重组枯草芽孢杆菌生产核黄素发酵优化及代谢组学研究
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摘要
本文在重组B. subtilis RH44产核黄素发酵优化的基础上,基于酶活测定、代谢通量分析等方法对具有显著影响的培养基成分在核黄素生产中的作用机理进行探讨,并利用LC-MS分析手段对产核黄素B. subtilis RH44的代谢物组学进行研究。
首先通过一系列统计实验设计方法对核黄素发酵培养基组成进行优化。根据Plackett-Burman实验确定影响核黄素生成的5个重要成分分别为葡萄糖、NaNO_3、K_2HPO_4、ZnSO_4和MnCl_2;然后,通过中心组成(CCD)设计和响应面方法(RSM)获得核黄素生产的优化培养基。该优化培养基在摇瓶培养中可获得核黄素6.65 g/L。采用RSM和神经网络(ANN)耦合遗传算法(GA)两种方法共同优化B. subtilis RH44在5 L罐中间歇发酵核黄素的培养参数(pH、接种量、通气量、搅拌速率和温度)。ANN-GA方法可获得核黄素最大产量为7.53 g/L,比RSM法高出8.6%。
对比研究了间隔补料、恒速补料和葡萄糖限制补料三种间歇补料方式对B. subtilis RH44发酵生产核黄素的影响。结果表明葡萄糖限制间歇补料模式(葡萄糖浓度维持在5~10 g/L)为最适合的补料方式。研究pH对B. subtilis RH44间歇补料发酵生产核黄素的影响表明,菌体生长的最适pH为6.8,但在pH7.2时,核黄素浓度和核黄素合成酶活性达到最大。使用pH转换策略可明显改善核黄素的生产,最大的核黄素浓度比常数pH操作的最好结果提高了13.3%。pH对副产物浓度及相关酶比活的影响表明优化的pH转换策略能够在一定程度上抑制副产物的形成和积累。用NH_4OH代替NaOH调节pH,pH转换策略可使核黄素浓度进一步提高,48 h达到17.4 g/L。
初步探讨了对B. subtilis RH44产核黄素具有显著促进作用的三种培养基成分(NaNO_3、ZnSO_4和MnCl_2)的作用机理。对比B. subtilis 168和B. subtilis RH44在NH_4~+存在时利用NO_3~–的情况说明B. subtilis RH44已经解除了NH_4~+对NO_3~–利用的抑制作用。进一步代谢通量分析表明,优化氮源使发酵中后期的葡萄糖代谢流由EMP途径向PP途径迁移,使得更多的通量流向核黄素合成的途径。通过酶学研究表明Mn~(2+)激活了PP途径的关键酶葡萄糖-6-磷酸脱氢酶(G6PDH)的比活性,并抑制形成乙酸的相关酶磷酸转乙酰酶(PTA)的比活性。根据预测的B. subtilis GTP环水解酶II(GCHII)的立体结构,推断Zn~(2+)对核黄素生产的促进作用可能与GCHII有密切关系。建立产核黄素B. subtilis代谢网络,利用代谢通量分析进一步研究Mn~(2+)和Zn~(2+)对核黄素生产过程中代谢流的影响。
建立利用LC-MS分析手段进行产核黄素B. subtilis代谢物组学研究的方法。对不同发酵阶段的胞内代谢物负离子ESI-MS数据进行主成分分析,结果表明代谢物组学方法可以区分不同发酵阶段的代谢产物。通过标样和二级质谱对代谢物进行定性分析,可初步确定16种代谢物。根据代谢物轮廓分析分别对比研究不同发酵时间、不同氮源和不同菌种的代谢物差异,并推测出B. subtilis RH44合成核黄素的可能限制因素。
Riboflavin fermentation process by recombinant Bacillus subtilis RH44 was optimized, and then the mechanisms of the significant factors enhancing riboflavin production were discussed according to enzyme activity assay and metabolic flux analysis. The metabolomics of B. subtilis RH44 was investigated primarily using LC-MS.
A sequential optimization strategy, based on statistical experimental designs, was used to enhance the production of riboflavin. Plackett-Burman design was implemented to screen medium components that significantly influence riboflavin production. Among the fifteen variables tested, glucose, NaNO_3, K_2HPO_4, ZnSO_4, and MnCl_2 were identified as the most significant factors for riboflavin production. The optimal values of these five variables were determined by response surface methodology (RSM) based on the central composite design (CCD). This optimum medium led to a maximum riboflavin concentration of 6.65 g/L in shake flasks. The optimal culture parameters (i.e. pH, inoculum level, stirring speed, temperature and airflow rate) for maximum riboflavin production by batch cultivations in a 5 L fermentor were determined by using artificial neural networks (ANN) incorporating genetic algorithm (GA) and RSM. ANN-GA led to the maximum riboflavin production of 7.53 g/L, which was 8.6% higher than that by RSM.
Three fed-batch modes, intermittent, constant rate and glucose-limited, were carried out to reduce overflow in this work. The maximum riboflavin titer was obtained in a glucose-limited fed-batch process by maintaining constant (5~10 g/L) glucose concentration in the culture broth. The effects of pH on riboflavin production were investigated using a series of glucose-limited fed-batch fermentations. Although constant pH 6.8 was favorable for the cell formation, constant pH 7.2 resulted in the highest riboflavin production and also maximum specific activity of riboflavin synthase of B. subtilis RH44. Hence, a pH-shift strategy was developed to improve riboflavin production. The results showed that the maximum riboflavin concentration was increased by 13.3% when compared with the best results of constant pH. The results of pH influence on both by-product levels and by-product forming enzyme activities indicated that the optimum pH-shift strategy had the capability of inhibiting the accumulation of by-products to a certain extent. In addition, when pH was adjusted with NH4OH instead of NaOH, in the pH-shift strategy, further improvement (17.4 g/L in 48 h) was achieved in riboflavin production.
The mechamisms of three significant factors enhancing riboflavin production were discussed further. The comparison of the consumption courses of NH_4~+ and NO_3~–of B. subtilis 168 and B. subtilis RH44 showed that the utilization of NO_3~– in B. subtilis RH44 did not appear to be inhibited by NH_4~+. The metabolic flux shifted from EMP to PP during the mid- and later phases when the optimum nitrogen sources were used. Mn~(2+) has an activation function to glucose-6-phosphate dehydrogenase (G6PDH), while an inhibition to the activity of phosphortransacetylase (PTA). Possibly, the effect of Zn~(2+) on riboflavin biosynthesis had a close relationship with GCHII. The functions of Mn~(2+) and Zn~(2+) to riboflavin production were further investigated using metabolic flux analysis.
A scheme of metabolomics analysis by LC-MS on B. subtilis was developed. The metabolomic analysis was valid to distinguish various culture phases by principal components analysis of negative ions ESI-MS data. In addition, 16 metabolites were determined by qualification analysis based on m/z of metabolites as well as standard and MS-MS. The limited factors of riboflavin production by B. subtilis RH44 were discussed according to the comparison of metabolites of different nitrogen sources and different strains by metabolic profiling analysis.
首先通过一系列统计实验设计方法对核黄素发酵培养基组成进行优化。根据Plackett-Burman实验确定影响核黄素生成的5个重要成分分别为葡萄糖、NaNO_3、K_2HPO_4、ZnSO_4和MnCl_2;然后,通过中心组成(CCD)设计和响应面方法(RSM)获得核黄素生产的优化培养基。该优化培养基在摇瓶培养中可获得核黄素6.65 g/L。采用RSM和神经网络(ANN)耦合遗传算法(GA)两种方法共同优化B. subtilis RH44在5 L罐中间歇发酵核黄素的培养参数(pH、接种量、通气量、搅拌速率和温度)。ANN-GA方法可获得核黄素最大产量为7.53 g/L,比RSM法高出8.6%。
对比研究了间隔补料、恒速补料和葡萄糖限制补料三种间歇补料方式对B. subtilis RH44发酵生产核黄素的影响。结果表明葡萄糖限制间歇补料模式(葡萄糖浓度维持在5~10 g/L)为最适合的补料方式。研究pH对B. subtilis RH44间歇补料发酵生产核黄素的影响表明,菌体生长的最适pH为6.8,但在pH7.2时,核黄素浓度和核黄素合成酶活性达到最大。使用pH转换策略可明显改善核黄素的生产,最大的核黄素浓度比常数pH操作的最好结果提高了13.3%。pH对副产物浓度及相关酶比活的影响表明优化的pH转换策略能够在一定程度上抑制副产物的形成和积累。用NH_4OH代替NaOH调节pH,pH转换策略可使核黄素浓度进一步提高,48 h达到17.4 g/L。
初步探讨了对B. subtilis RH44产核黄素具有显著促进作用的三种培养基成分(NaNO_3、ZnSO_4和MnCl_2)的作用机理。对比B. subtilis 168和B. subtilis RH44在NH_4~+存在时利用NO_3~–的情况说明B. subtilis RH44已经解除了NH_4~+对NO_3~–利用的抑制作用。进一步代谢通量分析表明,优化氮源使发酵中后期的葡萄糖代谢流由EMP途径向PP途径迁移,使得更多的通量流向核黄素合成的途径。通过酶学研究表明Mn~(2+)激活了PP途径的关键酶葡萄糖-6-磷酸脱氢酶(G6PDH)的比活性,并抑制形成乙酸的相关酶磷酸转乙酰酶(PTA)的比活性。根据预测的B. subtilis GTP环水解酶II(GCHII)的立体结构,推断Zn~(2+)对核黄素生产的促进作用可能与GCHII有密切关系。建立产核黄素B. subtilis代谢网络,利用代谢通量分析进一步研究Mn~(2+)和Zn~(2+)对核黄素生产过程中代谢流的影响。
建立利用LC-MS分析手段进行产核黄素B. subtilis代谢物组学研究的方法。对不同发酵阶段的胞内代谢物负离子ESI-MS数据进行主成分分析,结果表明代谢物组学方法可以区分不同发酵阶段的代谢产物。通过标样和二级质谱对代谢物进行定性分析,可初步确定16种代谢物。根据代谢物轮廓分析分别对比研究不同发酵时间、不同氮源和不同菌种的代谢物差异,并推测出B. subtilis RH44合成核黄素的可能限制因素。
Riboflavin fermentation process by recombinant Bacillus subtilis RH44 was optimized, and then the mechanisms of the significant factors enhancing riboflavin production were discussed according to enzyme activity assay and metabolic flux analysis. The metabolomics of B. subtilis RH44 was investigated primarily using LC-MS.
A sequential optimization strategy, based on statistical experimental designs, was used to enhance the production of riboflavin. Plackett-Burman design was implemented to screen medium components that significantly influence riboflavin production. Among the fifteen variables tested, glucose, NaNO_3, K_2HPO_4, ZnSO_4, and MnCl_2 were identified as the most significant factors for riboflavin production. The optimal values of these five variables were determined by response surface methodology (RSM) based on the central composite design (CCD). This optimum medium led to a maximum riboflavin concentration of 6.65 g/L in shake flasks. The optimal culture parameters (i.e. pH, inoculum level, stirring speed, temperature and airflow rate) for maximum riboflavin production by batch cultivations in a 5 L fermentor were determined by using artificial neural networks (ANN) incorporating genetic algorithm (GA) and RSM. ANN-GA led to the maximum riboflavin production of 7.53 g/L, which was 8.6% higher than that by RSM.
Three fed-batch modes, intermittent, constant rate and glucose-limited, were carried out to reduce overflow in this work. The maximum riboflavin titer was obtained in a glucose-limited fed-batch process by maintaining constant (5~10 g/L) glucose concentration in the culture broth. The effects of pH on riboflavin production were investigated using a series of glucose-limited fed-batch fermentations. Although constant pH 6.8 was favorable for the cell formation, constant pH 7.2 resulted in the highest riboflavin production and also maximum specific activity of riboflavin synthase of B. subtilis RH44. Hence, a pH-shift strategy was developed to improve riboflavin production. The results showed that the maximum riboflavin concentration was increased by 13.3% when compared with the best results of constant pH. The results of pH influence on both by-product levels and by-product forming enzyme activities indicated that the optimum pH-shift strategy had the capability of inhibiting the accumulation of by-products to a certain extent. In addition, when pH was adjusted with NH4OH instead of NaOH, in the pH-shift strategy, further improvement (17.4 g/L in 48 h) was achieved in riboflavin production.
The mechamisms of three significant factors enhancing riboflavin production were discussed further. The comparison of the consumption courses of NH_4~+ and NO_3~–of B. subtilis 168 and B. subtilis RH44 showed that the utilization of NO_3~– in B. subtilis RH44 did not appear to be inhibited by NH_4~+. The metabolic flux shifted from EMP to PP during the mid- and later phases when the optimum nitrogen sources were used. Mn~(2+) has an activation function to glucose-6-phosphate dehydrogenase (G6PDH), while an inhibition to the activity of phosphortransacetylase (PTA). Possibly, the effect of Zn~(2+) on riboflavin biosynthesis had a close relationship with GCHII. The functions of Mn~(2+) and Zn~(2+) to riboflavin production were further investigated using metabolic flux analysis.
A scheme of metabolomics analysis by LC-MS on B. subtilis was developed. The metabolomic analysis was valid to distinguish various culture phases by principal components analysis of negative ions ESI-MS data. In addition, 16 metabolites were determined by qualification analysis based on m/z of metabolites as well as standard and MS-MS. The limited factors of riboflavin production by B. subtilis RH44 were discussed according to the comparison of metabolites of different nitrogen sources and different strains by metabolic profiling analysis.
引文
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