~（13）C代谢通量分析平台的建立与改良
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摘要
近十年来,系统生物学的概念和理论得到了迅速的发展,系统生物学的研究如火如荼地开展。系统生物学的核心是要整合各个层面,各个构成要素的知识。这些层面当中,除开耳熟能详的基因组,转录组,蛋白质组和代谢组外,通量组(Fluxome)成为越来越重要一个组成部分。
对这个体系的研究产生了新的组学,即代谢通量组学(Fluxomics)。其重点是对目标体系内的代谢通量的速度的方向和取值进行测定。所获得的信息对刻画生物系统的生理特性、评估遗传和环境对细胞的影响具有重要意义。
代谢通量组学的主要研究手段是代谢通量分析,它可以分为纯计量性代谢通量分析和13C代谢通量分析两类。其中13C代谢通量分析是近十多年来,国际上新发展并仍然处于发展当中的技术。它除开具有纯计量性代谢通量分析的能力外,还具有获取信息更多,适用范围更广的优点。它能获得代谢途径的交换通量,并且不依赖于除稳态假设外的其他生理假设,因而适用各种试验条件。但是对于13C代谢通量分析技术,国内还未见有博士论文专题研究。
本博士论文的内容主要分成二部分,一部分描述在中国科技大学建立13C代谢通量分析平台的工作,另一部分是对通量分析平台中的13C质量同位素异构体检测技术进行改进的工作。
第一章详细介绍了13C代谢通量分析的基本理论。
代谢通量分析的基础是代谢通量拟稳态假设。在此假设基础上,可以建立各个代谢物的物质平衡方程。13C代谢通量分析实验在培养底物里引入不完全的13C标记。13C会分布到所有代谢物中,而由于13C在代谢物中数量和位置的不同,可以得到同一种物质的不同的13C同位素异构体和质量同位素异构体(同位素异构体的一类特殊组合形式)。从同位素异构体概念出发,通过原子转移矩阵和同位素异构体转移矩阵,可以将物质平衡方程推广到同位素异构体守恒方程。通过对中间代谢物建立同位素异构体守恒方程组,可以得到代谢通量和代谢物的同位素异构体分布之间的确定但是隐式的关系。这个关系是一个较为复杂的多元二次方程组。当我们测量了同位素异构体分布的信息,依据此大规模的方程组和参数优化的数值方法,可以反推出代谢通量。同时,通过构建理论的测量值空间,利用Monte Carlo采样,仿照此求解过程,可以估计代谢通量的置信区间。
第二章的主要内容是13C通量分析平台的建立和实例研究。
第二章的第一部分详细介绍了13C代谢通量分析的检测技术。
首先,详细介绍了13C标记技术,这是进行13C代谢通量分析的基础。对于估计最后的代谢通量而言,我们还需要获取两方面的信息。一方面是关于同位素异构体比例的信息。通过核磁(Nuclear magnetic resonance, NMR)波谱,可以获得特定的同位素异构体组合的比例信息。这包括J-resovled HSQC脉冲序列,它主要用于测量单键相连接的13C异构体组合。通过质谱(Mass spectrometry, MS),可以测量质量同位素异构体比例的信息。另一方面是关于代谢物流出代谢体系的量值信息。一部分中间代谢物的流出量值通过细胞的生物质的质量和成分构成；还有一部分中间代谢物的流出量值,通过测量这些中间代谢物在培养液中的残留浓度来获取。最后介绍了参数优化的目标函数和置信区间估计的方法。
第二章的第二部分,以连续培养的大肠杆菌JM101株的代谢通量分析为例子,描述了连续培养下进行13C代谢通量分析的完整流程,也就是13C代谢通量分析实验平台的建立和实现。
第三章阐述了对13C质量同位素异构体检测技术所作的改进。改进后的方法可以提高质量同位素异构体比例的测量确度,从而提高13C代谢通量分析的准确度。
第三章的第一部分首先粗略地介绍了质谱测量的原理和基本过程。然后按照测量发生的顺序,介绍了质谱仪的基本的结构和功能单元。这些单元包括进样器,离子源,质量分析仪和信号检测器。之后论文较为详细地描述了用于气质联用的衍生化方法,特别是氨基酸的特丁基二甲基硅烷衍生化方法。最后,仔细地讨论了用以解决重同位素引起的质量位移作用的数学框架修正举证。
第三章的第二部分首先详细介绍了用质谱进行13C质量同位素异构体检测的基本假设,并对该假设进行了数学化的描述。利用该数学描述,对之前的各种提高质谱测量确度的方法进行了分类和描述。之后则介绍了如何提高13C质量同位素异构体测量确度的方法。利用已知了同位素异构体比例的样品,作为标准样,制作任意质谱仪的校准曲线,是一种最具有广泛性的提高测量精度的方法。我们使用以甲醇作为碳源的嗜甲基菌Methylobacterium salsuginis sp.,将其在排除了天然CO2的环境下,以13C标记的甲醇作为唯一碳源来进行培养。产生的各种生成物的同位素异构体比例可以用二项式公式来计算。我们引进一个新的量,它是两个连续的质量同位素异构体(13C原子数目相差1)的比值,由此避开了对多维向量进行校准的麻烦。而且,我们后验地测定每个产物的整个分子的平均13C比例,从而使得生物同位素效应的对13C分布不均匀性的影响降至最低。
第三章的第三部分则是对第二部分理论的实验实现,包括实验程序,理论模拟和结果讨论。经过校准后的结果,其绝对误差都小于0.9mol%,比未校准的结果有明显进步。而且,若采用理想的实验步骤,则误差可预计下降到0.4mol%以下。
在13C MFA平台上,我们分析研究了大肠肝菌中心代谢通量在超氧化应激情况下的变化情况。这部分内容是由芮斌同学和我共同完成的,请参看芮斌同学的博士论文。
此外,我们还进行了“不同剂量的氧化剂引起代谢系统不同强度反应”的研究,正在成文中。
In recent years, the concept and theory of systems biology have been undergoing a major development in accordance with its wide application in various areas. The core of this newly established discipline is the information integration across different "omes". Among these omes, the fluxome has played an increasingly important role in linking omes of different level.
Investigation of fluxome gives birth to the fluxomics which aims at quantitatively analyzing the direction and quantity of metabolic flux. Insights acquired from fluxomics would be of significant biological importance for depicting the physiological characteristic of cell as well as assessing the influence of the genetic and environmental manipulations on cell.
The primary technique for fluxomics is metabolic flux analysis, which consists of stoichiometry metabolic flux analysis and 13C metabolic flux analysis (13C MFA). 13C MFA has been the research hotspot of metabolic engineering internationally due to its accuracy and applicability. However, there is no domestic doctorate thesis concerning about 13C metabolic flux analysis.
This PhD thesis consists of two parts. The first part details the fundamental principle of 13C MFA and the implementation of its experimental platform. The second part describes a method to improve the measurement accuracy of 13C mass isotopomer analysis.
Chapter 1 illustrates the fundamental principle of 13C MFA.
The first part of chapter 1 describes the fundamental principle of 13C MFA.13C MFA introduces partial 13C labeling in cultivation substrate.13C will distribute among intermediates and metabolites and results in different isotopomer distribution. Starting from the concept of isotopomer, the mass balance relationship could be extended as isotopomers balance relationship which relates the metabolic flux with the isotopomer distribution of intermediates and metabolites. Isotopomers balance relationship is a complicated square equation of multiple variables. Based on these equations, the metabolic flux quantity could be deduced from the measured isotopomer information through evolution algorithm based parameter optimization. Afterwards, we could construct the theoretical measurement space and quantify the confidence interval of estimated flux value by Monte Carlo sampling.
Chapter 2 focuses on the introduction and implementation of experimental technique for 13C MFA.
The first part of chapter 2 describes experimental techniques which are necessary for 13C MFA.
The 13C labeling technique is the basis for 13C MFA. To estimate the intracellular metabolic flux value, information of isotopomer distribution as well as the information of the metabolites efflux must be obtained. The information of specific isotopomers can be acquired through NMR measurements. J-resolved HSQC could be used to analyze the isotopomers containing directly connected carbon-carbon bond. The mass isotopomer distribution could be quantified by MS measurement. The metabolites efflux is the other kind of information necessary for 13C MFA. Efflux value of some certain metabolites could be determined by analysis of the accumulated amount and the cellular composition of biomass. Besides, quantitatively analyzing the residual concentration could determine efflux value of other intermediates and metabolites. At the last stage, the objectivity for parameter optimization and confidence interval estimation method are presented.
The second part of chapter 2 is exhaustive experimental protocol of 13C MFA in continuous cultivation. That is the first implementation of 13C MFA platform in USTC.
Chapter 2 describes the second part of our work that is the improvement of measurement accuracy of 13C mass isotopomer analysis hence the flux accuracy of 13C MFA.
The first part of chapter 2 introduces concisely the principle and process of MS measurement. Then the basic structural and functional units of MS instrument are discussed. These units includes samples introduction, ionization source, mass separation and signal detection. Additionally, the derivatization methods, especially the TMBDMS-derivatization for GC-MS, are illustrated detailedly. Then a mathematical framework, correction matrix, is described to address the mass shift effect introduced by heavy isotopes in nonskeleton carbon.
The second part of chapter 2 firstly describes in particular the basic assumption for 13C mass isotopomer analysis by MS measurement. Then we re-state this assumption in a mathematical framework. Based upon this mathematical frame, we can easily classify and depict the previous methods of improving the MS measurement accuracy. These methods utilize linear extrapolation, nonlinear relationship or theoretical correction. These methods indeed produce accurate results than simple measurement. However, they have a shared shortcoming that they are instrument specific
The second part describes how to increase the accuracy of mass iotopomer analysis through calibration curves constructed using biologically synthesized compounds. Using the compounds with known isotopomer distribution as the standard sample one could plot calibration curve for any instrument. Thus, the correction method relying on calibration curve would be a general method that is universally applicable to MS measurements. The bacterium strain Methylobacterium salsuginis sp. nov. is cultivated with partially 13C labeled methanol as the only carbon source to produce 13C enriched compounds. The resulting product isotopomers obey binomial distribution. We introduces a new variable to replace the mass isotopomer distribution as optimization objectivity in order to circumvent the calibration for MID. Moreover, posterior measurement of average 13C abundance minimized the interference of intramolecular inhomogeneity of 13C isotope abundances caused by biological isotope fractionation.
The third part deals with the experimental implementation of the theory raised in the second part. This includes experimental protocol, numeric modeling, results and discussion. The absolute uncertainty after correction by calibration curve has decreased to 0.9mol%, remarkably reduced compared to the uncalibrated results. If the average 13C abundance is measured by gas chromatography-combustion-isotope ratio mass spectrometry, the expected error would decrease to 0.4mol%.
Ground on this 13C MFA platform, Rui Bin and I performed a global investigation of central carbon metabolism in response to superoxide stress in E.coli. Please refer to Rui Bin's PhD thesis for detailed description.
Besides, we had performed an investigation titled "serial metabolic flux analysis revealed a dose-dependent response of E.coli metabolism to oxidative stress".
对这个体系的研究产生了新的组学,即代谢通量组学(Fluxomics)。其重点是对目标体系内的代谢通量的速度的方向和取值进行测定。所获得的信息对刻画生物系统的生理特性、评估遗传和环境对细胞的影响具有重要意义。
代谢通量组学的主要研究手段是代谢通量分析,它可以分为纯计量性代谢通量分析和13C代谢通量分析两类。其中13C代谢通量分析是近十多年来,国际上新发展并仍然处于发展当中的技术。它除开具有纯计量性代谢通量分析的能力外,还具有获取信息更多,适用范围更广的优点。它能获得代谢途径的交换通量,并且不依赖于除稳态假设外的其他生理假设,因而适用各种试验条件。但是对于13C代谢通量分析技术,国内还未见有博士论文专题研究。
本博士论文的内容主要分成二部分,一部分描述在中国科技大学建立13C代谢通量分析平台的工作,另一部分是对通量分析平台中的13C质量同位素异构体检测技术进行改进的工作。
第一章详细介绍了13C代谢通量分析的基本理论。
代谢通量分析的基础是代谢通量拟稳态假设。在此假设基础上,可以建立各个代谢物的物质平衡方程。13C代谢通量分析实验在培养底物里引入不完全的13C标记。13C会分布到所有代谢物中,而由于13C在代谢物中数量和位置的不同,可以得到同一种物质的不同的13C同位素异构体和质量同位素异构体(同位素异构体的一类特殊组合形式)。从同位素异构体概念出发,通过原子转移矩阵和同位素异构体转移矩阵,可以将物质平衡方程推广到同位素异构体守恒方程。通过对中间代谢物建立同位素异构体守恒方程组,可以得到代谢通量和代谢物的同位素异构体分布之间的确定但是隐式的关系。这个关系是一个较为复杂的多元二次方程组。当我们测量了同位素异构体分布的信息,依据此大规模的方程组和参数优化的数值方法,可以反推出代谢通量。同时,通过构建理论的测量值空间,利用Monte Carlo采样,仿照此求解过程,可以估计代谢通量的置信区间。
第二章的主要内容是13C通量分析平台的建立和实例研究。
第二章的第一部分详细介绍了13C代谢通量分析的检测技术。
首先,详细介绍了13C标记技术,这是进行13C代谢通量分析的基础。对于估计最后的代谢通量而言,我们还需要获取两方面的信息。一方面是关于同位素异构体比例的信息。通过核磁(Nuclear magnetic resonance, NMR)波谱,可以获得特定的同位素异构体组合的比例信息。这包括J-resovled HSQC脉冲序列,它主要用于测量单键相连接的13C异构体组合。通过质谱(Mass spectrometry, MS),可以测量质量同位素异构体比例的信息。另一方面是关于代谢物流出代谢体系的量值信息。一部分中间代谢物的流出量值通过细胞的生物质的质量和成分构成；还有一部分中间代谢物的流出量值,通过测量这些中间代谢物在培养液中的残留浓度来获取。最后介绍了参数优化的目标函数和置信区间估计的方法。
第二章的第二部分,以连续培养的大肠杆菌JM101株的代谢通量分析为例子,描述了连续培养下进行13C代谢通量分析的完整流程,也就是13C代谢通量分析实验平台的建立和实现。
第三章阐述了对13C质量同位素异构体检测技术所作的改进。改进后的方法可以提高质量同位素异构体比例的测量确度,从而提高13C代谢通量分析的准确度。
第三章的第一部分首先粗略地介绍了质谱测量的原理和基本过程。然后按照测量发生的顺序,介绍了质谱仪的基本的结构和功能单元。这些单元包括进样器,离子源,质量分析仪和信号检测器。之后论文较为详细地描述了用于气质联用的衍生化方法,特别是氨基酸的特丁基二甲基硅烷衍生化方法。最后,仔细地讨论了用以解决重同位素引起的质量位移作用的数学框架修正举证。
第三章的第二部分首先详细介绍了用质谱进行13C质量同位素异构体检测的基本假设,并对该假设进行了数学化的描述。利用该数学描述,对之前的各种提高质谱测量确度的方法进行了分类和描述。之后则介绍了如何提高13C质量同位素异构体测量确度的方法。利用已知了同位素异构体比例的样品,作为标准样,制作任意质谱仪的校准曲线,是一种最具有广泛性的提高测量精度的方法。我们使用以甲醇作为碳源的嗜甲基菌Methylobacterium salsuginis sp.,将其在排除了天然CO2的环境下,以13C标记的甲醇作为唯一碳源来进行培养。产生的各种生成物的同位素异构体比例可以用二项式公式来计算。我们引进一个新的量,它是两个连续的质量同位素异构体(13C原子数目相差1)的比值,由此避开了对多维向量进行校准的麻烦。而且,我们后验地测定每个产物的整个分子的平均13C比例,从而使得生物同位素效应的对13C分布不均匀性的影响降至最低。
第三章的第三部分则是对第二部分理论的实验实现,包括实验程序,理论模拟和结果讨论。经过校准后的结果,其绝对误差都小于0.9mol%,比未校准的结果有明显进步。而且,若采用理想的实验步骤,则误差可预计下降到0.4mol%以下。
在13C MFA平台上,我们分析研究了大肠肝菌中心代谢通量在超氧化应激情况下的变化情况。这部分内容是由芮斌同学和我共同完成的,请参看芮斌同学的博士论文。
此外,我们还进行了“不同剂量的氧化剂引起代谢系统不同强度反应”的研究,正在成文中。
In recent years, the concept and theory of systems biology have been undergoing a major development in accordance with its wide application in various areas. The core of this newly established discipline is the information integration across different "omes". Among these omes, the fluxome has played an increasingly important role in linking omes of different level.
Investigation of fluxome gives birth to the fluxomics which aims at quantitatively analyzing the direction and quantity of metabolic flux. Insights acquired from fluxomics would be of significant biological importance for depicting the physiological characteristic of cell as well as assessing the influence of the genetic and environmental manipulations on cell.
The primary technique for fluxomics is metabolic flux analysis, which consists of stoichiometry metabolic flux analysis and 13C metabolic flux analysis (13C MFA). 13C MFA has been the research hotspot of metabolic engineering internationally due to its accuracy and applicability. However, there is no domestic doctorate thesis concerning about 13C metabolic flux analysis.
This PhD thesis consists of two parts. The first part details the fundamental principle of 13C MFA and the implementation of its experimental platform. The second part describes a method to improve the measurement accuracy of 13C mass isotopomer analysis.
Chapter 1 illustrates the fundamental principle of 13C MFA.
The first part of chapter 1 describes the fundamental principle of 13C MFA.13C MFA introduces partial 13C labeling in cultivation substrate.13C will distribute among intermediates and metabolites and results in different isotopomer distribution. Starting from the concept of isotopomer, the mass balance relationship could be extended as isotopomers balance relationship which relates the metabolic flux with the isotopomer distribution of intermediates and metabolites. Isotopomers balance relationship is a complicated square equation of multiple variables. Based on these equations, the metabolic flux quantity could be deduced from the measured isotopomer information through evolution algorithm based parameter optimization. Afterwards, we could construct the theoretical measurement space and quantify the confidence interval of estimated flux value by Monte Carlo sampling.
Chapter 2 focuses on the introduction and implementation of experimental technique for 13C MFA.
The first part of chapter 2 describes experimental techniques which are necessary for 13C MFA.
The 13C labeling technique is the basis for 13C MFA. To estimate the intracellular metabolic flux value, information of isotopomer distribution as well as the information of the metabolites efflux must be obtained. The information of specific isotopomers can be acquired through NMR measurements. J-resolved HSQC could be used to analyze the isotopomers containing directly connected carbon-carbon bond. The mass isotopomer distribution could be quantified by MS measurement. The metabolites efflux is the other kind of information necessary for 13C MFA. Efflux value of some certain metabolites could be determined by analysis of the accumulated amount and the cellular composition of biomass. Besides, quantitatively analyzing the residual concentration could determine efflux value of other intermediates and metabolites. At the last stage, the objectivity for parameter optimization and confidence interval estimation method are presented.
The second part of chapter 2 is exhaustive experimental protocol of 13C MFA in continuous cultivation. That is the first implementation of 13C MFA platform in USTC.
Chapter 2 describes the second part of our work that is the improvement of measurement accuracy of 13C mass isotopomer analysis hence the flux accuracy of 13C MFA.
The first part of chapter 2 introduces concisely the principle and process of MS measurement. Then the basic structural and functional units of MS instrument are discussed. These units includes samples introduction, ionization source, mass separation and signal detection. Additionally, the derivatization methods, especially the TMBDMS-derivatization for GC-MS, are illustrated detailedly. Then a mathematical framework, correction matrix, is described to address the mass shift effect introduced by heavy isotopes in nonskeleton carbon.
The second part of chapter 2 firstly describes in particular the basic assumption for 13C mass isotopomer analysis by MS measurement. Then we re-state this assumption in a mathematical framework. Based upon this mathematical frame, we can easily classify and depict the previous methods of improving the MS measurement accuracy. These methods utilize linear extrapolation, nonlinear relationship or theoretical correction. These methods indeed produce accurate results than simple measurement. However, they have a shared shortcoming that they are instrument specific
The second part describes how to increase the accuracy of mass iotopomer analysis through calibration curves constructed using biologically synthesized compounds. Using the compounds with known isotopomer distribution as the standard sample one could plot calibration curve for any instrument. Thus, the correction method relying on calibration curve would be a general method that is universally applicable to MS measurements. The bacterium strain Methylobacterium salsuginis sp. nov. is cultivated with partially 13C labeled methanol as the only carbon source to produce 13C enriched compounds. The resulting product isotopomers obey binomial distribution. We introduces a new variable to replace the mass isotopomer distribution as optimization objectivity in order to circumvent the calibration for MID. Moreover, posterior measurement of average 13C abundance minimized the interference of intramolecular inhomogeneity of 13C isotope abundances caused by biological isotope fractionation.
The third part deals with the experimental implementation of the theory raised in the second part. This includes experimental protocol, numeric modeling, results and discussion. The absolute uncertainty after correction by calibration curve has decreased to 0.9mol%, remarkably reduced compared to the uncalibrated results. If the average 13C abundance is measured by gas chromatography-combustion-isotope ratio mass spectrometry, the expected error would decrease to 0.4mol%.
Ground on this 13C MFA platform, Rui Bin and I performed a global investigation of central carbon metabolism in response to superoxide stress in E.coli. Please refer to Rui Bin's PhD thesis for detailed description.
Besides, we had performed an investigation titled "serial metabolic flux analysis revealed a dose-dependent response of E.coli metabolism to oxidative stress".
引文
Bailey, J. E. (1991). "Toward a science of metabolic engineering." Science 252(5013):1668-75.
Beard, D. A., S. C. Liang, et al. (2002). "Energy balance for analysis of complex metabolic networks." Biophysical Journal 83(1):79-86.
Burgard, A. P. and C. D. Maranas (2001). "Probing the performance limits of the Escherichia coli metabolic network subject to gene additions or deletions." Biotechnol Bioeng 74(5): 364-75.
Christensen, B. and J. Nielsen (1999). "Isotopomer analysis using GC-MS." Metab Eng 1(4): 282-90.
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