橙色珍贵束丝放线菌发酵生产抗癌药物安丝菌素P-3的研究
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摘要
美登醇是一类具有良好抗癌活性的大环内酯类化合物,在美国已进入二期临床。安丝菌素是由橙色珍贵束丝放线菌(Actinosynnema pretiosum)合成的美登醇类抗癌药物,其中安丝菌素P-3(AP-3)的活性最为显著。
由于其重要的药理活性,近年来安丝菌素成为国内外研究的一个热点。尽管关于菌种筛选、培养基优化及途径调控以提高AP-3产量有一些报道,目前的低生产率及高生产成本仍然是制约其产业化的瓶颈之一。至今关于环境因子对AP-3的积累过程及其生物合成基因表达等的影响尚缺乏深入研究,了解和掌握相关信息对生产实践中有效提高其产量具有重要意义。
本研究首先采用文献报道的培养基进行AP-3的发酵试验,结果表明其产量很低,仅1-2 mgL-1。通过应用Plackett-Burman设计和折叠Plackett-Burman设计进行发酵筛选,得到一组AP-3产量为12.9 mgL-1的培养基,并从单因素实验观察到异丁醇和铵离子对AP-3产量分别具有正效应和负效应。进一步应用中心组合设计及响应面分析,优化得到AP-3的发酵培养基为(gL-1)：葡萄糖5、甘油40、酵母提取物10、玉米滤液20、碳酸钙5、磷酸氢二钾0.5、七水合硫酸亚铁0.002、异丁醇3。在上述发酵培养基的基础上,采用转速220 rpm,装液量60 mL/250 mL,接种量1.64×109CFUL-1的发酵条件,培养96h获得AP-3产量为68.2 mgL-1,生产率达17.1 mgL-ld-1,该生产率高于至今文献报道的水平。并且,基于摇瓶发酵的初始KLα,在实验室小型规模进行了放大探索,在3-L反应器、96h获得AP-3产量为52 mgL-1。
在上述培养基优化过程中观察到铵离子的去除能提高AP-3产量,但铵离子作为常用氮源及含氮物质的中间代谢物,往往在发酵过程中积累；因此,结合抗生素的生物合成途径并从蛋白质组学的角度研究其影响机制可为铵离子抑制的解除、后续培养基选择及代谢途径改造等提供重要信息。由此,对添加(37 mM)和不添加铵离子的发酵过程进行了分析,结果表明铵离子抑制菌体生长速度,促进胞外异丁酸的代谢。从酶活性的检测数据观察到铵离子在整个发酵过程中提高缬氨酸代谢的第一个酶缬氨酸脱氢酶的活性,而不像其它抗生素发酵体系中报道的抑制作用。转录分析表明大部分AP-3生物合成基因的转录水平受铵离子抑制,与产量变化一致。进一步应用双向电泳考察蛋白质组的响应,在pH3-5.6且PAGE浓度为13.5%的双向电泳条件下获得约1600个蛋白质点,质谱鉴定得到12个差异表达1.5倍以上的蛋白质,包括3-磷酸-甘油醛脱氢酶(下调2倍)、脂肪酸合成酶(上调1.7倍)、及负责丝氨酸生物合成的3-磷酸甘油酸脱氢酶(上调3.9倍)等。这些结果显示铵离子影响脂肪酸和丝氨酸的生物合成,并调节AP-3生物合成基因的转录水平。
已有文献表明异丁醇可作为AP-3的侧链异丁酰-辅酶A的前体,我们的实验也表明添加异丁醇可有效提高AP-3的产量,因此,本学位论文结合异丁醇的代谢及AP-3的生物合成途径又探索了其影响机制。首先考察了异丁醇添加条件对AP-3产量的影响,结果表明在第0h添加36 mM的异丁醇效果最显著,与不添加相比,发酵96h的AP-3产量提高了3.4倍。分析胞内辅酶A的积累动态,观察到添加异丁醇可以促进乙酰-辅酶A和丙二酰-辅酶A的积累,暗示异丁醇影响其它延伸单元的供应。对酶活性检测表明异丁醇分别在对数期和产素期提高异丁醇脱氢酶和缬氨酸脱氢酶的酶活性近2倍,且于36h组合添加缬氨酸可提高AP-3产量35%(82.3 mgL-1)。同时对AP-3生物合成途径及异丁酰-辅酶A代谢途径的基因转录分析,观察到其表达水平与抗生素的产量变化一致,其中AP-3侧链添加的基因asml9、调节基因asm40及异丁酰-辅酶A变构酶基因及甲基丙二酸半醛脱氢酶基因的转录水平在异丁醇条件下显著上调,后者暗示异丁醇可能改变异丁酰-辅酶A的代谢分布。进一步对蛋白质组研究表明,在异丁醇存在时,与细胞氧化还原状态相关的过氧化氢酶及LysR调节因子的蛋白表达水平均上调。此外,为进一步研究asml9和asm40对异丁醇的响应,对其基因工程菌株进行了发酵,观察到asml9的高表达可耐受更高浓度的异丁醇；asm40的基因缺失菌株在不添加异丁醇时其产量与野生型无显著差别,但添加异丁醇的AP-3产量则提高了20%,表明异丁醇的添加与asm40转录水平的激活具有相似的效应。上述结果表明异丁醇促进AP-3生物合成前体CoA的供应,并影响氧化还原相关的基因和蛋白的表达水平。
本研究通过对环境因子的考察,发现铵离子影响脂肪酸及丝氨酸生物合成途径并抑制AP-3生物合成基因的转录水平；异丁醇不但促进AP-3前体CoA的供应,还影响与胞内氧化还原水平相关的基因转录及蛋白质表达。这些信息不但为AP-3发酵操作及其生物合成途径的改造提供了有益信息,还可为其它大环内酯类抗生素的发酵提供借鉴。
Maytansinoids are extraordinary antitumor macrolactam agents in phase II clinical trials in America. Ansamitocins are classified as maytansinoids, and biosynthesized by Actinosynnema proetiosum, therein ansamitocin P-3 (AP-3) has an excellent activity.
Due to the important physiological activities, the interest in ansamitocins has increased around the world in recent years. Many studies have focused on strain improvement, medium optimization, and pathway regulation to enhance AP-3 production. However, its commercial application is still limited resulted from the low productivity and high price of AP-3. Until now there is no information related to environmental factor on AP-3 production based on the fermentation process and the molecular mechanism for regulation of AP-3 biosynthesis, albeit those knowledge is significant for increasing antibiotics productivity.
In this study, we first adopted the reported medium to produce AP-3 in the fermentation of Actinosynnem pretiosum spp. auranticum 31565, however, only an amount of 1-2 mgL-1 was observed. Thus, the Plackett-Burman and fold-over Plackett-Burman designs were applied to select fermentation medium, and the maximum AP-3 production was 12.9 mgL-1. Furthermore, one-time-one-factor method was used to simplify the medium compositions, and found that ammonium and isobutanol exerted negative and positive effects on AP-3 production respectively. The center composition design as well as response surface method were then employed to optimize the medium concentrations, the final fermentation medium were (gL-1):glucose 5, yeast extract 10, glycerol 40, corn filtrate 20, CaCO35, K2HPO40.5, FeSO4·7H2O 0.002, and isobutanol 3, the maximum AP-3 production was 68.2 mgL-1 with an inoculua of 1.64×109 CFUL-1 cultivated for 96 h in 60 mL/250 mL flask at 220 rpm, the productivity (17.1 mgL-1d-1) was higher among the published references. Fermentation based on flask initial KLa was carried out in 3-L bioreactor successfully, and the AP-3 production achieved 52 mgL-1 at 96 h.
It was observed that removal of ammonium from the fermentation medium was positive to AP-3 production. However, ammonium is an intermediate of nitrogen-contained compounds which always accumulated during antibiotics fermentation, information on ammonium effect from the viewpoint of biosynthetic gene transcription and proteomics has not yet reported, albeit it is beneficial to medium selection and pathway reconstruction. Hence, inhibition of AP-3 production was studied with (37 mM) and without ammonium based on fermentation process. Fermentation profiles showed that mycelium growth rate was repressed by ammonium, but the absorption rate of extracellular isobutyrate was facilitated. Assay of enzymatic activities showed that the activity of valine dehydrogenase, the first enzyme in valine metabolism pathway that always inhibited by ammonium in other systems, was induced during the whole process. Transcriptional levels of genes in AP-3 biosynthetic pathway were down-regulated by ammonium, which was in agreement with the production reduction. About 1600 protein spots by two-dimensional electrophoresis with pH3-5.6 and PAGE concentration of 13.5% were obtained; therein spots above 1.5-fold differential expression determined by mass determination were D-3-phosphoglycerate dehydrogenase, glyceraldehyde 3-phosphate dehydrogenase, and fatty acid synthase etc. The results showed that ammonium influenced the biosynthesis of fatty acid and serine, and regulated the transcription of AP-3 biosynthetic genes.
Previous work implied that isobutanol might act as a precursor of isobutyryl-CoA (side chain of AP-3), and the enhancement of AP-3 production by isobutanol addition was also found during the process of medium optimization. We first optimize the addition conditions, and found that isobutanol added at 0 h with 36 mM was optimal, resulting in 3.4-fold improvement of AP-3 and 4-fold decrease of AP-2 production at 96 h. Accumulation profiles of intracellular CoAs showed that acetyl-CoA and malonyl-CoA concentration increased in isobutanol supplemented culture, suggested isobutanol also influence pools of extender units of AP-3. In isobutanol supplemented culture activities of both isobutanol dehydrogenase and valine dehydrogenase were enhanced for about 2 folds in the growth phase and production phase, respectively; further combined addition of valine at 36 h based on isobutanol resulted in 35% improvement of AP-3 yield (82.3 mgL"1). Transcriptional response of genes in AP-3 biosynthetic and isobutyryl-CoA catabolic pathways showed a similar way as the increase of AP-3 production, therein the side-chain incorporating gene asm19 and regulatory gene asm40 in the former pathway were up-regulated by isobutanol significantly, and genes in the latter pathway were also induced, suggested a shunt of isobutyryl-CoA metabolism by isobutanol. Furthermore, protein expression of catalase and LysR family regulator related to the state of cell redox was up-regulated by isobutanol resulted from proteomics study. In addition, to testify the responses of asm19 and asm40 to isobutanol, their engineering strains were cultivated, and it was observed that overexpression of asm19 resulted in more tolerance of isobutanol than wild type, while deletion of asm40 induced AP-3 production for 20% by isobutanol, suggested an indirect role of asm40 in response to isobutanol. The information indicated that isobutanol disturbed the pools of precursor CoAs for AP-3 biosynthesis, and influenced the expression of redox-related genes and proteins in cells.
Collectively, this work revealed that ammonium could activate the biosynthetic pathways of fatty acid and serine, as well as down-regulated of the transcription of AP-3 biosynthetic genes; meanwhile, the positive role of isobutanol was caused by changes of precursor supply, and influence of expression of genes and proteins related to the redox state of cells. The information is helpful to development of fermentation medium and reconstitution of AP-3 biosynthetic pathway, and also taken as a reference to other antibiotics fermentation.
由于其重要的药理活性,近年来安丝菌素成为国内外研究的一个热点。尽管关于菌种筛选、培养基优化及途径调控以提高AP-3产量有一些报道,目前的低生产率及高生产成本仍然是制约其产业化的瓶颈之一。至今关于环境因子对AP-3的积累过程及其生物合成基因表达等的影响尚缺乏深入研究,了解和掌握相关信息对生产实践中有效提高其产量具有重要意义。
本研究首先采用文献报道的培养基进行AP-3的发酵试验,结果表明其产量很低,仅1-2 mgL-1。通过应用Plackett-Burman设计和折叠Plackett-Burman设计进行发酵筛选,得到一组AP-3产量为12.9 mgL-1的培养基,并从单因素实验观察到异丁醇和铵离子对AP-3产量分别具有正效应和负效应。进一步应用中心组合设计及响应面分析,优化得到AP-3的发酵培养基为(gL-1)：葡萄糖5、甘油40、酵母提取物10、玉米滤液20、碳酸钙5、磷酸氢二钾0.5、七水合硫酸亚铁0.002、异丁醇3。在上述发酵培养基的基础上,采用转速220 rpm,装液量60 mL/250 mL,接种量1.64×109CFUL-1的发酵条件,培养96h获得AP-3产量为68.2 mgL-1,生产率达17.1 mgL-ld-1,该生产率高于至今文献报道的水平。并且,基于摇瓶发酵的初始KLα,在实验室小型规模进行了放大探索,在3-L反应器、96h获得AP-3产量为52 mgL-1。
在上述培养基优化过程中观察到铵离子的去除能提高AP-3产量,但铵离子作为常用氮源及含氮物质的中间代谢物,往往在发酵过程中积累；因此,结合抗生素的生物合成途径并从蛋白质组学的角度研究其影响机制可为铵离子抑制的解除、后续培养基选择及代谢途径改造等提供重要信息。由此,对添加(37 mM)和不添加铵离子的发酵过程进行了分析,结果表明铵离子抑制菌体生长速度,促进胞外异丁酸的代谢。从酶活性的检测数据观察到铵离子在整个发酵过程中提高缬氨酸代谢的第一个酶缬氨酸脱氢酶的活性,而不像其它抗生素发酵体系中报道的抑制作用。转录分析表明大部分AP-3生物合成基因的转录水平受铵离子抑制,与产量变化一致。进一步应用双向电泳考察蛋白质组的响应,在pH3-5.6且PAGE浓度为13.5%的双向电泳条件下获得约1600个蛋白质点,质谱鉴定得到12个差异表达1.5倍以上的蛋白质,包括3-磷酸-甘油醛脱氢酶(下调2倍)、脂肪酸合成酶(上调1.7倍)、及负责丝氨酸生物合成的3-磷酸甘油酸脱氢酶(上调3.9倍)等。这些结果显示铵离子影响脂肪酸和丝氨酸的生物合成,并调节AP-3生物合成基因的转录水平。
已有文献表明异丁醇可作为AP-3的侧链异丁酰-辅酶A的前体,我们的实验也表明添加异丁醇可有效提高AP-3的产量,因此,本学位论文结合异丁醇的代谢及AP-3的生物合成途径又探索了其影响机制。首先考察了异丁醇添加条件对AP-3产量的影响,结果表明在第0h添加36 mM的异丁醇效果最显著,与不添加相比,发酵96h的AP-3产量提高了3.4倍。分析胞内辅酶A的积累动态,观察到添加异丁醇可以促进乙酰-辅酶A和丙二酰-辅酶A的积累,暗示异丁醇影响其它延伸单元的供应。对酶活性检测表明异丁醇分别在对数期和产素期提高异丁醇脱氢酶和缬氨酸脱氢酶的酶活性近2倍,且于36h组合添加缬氨酸可提高AP-3产量35%(82.3 mgL-1)。同时对AP-3生物合成途径及异丁酰-辅酶A代谢途径的基因转录分析,观察到其表达水平与抗生素的产量变化一致,其中AP-3侧链添加的基因asml9、调节基因asm40及异丁酰-辅酶A变构酶基因及甲基丙二酸半醛脱氢酶基因的转录水平在异丁醇条件下显著上调,后者暗示异丁醇可能改变异丁酰-辅酶A的代谢分布。进一步对蛋白质组研究表明,在异丁醇存在时,与细胞氧化还原状态相关的过氧化氢酶及LysR调节因子的蛋白表达水平均上调。此外,为进一步研究asml9和asm40对异丁醇的响应,对其基因工程菌株进行了发酵,观察到asml9的高表达可耐受更高浓度的异丁醇；asm40的基因缺失菌株在不添加异丁醇时其产量与野生型无显著差别,但添加异丁醇的AP-3产量则提高了20%,表明异丁醇的添加与asm40转录水平的激活具有相似的效应。上述结果表明异丁醇促进AP-3生物合成前体CoA的供应,并影响氧化还原相关的基因和蛋白的表达水平。
本研究通过对环境因子的考察,发现铵离子影响脂肪酸及丝氨酸生物合成途径并抑制AP-3生物合成基因的转录水平；异丁醇不但促进AP-3前体CoA的供应,还影响与胞内氧化还原水平相关的基因转录及蛋白质表达。这些信息不但为AP-3发酵操作及其生物合成途径的改造提供了有益信息,还可为其它大环内酯类抗生素的发酵提供借鉴。
Maytansinoids are extraordinary antitumor macrolactam agents in phase II clinical trials in America. Ansamitocins are classified as maytansinoids, and biosynthesized by Actinosynnema proetiosum, therein ansamitocin P-3 (AP-3) has an excellent activity.
Due to the important physiological activities, the interest in ansamitocins has increased around the world in recent years. Many studies have focused on strain improvement, medium optimization, and pathway regulation to enhance AP-3 production. However, its commercial application is still limited resulted from the low productivity and high price of AP-3. Until now there is no information related to environmental factor on AP-3 production based on the fermentation process and the molecular mechanism for regulation of AP-3 biosynthesis, albeit those knowledge is significant for increasing antibiotics productivity.
In this study, we first adopted the reported medium to produce AP-3 in the fermentation of Actinosynnem pretiosum spp. auranticum 31565, however, only an amount of 1-2 mgL-1 was observed. Thus, the Plackett-Burman and fold-over Plackett-Burman designs were applied to select fermentation medium, and the maximum AP-3 production was 12.9 mgL-1. Furthermore, one-time-one-factor method was used to simplify the medium compositions, and found that ammonium and isobutanol exerted negative and positive effects on AP-3 production respectively. The center composition design as well as response surface method were then employed to optimize the medium concentrations, the final fermentation medium were (gL-1):glucose 5, yeast extract 10, glycerol 40, corn filtrate 20, CaCO35, K2HPO40.5, FeSO4·7H2O 0.002, and isobutanol 3, the maximum AP-3 production was 68.2 mgL-1 with an inoculua of 1.64×109 CFUL-1 cultivated for 96 h in 60 mL/250 mL flask at 220 rpm, the productivity (17.1 mgL-1d-1) was higher among the published references. Fermentation based on flask initial KLa was carried out in 3-L bioreactor successfully, and the AP-3 production achieved 52 mgL-1 at 96 h.
It was observed that removal of ammonium from the fermentation medium was positive to AP-3 production. However, ammonium is an intermediate of nitrogen-contained compounds which always accumulated during antibiotics fermentation, information on ammonium effect from the viewpoint of biosynthetic gene transcription and proteomics has not yet reported, albeit it is beneficial to medium selection and pathway reconstruction. Hence, inhibition of AP-3 production was studied with (37 mM) and without ammonium based on fermentation process. Fermentation profiles showed that mycelium growth rate was repressed by ammonium, but the absorption rate of extracellular isobutyrate was facilitated. Assay of enzymatic activities showed that the activity of valine dehydrogenase, the first enzyme in valine metabolism pathway that always inhibited by ammonium in other systems, was induced during the whole process. Transcriptional levels of genes in AP-3 biosynthetic pathway were down-regulated by ammonium, which was in agreement with the production reduction. About 1600 protein spots by two-dimensional electrophoresis with pH3-5.6 and PAGE concentration of 13.5% were obtained; therein spots above 1.5-fold differential expression determined by mass determination were D-3-phosphoglycerate dehydrogenase, glyceraldehyde 3-phosphate dehydrogenase, and fatty acid synthase etc. The results showed that ammonium influenced the biosynthesis of fatty acid and serine, and regulated the transcription of AP-3 biosynthetic genes.
Previous work implied that isobutanol might act as a precursor of isobutyryl-CoA (side chain of AP-3), and the enhancement of AP-3 production by isobutanol addition was also found during the process of medium optimization. We first optimize the addition conditions, and found that isobutanol added at 0 h with 36 mM was optimal, resulting in 3.4-fold improvement of AP-3 and 4-fold decrease of AP-2 production at 96 h. Accumulation profiles of intracellular CoAs showed that acetyl-CoA and malonyl-CoA concentration increased in isobutanol supplemented culture, suggested isobutanol also influence pools of extender units of AP-3. In isobutanol supplemented culture activities of both isobutanol dehydrogenase and valine dehydrogenase were enhanced for about 2 folds in the growth phase and production phase, respectively; further combined addition of valine at 36 h based on isobutanol resulted in 35% improvement of AP-3 yield (82.3 mgL"1). Transcriptional response of genes in AP-3 biosynthetic and isobutyryl-CoA catabolic pathways showed a similar way as the increase of AP-3 production, therein the side-chain incorporating gene asm19 and regulatory gene asm40 in the former pathway were up-regulated by isobutanol significantly, and genes in the latter pathway were also induced, suggested a shunt of isobutyryl-CoA metabolism by isobutanol. Furthermore, protein expression of catalase and LysR family regulator related to the state of cell redox was up-regulated by isobutanol resulted from proteomics study. In addition, to testify the responses of asm19 and asm40 to isobutanol, their engineering strains were cultivated, and it was observed that overexpression of asm19 resulted in more tolerance of isobutanol than wild type, while deletion of asm40 induced AP-3 production for 20% by isobutanol, suggested an indirect role of asm40 in response to isobutanol. The information indicated that isobutanol disturbed the pools of precursor CoAs for AP-3 biosynthesis, and influenced the expression of redox-related genes and proteins in cells.
Collectively, this work revealed that ammonium could activate the biosynthetic pathways of fatty acid and serine, as well as down-regulated of the transcription of AP-3 biosynthetic genes; meanwhile, the positive role of isobutanol was caused by changes of precursor supply, and influence of expression of genes and proteins related to the redox state of cells. The information is helpful to development of fermentation medium and reconstitution of AP-3 biosynthetic pathway, and also taken as a reference to other antibiotics fermentation.
引文
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