宏观和微观代谢分析相结合的系统生物过程研究—维生素B_（12）发酵过程优化
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摘要
当前,微生物发酵过程研究正逐渐由胞外深入到胞内,由宏观扩展到微观。建立起能检测并综合利用胞内外的宏观和微观代谢信息的方法对我国从发酵大国发展到发酵强国具有重要意义。本文以脱氮假单胞菌(Pseudomonas denitrificans)生产维生素B12发酵过程为对象,探讨在微生物发酵过程中进行微观和宏观代谢信息综合检测和分析的方法。维生素B12在医药和添加剂等行业中有着广泛应用,如何实现维生素B12发酵过程的优化控制及其产率提高已逐渐成为研究的热点,本研究采用微观和宏观代谢信息相结合的方法系统地研究了维生素B12合成前体甜菜碱、供氧和过程中C02的优化控制和放大优化策略。具体结果如下：
P. denitrificans发酵生产维生素B12代谢途径网络的分析。分析了利用同位素13C葡萄糖标记实验进行代谢通量考察的原理、数据处理和代谢速率的计算过程,以及以同位素标记实验得到的代谢网络节点通量比率为约束条件的整体代谢通量分析。建立了以宏观代谢参数相同为控制指标的可用于同位素标记实验的微型传感反应系统,该微型反应器体积小(200ml),能够精确采集和在线控制温度、溶氧、pH、氧摄取速率(OUR)、C02释放速率(CER)、呼吸商(RQ)等参数,并配备有尾气质谱仪检测系统对发酵过程尾气中的同位素标记的45CO2进行精确定量分析。该系统能很好地对生产发酵过程中的代谢状态进行同位素示踪考察。利用[1-13C]和[U-13C]葡萄糖标记代谢实验,建立并鉴定了P. denitrificans发酵生产维生素B12的代谢途径网络,研究表明该菌主要利用ED途径和磷酸戊糖途径(PPP)代谢葡萄糖,而EMP途径几乎没有活性,含有丙酮酸羧化酶和磷酸烯醇式丙酮酸羧化激酶催化的回补和糖异生途径。
甜菜碱的代谢机制考察及控制策略的优化。利用[U-13C]葡萄糖考察了甜菜碱在发酵过程中的代谢去向,通过对菌体蛋白原氨基酸的标记信息和尾气中二氧化碳的丰度分析,结合宏观代谢参数的变化,定性和定量分析了甜菜碱在发酵过程中的代谢过程。结果表明,在菌体生长阶段,大量的甜菜碱参与到中心代谢并被用于菌体的合成。进一步研究发现适量的甜菜碱浓度对发酵过程中pH的维持和菌体的呼吸有很大的影响,因此对甜菜碱的添加策略进行了合理的调整,在初始培养基中不添加甜菜碱,而是在进入指数增长期后期(以OUR开始下降为指示点)开始连续补加甜菜碱以维持最佳的浓度3-5g/l,能明显促进菌体生长和VB12合成,同时将甜菜碱的消耗量降低了58.7%。
根据宏观和微观代谢信息综合分析,建立了以OUR为控制变量的代谢过程优化控制工艺。首先通过分批和连续培养详细考察了P. denitrificans的生理代谢特性,研究表明该菌对氧有极高的亲和力,供氧对发酵过程有着显著的影响。因此进一步在50 L高级反应器中详细研究了不同氧消耗速率(OUR)下P. denitrificans发酵过程的宏观代谢参数的变化,并进行了详细的微观代谢通量变化分析,提出了以OUR为在线控制参数的分阶段供氧调控策略。进而结合120 m3反应器中的流场特性分析,成功地将该优化控制策略进行了生产放大,发酵单位提高了17.3%,单位维生素B12合成所消耗葡萄糖量减少了34.4%,同时大大降低了动力消耗,提高了生产效益。
在利用菌体蛋白氨基酸进行稳态同位素代谢分析实验的基础上,建立了利用13C同位素研究P. denitrificans生长非稳态时代谢通量的方法。通过微型传感反应器跟踪生产发酵罐进行同位素标记实验,利用GC-MS分析菌体胞内游离氨基酸的标记信息,对维生素B12分批发酵过程不同阶段的代谢通量进行精确分析。结果表明,该方法能很好地对分批发酵过程中的代谢情况进行实时跟踪考察,同时发现随着发酵过程中VB12合成速率的增加丙酮酸羧化生成草酰乙酸的途径通量大大增强。鉴于羧化回补途径中CO2的重要性,采用静止细胞培养方式研究了C02对VB12合成阶段发酵过程的影响,结合宏观代谢相关参数变化和微观代谢途径通量分析,提出了发酵过程中基于搅拌和通气协同作用的C02优化控制策略,该优化策略下VB12的发酵单位达到了235.4mg/l,比最初的原始工艺(177.1mg/l)提高了32.9%。
总之,在微生物发酵过程中检测并综合利用胞内外的宏观和微观代谢信息进行发酵过程优化的方法是可行的。该方法能够更深入地了解发酵过程现象背后的机理,洞察基因改造和环境参数对细胞代谢的影响,更好地进行工业微生物发酵过程优化。
Currently, the researches on microbial fermentation process are getting more and more profound, which has been developed from the extracellular to intracellular analysis, from macrocosmic to microcosmic metabolism of the microbes. Therefore, an industrial systems bioprocess engineering by integrating the multi scale physiological metabolism information is more essential for elevating the power of the domestic industrial fermentation. In the present work, the methods for determining and analyzing the macro-and micro-metabolic information were established in the industrial vitamin B12 fermentation by Pseudomonas denitrificans. Vitamin B12 has become one of the most important industrial materials for its well utilization in medicine and nutrition; more and more researches were focused on the improvement of the productivity and the optimization of the fermentation process controlling strategy. Integrated with the systematical analysis of the macro and micro metabolism information, the effects and the controlling strategies of the betaine, oxygen supply, and CO2 on the vitamin B12 fermentation and scale-up were investigated in this thesis.
The structurally conserved and ubiquitous pathways of central carbon metabolism were identified and quantified in vitamin B12 producing strain P. denitrificans. The protocol for fast sampling and the principles underlying the calculation of metabolic flux ratios from the mass spectra of amino acids were developed. Furthermore, a mini-scale sensor reactor system was constructed for the 13C-labeling experiments, which has only 200 ml volume and all the online parameters reflecting the physiological characters (like pH, dissolved oxygen, OUR, CER, RQ, etc.) can be monitored and controlled. And also the labeled 45CO2 could be well determined. The central carbon metabolism in vitamin B12 producing strain P. denitrificans were identified and quantified with labeling experiments based on the [1-13C] and [U-13C] glucose. The results demonstrated that glucose was mainly consumed along the Entner-Doudoroff pathway, the pentose phosphate pathway, and the EMP pathway was inactive. Although the main result was identical to other reported Pseudomonas, but there was a high pentose phosphate pathway and no malic enzyme activity in this strain. The C1 metabolism associated with the serine, glycine and betaine was also illustrated in detail.
The mechanism and the optimal controlling strategy of betaine were constructed in vitamin B12 production based on the [U-13C] glucose experiments. The fate of betaine and the metabolic fluxes analysis were illustrated under 13C-constrained flux balancing analysis, complemented with stoichiometric relations and measured extracellular rates. Fluxes in central metabolism of exponentially growing P. denitrificans revealed that most of the betaine was disassembled for cell growth, only small amount of it was served as methyl group donor for vitamin B12 biosynthesis. Meanwhile the betaine also had the function for enhancement of the respiration and maintaining the constant pH in the fermentation process. Furthermore, the feeding strategy of the betaine was optimized combined with OUR. The optimal betaine supplementation time began just at the moment of the decreasing point of OUR, which would not only accelerate vitamin B12 production rate and decrease the consumption of the betaine significantly (about 58.7% lower than that of control), but also avoid the inhibition of high betaine concentration on cell growth, and thus a cost-effective industrial vitamin B12 fermentation technology was achieved.
Integrated with the macro and micro metabolic parameters analysis, a novel oxygen supply controlling strategy based on oxygen uptake rates (OUR) was achieved for cost effective vitamin B12 production. The physiological metabolic characters of P. denitrificans on vitamin B12 fermentation were investigated under fed-batch and continuous cultivations, a high affinity to oxygen was demonstrated in the strain, and oxygen supply played an important role on vitamin B12 production. Therefore, the effects of different oxygen transfer rates (OTR) on the cell growth and vitamin B12 biosynthesis of P. denitrificans were investigated under dissolved oxygen limiting conditions. The results demonstrated that high OTR accelerated cell growth and initial vitamin B12 biosynthesis rate, while lower OTR was critical for higher productivity in the late fermentation process. The OUR corresponded well with OTR. Based on the metabolic intermediates analysis and the metabolic flux analysis, a step-wise OUR control strategy was proposed. The strategy was successfully implemented in scale-up to an industrial fermenter (120 m3). A stable maximum vitamin B12 production of 208±2.5 mg/1 was achieved, which was increased by 17.3 percent compared with the control. Furthermore, the glucose consumption coefficient to vitamin B12 was 34.4 percent lower than that of the control. An efficient and economical fermentation process based on OUR criterion was established for industrial vitamin B12 fermentation by P. denitrificans.
Metabolic flux analysis using 13C-labeled substrates is a well-developed method for investigating cellular behavior in steady state culture condition. To extend its application, in particular to typical industrial conditions, such as batch and fed-batch cultivations, a novel method of 13C metabolic flux analysis based on intracellular free amino acids was proposed. Metabolic flux distributions were determined in both exponential and stationary phases. Using this new approach, a culture phase-dependent metabolic shift on anaplerotic reaction catalyzed by pyruvate carboxylase was detected in the industrial fed-batch fermentation. The approach presented here has great potential for investigating cellular behavior in industrial processes. Considering the importance of the CO2 on the anaplerotic reaction, the effect of increased levels of dissolved CO2 on fed-batch cultures of P. denitrificans was investigated by means of continuous gassing with inlet gas mixtures containing various ranges of CO2 concentration. Combined with the systematical analysis of the macro and micro metabolism information, an optimal CO2 controlling strategy through adjustment of the agitation and aeration strategy was proposed, with which the highest vitamin B12production of 235.4 mg/1 was obtained, which was 32.9% higher than that of the control (177.1 mg/1) before the optimization.
Overall, detecting and integrating the macro and micro metabolism information of industrial microorganisms are feasible approach for the optimization of fermentation process. This strategy could also be well utilized for better understanding the mechanism behind the fermentation phenomenon and revealing the synergistic effects of genetic modifications and environment parameters on cell metabolism, thus the better industrial fermentation process optimization could be achieved.
P. denitrificans发酵生产维生素B12代谢途径网络的分析。分析了利用同位素13C葡萄糖标记实验进行代谢通量考察的原理、数据处理和代谢速率的计算过程,以及以同位素标记实验得到的代谢网络节点通量比率为约束条件的整体代谢通量分析。建立了以宏观代谢参数相同为控制指标的可用于同位素标记实验的微型传感反应系统,该微型反应器体积小(200ml),能够精确采集和在线控制温度、溶氧、pH、氧摄取速率(OUR)、C02释放速率(CER)、呼吸商(RQ)等参数,并配备有尾气质谱仪检测系统对发酵过程尾气中的同位素标记的45CO2进行精确定量分析。该系统能很好地对生产发酵过程中的代谢状态进行同位素示踪考察。利用[1-13C]和[U-13C]葡萄糖标记代谢实验,建立并鉴定了P. denitrificans发酵生产维生素B12的代谢途径网络,研究表明该菌主要利用ED途径和磷酸戊糖途径(PPP)代谢葡萄糖,而EMP途径几乎没有活性,含有丙酮酸羧化酶和磷酸烯醇式丙酮酸羧化激酶催化的回补和糖异生途径。
甜菜碱的代谢机制考察及控制策略的优化。利用[U-13C]葡萄糖考察了甜菜碱在发酵过程中的代谢去向,通过对菌体蛋白原氨基酸的标记信息和尾气中二氧化碳的丰度分析,结合宏观代谢参数的变化,定性和定量分析了甜菜碱在发酵过程中的代谢过程。结果表明,在菌体生长阶段,大量的甜菜碱参与到中心代谢并被用于菌体的合成。进一步研究发现适量的甜菜碱浓度对发酵过程中pH的维持和菌体的呼吸有很大的影响,因此对甜菜碱的添加策略进行了合理的调整,在初始培养基中不添加甜菜碱,而是在进入指数增长期后期(以OUR开始下降为指示点)开始连续补加甜菜碱以维持最佳的浓度3-5g/l,能明显促进菌体生长和VB12合成,同时将甜菜碱的消耗量降低了58.7%。
根据宏观和微观代谢信息综合分析,建立了以OUR为控制变量的代谢过程优化控制工艺。首先通过分批和连续培养详细考察了P. denitrificans的生理代谢特性,研究表明该菌对氧有极高的亲和力,供氧对发酵过程有着显著的影响。因此进一步在50 L高级反应器中详细研究了不同氧消耗速率(OUR)下P. denitrificans发酵过程的宏观代谢参数的变化,并进行了详细的微观代谢通量变化分析,提出了以OUR为在线控制参数的分阶段供氧调控策略。进而结合120 m3反应器中的流场特性分析,成功地将该优化控制策略进行了生产放大,发酵单位提高了17.3%,单位维生素B12合成所消耗葡萄糖量减少了34.4%,同时大大降低了动力消耗,提高了生产效益。
在利用菌体蛋白氨基酸进行稳态同位素代谢分析实验的基础上,建立了利用13C同位素研究P. denitrificans生长非稳态时代谢通量的方法。通过微型传感反应器跟踪生产发酵罐进行同位素标记实验,利用GC-MS分析菌体胞内游离氨基酸的标记信息,对维生素B12分批发酵过程不同阶段的代谢通量进行精确分析。结果表明,该方法能很好地对分批发酵过程中的代谢情况进行实时跟踪考察,同时发现随着发酵过程中VB12合成速率的增加丙酮酸羧化生成草酰乙酸的途径通量大大增强。鉴于羧化回补途径中CO2的重要性,采用静止细胞培养方式研究了C02对VB12合成阶段发酵过程的影响,结合宏观代谢相关参数变化和微观代谢途径通量分析,提出了发酵过程中基于搅拌和通气协同作用的C02优化控制策略,该优化策略下VB12的发酵单位达到了235.4mg/l,比最初的原始工艺(177.1mg/l)提高了32.9%。
总之,在微生物发酵过程中检测并综合利用胞内外的宏观和微观代谢信息进行发酵过程优化的方法是可行的。该方法能够更深入地了解发酵过程现象背后的机理,洞察基因改造和环境参数对细胞代谢的影响,更好地进行工业微生物发酵过程优化。
Currently, the researches on microbial fermentation process are getting more and more profound, which has been developed from the extracellular to intracellular analysis, from macrocosmic to microcosmic metabolism of the microbes. Therefore, an industrial systems bioprocess engineering by integrating the multi scale physiological metabolism information is more essential for elevating the power of the domestic industrial fermentation. In the present work, the methods for determining and analyzing the macro-and micro-metabolic information were established in the industrial vitamin B12 fermentation by Pseudomonas denitrificans. Vitamin B12 has become one of the most important industrial materials for its well utilization in medicine and nutrition; more and more researches were focused on the improvement of the productivity and the optimization of the fermentation process controlling strategy. Integrated with the systematical analysis of the macro and micro metabolism information, the effects and the controlling strategies of the betaine, oxygen supply, and CO2 on the vitamin B12 fermentation and scale-up were investigated in this thesis.
The structurally conserved and ubiquitous pathways of central carbon metabolism were identified and quantified in vitamin B12 producing strain P. denitrificans. The protocol for fast sampling and the principles underlying the calculation of metabolic flux ratios from the mass spectra of amino acids were developed. Furthermore, a mini-scale sensor reactor system was constructed for the 13C-labeling experiments, which has only 200 ml volume and all the online parameters reflecting the physiological characters (like pH, dissolved oxygen, OUR, CER, RQ, etc.) can be monitored and controlled. And also the labeled 45CO2 could be well determined. The central carbon metabolism in vitamin B12 producing strain P. denitrificans were identified and quantified with labeling experiments based on the [1-13C] and [U-13C] glucose. The results demonstrated that glucose was mainly consumed along the Entner-Doudoroff pathway, the pentose phosphate pathway, and the EMP pathway was inactive. Although the main result was identical to other reported Pseudomonas, but there was a high pentose phosphate pathway and no malic enzyme activity in this strain. The C1 metabolism associated with the serine, glycine and betaine was also illustrated in detail.
The mechanism and the optimal controlling strategy of betaine were constructed in vitamin B12 production based on the [U-13C] glucose experiments. The fate of betaine and the metabolic fluxes analysis were illustrated under 13C-constrained flux balancing analysis, complemented with stoichiometric relations and measured extracellular rates. Fluxes in central metabolism of exponentially growing P. denitrificans revealed that most of the betaine was disassembled for cell growth, only small amount of it was served as methyl group donor for vitamin B12 biosynthesis. Meanwhile the betaine also had the function for enhancement of the respiration and maintaining the constant pH in the fermentation process. Furthermore, the feeding strategy of the betaine was optimized combined with OUR. The optimal betaine supplementation time began just at the moment of the decreasing point of OUR, which would not only accelerate vitamin B12 production rate and decrease the consumption of the betaine significantly (about 58.7% lower than that of control), but also avoid the inhibition of high betaine concentration on cell growth, and thus a cost-effective industrial vitamin B12 fermentation technology was achieved.
Integrated with the macro and micro metabolic parameters analysis, a novel oxygen supply controlling strategy based on oxygen uptake rates (OUR) was achieved for cost effective vitamin B12 production. The physiological metabolic characters of P. denitrificans on vitamin B12 fermentation were investigated under fed-batch and continuous cultivations, a high affinity to oxygen was demonstrated in the strain, and oxygen supply played an important role on vitamin B12 production. Therefore, the effects of different oxygen transfer rates (OTR) on the cell growth and vitamin B12 biosynthesis of P. denitrificans were investigated under dissolved oxygen limiting conditions. The results demonstrated that high OTR accelerated cell growth and initial vitamin B12 biosynthesis rate, while lower OTR was critical for higher productivity in the late fermentation process. The OUR corresponded well with OTR. Based on the metabolic intermediates analysis and the metabolic flux analysis, a step-wise OUR control strategy was proposed. The strategy was successfully implemented in scale-up to an industrial fermenter (120 m3). A stable maximum vitamin B12 production of 208±2.5 mg/1 was achieved, which was increased by 17.3 percent compared with the control. Furthermore, the glucose consumption coefficient to vitamin B12 was 34.4 percent lower than that of the control. An efficient and economical fermentation process based on OUR criterion was established for industrial vitamin B12 fermentation by P. denitrificans.
Metabolic flux analysis using 13C-labeled substrates is a well-developed method for investigating cellular behavior in steady state culture condition. To extend its application, in particular to typical industrial conditions, such as batch and fed-batch cultivations, a novel method of 13C metabolic flux analysis based on intracellular free amino acids was proposed. Metabolic flux distributions were determined in both exponential and stationary phases. Using this new approach, a culture phase-dependent metabolic shift on anaplerotic reaction catalyzed by pyruvate carboxylase was detected in the industrial fed-batch fermentation. The approach presented here has great potential for investigating cellular behavior in industrial processes. Considering the importance of the CO2 on the anaplerotic reaction, the effect of increased levels of dissolved CO2 on fed-batch cultures of P. denitrificans was investigated by means of continuous gassing with inlet gas mixtures containing various ranges of CO2 concentration. Combined with the systematical analysis of the macro and micro metabolism information, an optimal CO2 controlling strategy through adjustment of the agitation and aeration strategy was proposed, with which the highest vitamin B12production of 235.4 mg/1 was obtained, which was 32.9% higher than that of the control (177.1 mg/1) before the optimization.
Overall, detecting and integrating the macro and micro metabolism information of industrial microorganisms are feasible approach for the optimization of fermentation process. This strategy could also be well utilized for better understanding the mechanism behind the fermentation phenomenon and revealing the synergistic effects of genetic modifications and environment parameters on cell metabolism, thus the better industrial fermentation process optimization could be achieved.
引文
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