziB的脱水功能域(DH domain),酮基还原功能域(KR domain)的特异性位点突变,结果AziB的DH,KR的突变体中没有检测到可能的中间体,而在ChlB1的947的H突变成F的DH突变体,检测到6-甲基水杨酸,1540位的Y突变成F后的KR突变体产生了苔色酸(OSA),说明在Ⅰ型重复使用聚酮合成酶的催化过程中DH的功能是重要的但不是必须的,KR的功能的缺失并不影响其进一步的延伸反应。
通过对Azinomycin B生物合成基因簇中p450羟化酶AziB1,氧甲基转移酶AziB2,非核糖体聚肽合成酶(NRPS) AziAl的体外测活研究,证明了AziB1催化的是Ⅰ型重复使用聚酮合成酶的产物5-甲基萘甲酸C-3位置的羟化,AziB2催化的是接下来氧甲基化,最后有AziA1识别3-甲氧基-5-甲基萘甲酸并以之为起始单元,起始Azinomycin B的生物合成,证明了Ⅰ型重复使用聚酮合成酶AziB产物的后修饰是发生在游离小分水平上的,而不是发生在酰基载体蛋白(ACP)连接的蛋白水平上的。
氯丝菌素具有较好的抗菌和抗肿瘤活性,在前期的研究中发现的其Ⅰ型重复使用聚酮合成酶ChlB1产物6-甲基水杨酸的后修饰是发生在ACP连接小分子的蛋白水平上的,在这个过程中,两个酰基转运蛋白(AT) ChlB3, ChlB6的底物容忍性相对宽泛,而且在对ChlB1这一Ⅰ型重复使用聚酮合成酶的机制研究的过程中,通过点突变KR结构域的方法成功的把ChlB1这一六甲基水杨酸合成酶(6-MSAS)改造成了苔色酸合成酶(OSAS),在这些基础上,把ChlB1遗传改造来的OSAS,导入到Chlorothricin产生菌S.antibioticus DSM40725的chlB1中断的突变菌株中,得到的新的重组菌株产生了新的Chlorothricin类似物7和8,7和8显示出更高的抗菌活性。从而完成了从生物合成机制的基础研究到组合生物合成利用的一个经典过程。
Azinomycin B, also named Carzinophilin A, first isolated from Streptomyces sahachiroi by Japanese scientists in 1954, has potent antitumor activity in vivo and cytotoxicity. Then scientists isolated other Azinomycin B analogues-Azinomycins form the fermentation culture of Streptomyces griseofuscus. Azinomycins feature a set of unusual, densely assembled functionalities:a 3-methoxy-5-methyl naphthoic acid (NPA) moiety, a 2-amino-1,3-dicarbonyl group, an epoxide domain, and an unprecedented aziridino [1,2a] pyrrolidine (1-azabicyclo [3.1.0] hexane) ring system which has been the uniqueness structure in nature product. Azinomycin B has the best bioactivity among the Azinomycins. Its effect in vivo is comparable to that of the clinically used DNA ISC drug mitomycin C. Azinomycin B binds within the major groove of DNA, and forms covalent interstrand crosslinks (ISCs) with apparent sequence selectivity by electrophilic attacks of C10 and C21 onto N7 positions of purine bases. Because of the poor availability and extreme instability of Azinomycin B, extensive synthetic efforts have been carried out but very expensive to generate a number of azinomycin analogues for investigations into the structure-bioactivity relationship. Base on the research for the biosysthsis path way of Azinomycin B, Combinatorial biosynthesis of the Azinomycin B may be a economical way to produce new Azinomycin B analogues with better bioactivity and stability.
A DNA fragment was got by PCR amplification with a general primers designed in accordance with the conservative amino acid of the iterative typeⅠpolyketides(PKS). After screening the cosmid library of the genome of the Streptomyces sahachiroi NRR2485 with the PCR product as a probe, A 60kb DNA fragment was sequenced and deduced to be the biosysthesis gene cluster of the Azinomycin B which cotains 39 ORFS. Heterogeneous expression of aziB solo in the Streptomyces albus generated 5-methyl NPA, Co-heterogeneous expression of aziB, aziBl, aziB2 produced 3-methoxy-5-methyl NPA. These results confirmed the DNA sequence we cloned take responsibility for the biosysthesis of Azinomycin B. The mutant for ORF 36 knocked out still produced Azinomycin B, indicated that ORF36 was the boundary of Azinomycin B biosysthesis gene cluster.
Chlorothricin is a spirotetronate antibiotics produced by Streptomyces antibioticus DSM 40725. The spirotetronate antibiotics have bioactivity including anti-infection,antitumer, antimalaria, and cholesterol biosynthesis. A 122kb DNA fragment encoding the biosynthetic gene cluster of Chlorothricin was cloned form the genome withⅠtype PKS as probes, we found a iterative typeⅠpolyketides ChlB1 which has the same organization and high sequence indensity with AziB form Azinomycin B gene cluster. Surprisedly, ChlB1 synthesis signal ring product-6-Methylsalicylic acid (6-MSA), AziB synthesis two rings product 5-methyl-NPA. what is the catalysis mechanism for them? we mutanted the dehydratase(DH) domain, ketereductase(KR) domain of ChlB1 and AziB. All mutants of AziB did not produce any intermediates, but DH mutant of ChlB1 (H947F) still produced 6-MSA and KR mutant of ChlB1 (produced orsellinic acid (OSA). All these information indicated that the DH domain of the iterative typeⅠPKS is very important but not the essential and the deletion of the function of KR domain did not affect the next extension reaction.
Over-expression of the p450 hydroxylase aziB1, the O-methyltransferase aziB2, the non-ribosomal peptide synthetase aziA1 in Ecoli BL21(DE3). We characterized that AziB1 catalyzes a regiospecific hydroxylation at C3 position of 5-methyl-NPA, and the resulting hydroxyl group can be subsequently O-methylated by AziB2 to furnish the methoxy functionality to give 3-methoxy-5-methyl NPA, then 3-methoxy-5-methyl NPA was specifically recognize/activated by the NRPS AziAl in vitro, supporting its function as a loading module to employ 3-methoxy-5-methyl-naphthoyl as the starting unit for initiating the backbone formation of azinomycin B. These dates comfirmed the functions of the aziB 1, azi B2, aziA1 and that the
post-modification of product of iterative typeⅠpolyketides azi B occurred on the free naphthoic acids.
Because of good antibacterial and antitumor activity, Chlorothricin was a candidate for combinatorial biosynthesis. Post-modification of product of iterative typeⅠpolyketides chlB1 occurred on the acyl carrier protein (ACP)-tethered 6-MSA.Former research work indicated that two acyltransferases(AT) chl B3,Chl B6 were less substrate specifically recognize, moreover, during study the mechanism of iterative typeⅠpolyketides, we successfully changed the 6-Methylsalicylic acid synthase (6-MSAS) Chl B1 to orsellinic acid synthase (OSAS). This KR mutant chl B1 was introduced in the chl Bl knocked out mutant of Streptomyces antibioticus DSM 40725, surprisedly,this new mutant produced two new Chlorothricin analogues 7 and 8which have improved bioactivity.
利用Ⅰ型重复使用聚酮合成酶(iterative typeⅠpolyketides, iPKS)的保守序列,设计兼并性引物,PCR扩增到Ⅰ型重复使用聚酮合成酶的DNA片段,并以之为探针筛选Azinomycin B的产生菌Streptomyces sahachiroi NRR2485的Cosmid基因组文库,克隆到了基因组上约60kb的DNA序列,生物信息学分析显示其为Azinomycin B的生物合成基因簇,包含39个开放阅读框。通过在异源宿主Streptomyces albus中单独表达aziB,得到产物5-甲基萘甲酸,共表达aziB,aziB1,aziB2得到产物3-甲氧基-5-甲基萘甲酸,从而证明了克隆的DNA序列包含Azinomycin B的生物合成基因簇。通过同源重组的方法对ORF 36进行了基因中断后,还能检测到Azinomycin B的产生。从而确定了Azinomycin B的生物合成基因簇的边界。
氯丝菌素(Chlorothricin,CHL)是一个产生于S.antibioticus DSM40725的螺环乙酰乙酸内酯家族抗生素,该家族天然产物具有广泛生物活性(包括抗感染、抗肿瘤、抗疟和胆固醇合成抑制等),以Ⅰ型聚酮合成酶基因片段作为探针,结合染色体步移的方法克隆了S.antibioticus DSM 40725染色体上122 kb左右的完整CHL生物合成基因簇。发现在其中chlBl编码的是一个Ⅰ型重复使用聚酮合成酶。Azinomycin B生物合成基因簇中的aziB编码的也是一个Ⅰ型重复使用聚酮合成酶。ChlB1和AziB1组织结构相同,蛋白序列同源性高,但是ChlB1催化合成单环芳香化合物6-甲基水杨酸,而AziB催化合成双环的5-甲基萘甲酸。以ChlB1和AziB为对象研究Ⅰ型重复使用聚酮合成酶的催化机制,对ChlB1和AziB的脱水功能域(DH domain),酮基还原功能域(KR domain)的特异性位点突变,结果AziB的DH,KR的突变体中没有检测到可能的中间体,而在ChlB1的947的H突变成F的DH突变体,检测到6-甲基水杨酸,1540位的Y突变成F后的KR突变体产生了苔色酸(OSA),说明在Ⅰ型重复使用聚酮合成酶的催化过程中DH的功能是重要的但不是必须的,KR的功能的缺失并不影响其进一步的延伸反应。
通过对Azinomycin B生物合成基因簇中p450羟化酶AziB1,氧甲基转移酶AziB2,非核糖体聚肽合成酶(NRPS) AziAl的体外测活研究,证明了AziB1催化的是Ⅰ型重复使用聚酮合成酶的产物5-甲基萘甲酸C-3位置的羟化,AziB2催化的是接下来氧甲基化,最后有AziA1识别3-甲氧基-5-甲基萘甲酸并以之为起始单元,起始Azinomycin B的生物合成,证明了Ⅰ型重复使用聚酮合成酶AziB产物的后修饰是发生在游离小分水平上的,而不是发生在酰基载体蛋白(ACP)连接的蛋白水平上的。
氯丝菌素具有较好的抗菌和抗肿瘤活性,在前期的研究中发现的其Ⅰ型重复使用聚酮合成酶ChlB1产物6-甲基水杨酸的后修饰是发生在ACP连接小分子的蛋白水平上的,在这个过程中,两个酰基转运蛋白(AT) ChlB3, ChlB6的底物容忍性相对宽泛,而且在对ChlB1这一Ⅰ型重复使用聚酮合成酶的机制研究的过程中,通过点突变KR结构域的方法成功的把ChlB1这一六甲基水杨酸合成酶(6-MSAS)改造成了苔色酸合成酶(OSAS),在这些基础上,把ChlB1遗传改造来的OSAS,导入到Chlorothricin产生菌S.antibioticus DSM40725的chlB1中断的突变菌株中,得到的新的重组菌株产生了新的Chlorothricin类似物7和8,7和8显示出更高的抗菌活性。从而完成了从生物合成机制的基础研究到组合生物合成利用的一个经典过程。
Azinomycin B, also named Carzinophilin A, first isolated from Streptomyces sahachiroi by Japanese scientists in 1954, has potent antitumor activity in vivo and cytotoxicity. Then scientists isolated other Azinomycin B analogues-Azinomycins form the fermentation culture of Streptomyces griseofuscus. Azinomycins feature a set of unusual, densely assembled functionalities:a 3-methoxy-5-methyl naphthoic acid (NPA) moiety, a 2-amino-1,3-dicarbonyl group, an epoxide domain, and an unprecedented aziridino [1,2a] pyrrolidine (1-azabicyclo [3.1.0] hexane) ring system which has been the uniqueness structure in nature product. Azinomycin B has the best bioactivity among the Azinomycins. Its effect in vivo is comparable to that of the clinically used DNA ISC drug mitomycin C. Azinomycin B binds within the major groove of DNA, and forms covalent interstrand crosslinks (ISCs) with apparent sequence selectivity by electrophilic attacks of C10 and C21 onto N7 positions of purine bases. Because of the poor availability and extreme instability of Azinomycin B, extensive synthetic efforts have been carried out but very expensive to generate a number of azinomycin analogues for investigations into the structure-bioactivity relationship. Base on the research for the biosysthsis path way of Azinomycin B, Combinatorial biosynthesis of the Azinomycin B may be a economical way to produce new Azinomycin B analogues with better bioactivity and stability.
A DNA fragment was got by PCR amplification with a general primers designed in accordance with the conservative amino acid of the iterative typeⅠpolyketides(PKS). After screening the cosmid library of the genome of the Streptomyces sahachiroi NRR2485 with the PCR product as a probe, A 60kb DNA fragment was sequenced and deduced to be the biosysthesis gene cluster of the Azinomycin B which cotains 39 ORFS. Heterogeneous expression of aziB solo in the Streptomyces albus generated 5-methyl NPA, Co-heterogeneous expression of aziB, aziBl, aziB2 produced 3-methoxy-5-methyl NPA. These results confirmed the DNA sequence we cloned take responsibility for the biosysthesis of Azinomycin B. The mutant for ORF 36 knocked out still produced Azinomycin B, indicated that ORF36 was the boundary of Azinomycin B biosysthesis gene cluster.
Chlorothricin is a spirotetronate antibiotics produced by Streptomyces antibioticus DSM 40725. The spirotetronate antibiotics have bioactivity including anti-infection,antitumer, antimalaria, and cholesterol biosynthesis. A 122kb DNA fragment encoding the biosynthetic gene cluster of Chlorothricin was cloned form the genome withⅠtype PKS as probes, we found a iterative typeⅠpolyketides ChlB1 which has the same organization and high sequence indensity with AziB form Azinomycin B gene cluster. Surprisedly, ChlB1 synthesis signal ring product-6-Methylsalicylic acid (6-MSA), AziB synthesis two rings product 5-methyl-NPA. what is the catalysis mechanism for them? we mutanted the dehydratase(DH) domain, ketereductase(KR) domain of ChlB1 and AziB. All mutants of AziB did not produce any intermediates, but DH mutant of ChlB1 (H947F) still produced 6-MSA and KR mutant of ChlB1 (produced orsellinic acid (OSA). All these information indicated that the DH domain of the iterative typeⅠPKS is very important but not the essential and the deletion of the function of KR domain did not affect the next extension reaction.
Over-expression of the p450 hydroxylase aziB1, the O-methyltransferase aziB2, the non-ribosomal peptide synthetase aziA1 in Ecoli BL21(DE3). We characterized that AziB1 catalyzes a regiospecific hydroxylation at C3 position of 5-methyl-NPA, and the resulting hydroxyl group can be subsequently O-methylated by AziB2 to furnish the methoxy functionality to give 3-methoxy-5-methyl NPA, then 3-methoxy-5-methyl NPA was specifically recognize/activated by the NRPS AziAl in vitro, supporting its function as a loading module to employ 3-methoxy-5-methyl-naphthoyl as the starting unit for initiating the backbone formation of azinomycin B. These dates comfirmed the functions of the aziB 1, azi B2, aziA1 and that the
post-modification of product of iterative typeⅠpolyketides azi B occurred on the free naphthoic acids.
Because of good antibacterial and antitumor activity, Chlorothricin was a candidate for combinatorial biosynthesis. Post-modification of product of iterative typeⅠpolyketides chlB1 occurred on the acyl carrier protein (ACP)-tethered 6-MSA.Former research work indicated that two acyltransferases(AT) chl B3,Chl B6 were less substrate specifically recognize, moreover, during study the mechanism of iterative typeⅠpolyketides, we successfully changed the 6-Methylsalicylic acid synthase (6-MSAS) Chl B1 to orsellinic acid synthase (OSAS). This KR mutant chl B1 was introduced in the chl Bl knocked out mutant of Streptomyces antibioticus DSM 40725, surprisedly,this new mutant produced two new Chlorothricin analogues 7 and 8which have improved bioactivity.
引文
1．戴纪刚等《中华医史杂志》1999,29卷,第2期
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