甘油生物歧化过程酶催化和基因调控的非线性数学模拟与分析
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摘要
受石油价格不断攀升的影响,生物基化学品的生产逐渐引起人们的重视。甘油生物转化生产1,3-丙二醇因为原料的可再生性和1,3-丙二醇(1,3-PD)的潜在用途而日益受到关注。本论文针对克雷伯氏杆菌转化甘油为1,3-丙二醇过程,建立了酶催化和基因调控非线性动力学方程,对甘油生物转化及其基因调控过程进行了模拟分析,主要研究内容如下：
首先,建立了甘油生物歧化过程酶催化动力学方程,包括甘油代谢过程中关键酶——甘油脱水酶(GDHt)、1,3-丙二醇氧化还原酶(PDOR)、甘油脱氢酶(GDH)、丙酮酸激酶(PK)、丙酮酸甲酸裂解酶(PFL)和丙酮酸脱氢酶(PDH)的酶催化动力学,3-羟基丙醛(3-HPA)对GDHt、PDOR和GDH的抑制动力学,甘油和产物的跨膜转运动力学。酶催化动力学能够很好地描述甘油连续发酵过程中底物的消耗和产物如1,3-PD,乙酸、乙醇、琥珀酸和甲酸的形成,对间歇培养过程适应期和对数生长期的描述也很合理；该动力学系统能够预测连续培养条件下胞内物质的浓度,如胞内残余甘油、3-HPA、1,3-PD、琥珀酸、甲酸和乙酸,且能预测连续发酵过程中出现的多稳态现象。分析结果表明,连续发酵培养条件下,二羟基丙酮、磷酸二羟基丙酮、磷酸烯醇式丙酮酸、乙酰CoA在胞内没有积累,全部进入下一级代谢；另外,过多的3-HPA积累和残余底物甘油对1,3-PD的生成是不利的；3-HPA的积累对PDOR的抑制作用要强于对GDHt和GDH的抑制作用,即底物过量导致3-HPA积累时,PDOR是甘油代谢过程的限速酶。
其次,对色氨酸操纵子基因调控动力学进行了深入研究,为甘油生物歧化过程的基因调控动力学研究奠定了基础。重点考察了色氨酸操纵子中多基因间的相互作用以及胞内色氨酸向胞外的转运机制,建立了一个包括阻遏蛋白基因和色氨酸关键酶基因之间相互作用以及色氨酸由胞内向胞外转运的色氨酸操纵子基因调控系统。鲁棒性分析表明,该系统具有很强的鲁棒性,求取的参数值和动力学描述合理。考察了比生长速率对色氨酸生物合成和系统稳定性的影响,对色氨酸合成过程的动态行为进行了理论预测和分析。采用间接优化方法对色氨酸的生产进行了优化分析,细胞生长速率为0.00624 h-1时色氨酸的产量提高了4.8倍。
再次,建立了甘油生物歧化过程基因调控动力学方程,重点研究了甘油代谢还原途径的中间产物3-羟基丙醛对dha调节子基因表达的阻遏作用,对GDHt和PDOR的反馈抑制作用。建立了包括调控蛋白(dhaR)、GDHt和PDOR及其相关基因表达调控,以及酶催化代谢产物之间的复杂网络。鲁棒性分析表明,该动力学系统具有很强的鲁棒性,求取的参数值和动力学描述合理。和酶催化动力学系统一样,多稳态现象在基因调控动力学中同样存在。对发酵过程进行模拟的结果表明,3-HPA的积累导致甘油代谢还原途径中酶的基因表达受阻,表达量减少；3-羟基丙醛参与了dha调节子的基因表达与调控,是dha调节子上的负调控因子。在dha调节子中存在两种负反馈调控机制：阻遏作用和酶抑制。两种并存机制能更为合理地阐释实验结果。
最后,对微生物转化法生产1,3-丙二醇、2,3-丁二醇和氢气进行了化学计量分析。综合考虑了质量、能量和还原当量的平衡,通过“原子经济性”理论分析,实现底物向产物的最大转化。结果表明：共底物发酵有利于提高目标产物的收率,并且还原当量的合理分配对目标产物的收率有非常重要的影响。在葡萄糖和甘油共底物厌氧生产1,3-丙二醇过程中,甘油既不进入氧化途径也不用来生成生物量,该部分能量由葡萄糖代谢提供,甘油可以完全转化为1,3-丙二醇,此时底物中葡萄糖相对于甘油的比率为0.32mol.mol-1。葡萄糖和甘油共底物厌氧联产1,3-丙二醇和2,3-丁二醇时,葡萄糖代谢提供细胞生长所需能量和1,3-丙二醇生成所需的还原当量；当葡萄糖与甘油的比率为1.13mol.mol-1时,甘油可以完全转化为1,3-丙二醇,而2,3-丁二醇相对于葡萄糖的收率为0.88mol.mol-1,此时基本的假定条件是高浓度葡萄糖对甘油代谢酶没有抑制作用。葡萄糖和木糖共底物微氧发酵生产2,3-丁二醇和氢气时,理论上可获得2,3-丁二醇和氢气相对于底物葡萄糖和木糖的最大质量收率分别为0.5g.g-1和0.008g.g-1,此时呼吸商为14。葡萄糖厌氧发酵生产氢气时,最大收率为2.86 mol.mol-1；微氧发酵呼吸商为2.26时,氢气最大收率可达6.68 mol.mol-1。
上述研究工作对深入理解克雷伯氏杆菌的甘油代谢途径、菌种的基因工程改造、甘油代谢过程基因表达的全局调控、甘油生物转化为1,3-丙二醇过程的在线控制和代谢控制分析具有重要的参考价值和指导作用。
The bioconversion of glycerol to 1,3-propanediol (1,3-PD) was particularly attractive to industry because of renewable feedbacks and potential uses of 1,3-PD.1,3-PD was discussed as a bifunctional chemical on a large commercial scale, especially as a monomer for polyesters, polyethers and polyurethanes. In this paper, nonlinear mathematical equations of the enzyme-catalytic kinetics and genetic regulation were set up to describe the continuous and batch fermentations of glycerol by Klebsiella pneumoniae. The main work of this paper was summarized as follows:
Firstly, a nonlinear dynamical system was presented to describe the continuous and batch fermentations of glycerol metabolism in K. pneumoniae, in which the enzyme-catalytic kinetics on the reductive and oxidative pathway, the inhibition of 3-hydroxypropionaldehyde (3-HPA) to glycerol dehydratase (GDHt),1,3-PD oxydoreductase (PDOR) and glycerol dehydrogenase (GDH), and the transport of glycerol and diffusion of products across cell membrane were all taken into consideration. Moreover, the enzyme-catalytic kinetics of GDHt, PDOR, GDH, pyruvate kinase (PK), pyruvate formate-lyase (PFL) and pyruvate dehydrogenase (PDH) were also investigated. Comparisons between simulated and experimental results indicated that the model could be used to describe the continuous fermentation under steady states reasonably. The intracellular concentrations of glycerol, 1,3-propanediol,3-HPA, succinic acid, lactic acid,2,3-butanediol (2,3-BD), format, ethanol and acetate acid could also be predicted for continuous cultivations. Multiplicity analysis for continuous cultures was developed. The simulation results disclosed that dihydroxyacetone, dihydroxyacetone phosphate, phosphoenolpyruvate, acetyl coenzyme A were not accumulated under continuous culture and all entered into the following step. Furthermore,3-HPA accumulation was disadvantageous for the formation of the target product 1,3-PD and the inhibition of 3-HPA to PDOR was stronger than that to GDHt and GDH which indicated that PDOR might be the rate-limit enzyme. This model would give new insights into the metabolic and genetic regulation of dha regulon of glycerol metabolism in K. pneumoniae.
Thirdly, an expended mathematical model for the tryptophan operon regulation on the effects of repression, feedback enzyme inhibition, attenuation, interaction among genes and excretion of tryptophan was presented. The new model was first translated into the corresponding S-system version. The robustness of this model was then discussed by using the S-system model and the sensitivity analysis showed that the model is robust enough. The influences of cell growth rate on the biosynthesis of tryptophan, stability and dynamic behavior of the trp operon were also well investigated. Furthermore, a steady-state optimization model was established based on trp operon models according to indirect optimization method. The optimization results indicated that it was possible to attain a stable and robust steady state with a rate of tryptophan production increased more than 4.8 times in which the growth rate was kept as 0.00624h-1 and some key parameters were modulated.
Fourthly, the fourteen-dimensional nonlinear dynamical system was presented to describe the continuous cultures and multiplicity analysis of the dha regulon for glycerol metabolism in K. pneumoniae, in which two regulated negative-feedback mechanisms of repression and enzyme inhibition were well investigated. The model describing the expression of gene-mRNA-enzyme-product was established according to the repression of the dha regulon by 3-hydroxypropionaldehy (3-HPA). Comparisons between simulated and experimental results indicated that the model could be used to describe the production of 1,3-PD in continuous fermentations. The new model was first translated into the corresponding S-system version. The robustness of this model was then discussed by using the S-system model and the sensitivity analysis showed that the model was sufficiently robust. Moreover, multiplicity analysis for continuous cultures was developed, and application of this analysis to the regulation of the dha regulon revealed two regions of multiplicity. The influences of initial glycerol concentration and dilution rate on the biosynthesis of 1,3-PD and the stability of the dha regulon model were also well investigated. The intracellular concentrations of glycerol,1,3-PD,3-HPA, repressor mRNA, repressor, mRNA and protein levels of GDHt and PDOR could also be predicted for continuous cultivations. The results of simulation and analysis indicated that 3-HPA accumulation would repress the expression of the dha regulon at the transcriptional level.
Finally, the bioconversion processes such as 1,3-PD,2,3-butanediol (2,3-BD) and hydrogen were stoichiometrically analyzed according to mass, energy (ATP) and reducing equivalent balances. Atom economy was used for optimization of 1,3-PD,2,3-BD and hydrogen production. The results indicated that the regulation of reducing equivalents balance would directly affect the yields of products to substrate, especially under microaerobic conditions. The ratio between two substrates was an important parameter in microbial cofermentation which also affected the yields of products to substrate. Respiratory quotient was proved to be a control parameter for optimum production of 1,3-PD,2,3-BD and hydrogen. The theoretical analysis of the glycerol-glucose cometabolism by K. pneumoniae to 1,3-PD indicated that the maximum ratio of 0.32 mol glucose per mol glycerol was needed to convert glycerol completely to 1,3-propanediol under anaerobic conditions if glycerol neither entered oxidation pathways nor formed biomass. The theoretical analysis of glycerol-glucose cometabolism to 1,3-PD and 2,3-BD revealed that the ratio of 1.13 mol glucose per mol glycerol was needed to convert glycerol completely to 1,3-PD under anaerobic conditions if glucose was used for cell growth and reducing equivalent formation, whereas the yield of 2,3-BD to glucose was 0.88mol/mol. The optimal theoretical mass yield of 2,3-butanediol and hydrogen to glucose could reach to 0.50 g/g and 0.008 g/g at the respiratory quotient value of 14, respectively. Supposed that substrate was glucose or xylose alone, the molar yield of hydrogen to substrate was 0.71 mol/mol and 0.60mol/mol, respectively, whereas the optimal theoretical molar yield of hydrogen to glucose by Klebsiella pneumoniae could reach 6.68 mol/mol at the respiratory quotient value of 2.26 if no formation of 2,3-butanediol under microaerobic condition. The theoretical analysis could help us understand the metabolic principles and control the bioprocess.
首先,建立了甘油生物歧化过程酶催化动力学方程,包括甘油代谢过程中关键酶——甘油脱水酶(GDHt)、1,3-丙二醇氧化还原酶(PDOR)、甘油脱氢酶(GDH)、丙酮酸激酶(PK)、丙酮酸甲酸裂解酶(PFL)和丙酮酸脱氢酶(PDH)的酶催化动力学,3-羟基丙醛(3-HPA)对GDHt、PDOR和GDH的抑制动力学,甘油和产物的跨膜转运动力学。酶催化动力学能够很好地描述甘油连续发酵过程中底物的消耗和产物如1,3-PD,乙酸、乙醇、琥珀酸和甲酸的形成,对间歇培养过程适应期和对数生长期的描述也很合理；该动力学系统能够预测连续培养条件下胞内物质的浓度,如胞内残余甘油、3-HPA、1,3-PD、琥珀酸、甲酸和乙酸,且能预测连续发酵过程中出现的多稳态现象。分析结果表明,连续发酵培养条件下,二羟基丙酮、磷酸二羟基丙酮、磷酸烯醇式丙酮酸、乙酰CoA在胞内没有积累,全部进入下一级代谢；另外,过多的3-HPA积累和残余底物甘油对1,3-PD的生成是不利的；3-HPA的积累对PDOR的抑制作用要强于对GDHt和GDH的抑制作用,即底物过量导致3-HPA积累时,PDOR是甘油代谢过程的限速酶。
其次,对色氨酸操纵子基因调控动力学进行了深入研究,为甘油生物歧化过程的基因调控动力学研究奠定了基础。重点考察了色氨酸操纵子中多基因间的相互作用以及胞内色氨酸向胞外的转运机制,建立了一个包括阻遏蛋白基因和色氨酸关键酶基因之间相互作用以及色氨酸由胞内向胞外转运的色氨酸操纵子基因调控系统。鲁棒性分析表明,该系统具有很强的鲁棒性,求取的参数值和动力学描述合理。考察了比生长速率对色氨酸生物合成和系统稳定性的影响,对色氨酸合成过程的动态行为进行了理论预测和分析。采用间接优化方法对色氨酸的生产进行了优化分析,细胞生长速率为0.00624 h-1时色氨酸的产量提高了4.8倍。
再次,建立了甘油生物歧化过程基因调控动力学方程,重点研究了甘油代谢还原途径的中间产物3-羟基丙醛对dha调节子基因表达的阻遏作用,对GDHt和PDOR的反馈抑制作用。建立了包括调控蛋白(dhaR)、GDHt和PDOR及其相关基因表达调控,以及酶催化代谢产物之间的复杂网络。鲁棒性分析表明,该动力学系统具有很强的鲁棒性,求取的参数值和动力学描述合理。和酶催化动力学系统一样,多稳态现象在基因调控动力学中同样存在。对发酵过程进行模拟的结果表明,3-HPA的积累导致甘油代谢还原途径中酶的基因表达受阻,表达量减少；3-羟基丙醛参与了dha调节子的基因表达与调控,是dha调节子上的负调控因子。在dha调节子中存在两种负反馈调控机制：阻遏作用和酶抑制。两种并存机制能更为合理地阐释实验结果。
最后,对微生物转化法生产1,3-丙二醇、2,3-丁二醇和氢气进行了化学计量分析。综合考虑了质量、能量和还原当量的平衡,通过“原子经济性”理论分析,实现底物向产物的最大转化。结果表明：共底物发酵有利于提高目标产物的收率,并且还原当量的合理分配对目标产物的收率有非常重要的影响。在葡萄糖和甘油共底物厌氧生产1,3-丙二醇过程中,甘油既不进入氧化途径也不用来生成生物量,该部分能量由葡萄糖代谢提供,甘油可以完全转化为1,3-丙二醇,此时底物中葡萄糖相对于甘油的比率为0.32mol.mol-1。葡萄糖和甘油共底物厌氧联产1,3-丙二醇和2,3-丁二醇时,葡萄糖代谢提供细胞生长所需能量和1,3-丙二醇生成所需的还原当量；当葡萄糖与甘油的比率为1.13mol.mol-1时,甘油可以完全转化为1,3-丙二醇,而2,3-丁二醇相对于葡萄糖的收率为0.88mol.mol-1,此时基本的假定条件是高浓度葡萄糖对甘油代谢酶没有抑制作用。葡萄糖和木糖共底物微氧发酵生产2,3-丁二醇和氢气时,理论上可获得2,3-丁二醇和氢气相对于底物葡萄糖和木糖的最大质量收率分别为0.5g.g-1和0.008g.g-1,此时呼吸商为14。葡萄糖厌氧发酵生产氢气时,最大收率为2.86 mol.mol-1；微氧发酵呼吸商为2.26时,氢气最大收率可达6.68 mol.mol-1。
上述研究工作对深入理解克雷伯氏杆菌的甘油代谢途径、菌种的基因工程改造、甘油代谢过程基因表达的全局调控、甘油生物转化为1,3-丙二醇过程的在线控制和代谢控制分析具有重要的参考价值和指导作用。
The bioconversion of glycerol to 1,3-propanediol (1,3-PD) was particularly attractive to industry because of renewable feedbacks and potential uses of 1,3-PD.1,3-PD was discussed as a bifunctional chemical on a large commercial scale, especially as a monomer for polyesters, polyethers and polyurethanes. In this paper, nonlinear mathematical equations of the enzyme-catalytic kinetics and genetic regulation were set up to describe the continuous and batch fermentations of glycerol by Klebsiella pneumoniae. The main work of this paper was summarized as follows:
Firstly, a nonlinear dynamical system was presented to describe the continuous and batch fermentations of glycerol metabolism in K. pneumoniae, in which the enzyme-catalytic kinetics on the reductive and oxidative pathway, the inhibition of 3-hydroxypropionaldehyde (3-HPA) to glycerol dehydratase (GDHt),1,3-PD oxydoreductase (PDOR) and glycerol dehydrogenase (GDH), and the transport of glycerol and diffusion of products across cell membrane were all taken into consideration. Moreover, the enzyme-catalytic kinetics of GDHt, PDOR, GDH, pyruvate kinase (PK), pyruvate formate-lyase (PFL) and pyruvate dehydrogenase (PDH) were also investigated. Comparisons between simulated and experimental results indicated that the model could be used to describe the continuous fermentation under steady states reasonably. The intracellular concentrations of glycerol, 1,3-propanediol,3-HPA, succinic acid, lactic acid,2,3-butanediol (2,3-BD), format, ethanol and acetate acid could also be predicted for continuous cultivations. Multiplicity analysis for continuous cultures was developed. The simulation results disclosed that dihydroxyacetone, dihydroxyacetone phosphate, phosphoenolpyruvate, acetyl coenzyme A were not accumulated under continuous culture and all entered into the following step. Furthermore,3-HPA accumulation was disadvantageous for the formation of the target product 1,3-PD and the inhibition of 3-HPA to PDOR was stronger than that to GDHt and GDH which indicated that PDOR might be the rate-limit enzyme. This model would give new insights into the metabolic and genetic regulation of dha regulon of glycerol metabolism in K. pneumoniae.
Thirdly, an expended mathematical model for the tryptophan operon regulation on the effects of repression, feedback enzyme inhibition, attenuation, interaction among genes and excretion of tryptophan was presented. The new model was first translated into the corresponding S-system version. The robustness of this model was then discussed by using the S-system model and the sensitivity analysis showed that the model is robust enough. The influences of cell growth rate on the biosynthesis of tryptophan, stability and dynamic behavior of the trp operon were also well investigated. Furthermore, a steady-state optimization model was established based on trp operon models according to indirect optimization method. The optimization results indicated that it was possible to attain a stable and robust steady state with a rate of tryptophan production increased more than 4.8 times in which the growth rate was kept as 0.00624h-1 and some key parameters were modulated.
Fourthly, the fourteen-dimensional nonlinear dynamical system was presented to describe the continuous cultures and multiplicity analysis of the dha regulon for glycerol metabolism in K. pneumoniae, in which two regulated negative-feedback mechanisms of repression and enzyme inhibition were well investigated. The model describing the expression of gene-mRNA-enzyme-product was established according to the repression of the dha regulon by 3-hydroxypropionaldehy (3-HPA). Comparisons between simulated and experimental results indicated that the model could be used to describe the production of 1,3-PD in continuous fermentations. The new model was first translated into the corresponding S-system version. The robustness of this model was then discussed by using the S-system model and the sensitivity analysis showed that the model was sufficiently robust. Moreover, multiplicity analysis for continuous cultures was developed, and application of this analysis to the regulation of the dha regulon revealed two regions of multiplicity. The influences of initial glycerol concentration and dilution rate on the biosynthesis of 1,3-PD and the stability of the dha regulon model were also well investigated. The intracellular concentrations of glycerol,1,3-PD,3-HPA, repressor mRNA, repressor, mRNA and protein levels of GDHt and PDOR could also be predicted for continuous cultivations. The results of simulation and analysis indicated that 3-HPA accumulation would repress the expression of the dha regulon at the transcriptional level.
Finally, the bioconversion processes such as 1,3-PD,2,3-butanediol (2,3-BD) and hydrogen were stoichiometrically analyzed according to mass, energy (ATP) and reducing equivalent balances. Atom economy was used for optimization of 1,3-PD,2,3-BD and hydrogen production. The results indicated that the regulation of reducing equivalents balance would directly affect the yields of products to substrate, especially under microaerobic conditions. The ratio between two substrates was an important parameter in microbial cofermentation which also affected the yields of products to substrate. Respiratory quotient was proved to be a control parameter for optimum production of 1,3-PD,2,3-BD and hydrogen. The theoretical analysis of the glycerol-glucose cometabolism by K. pneumoniae to 1,3-PD indicated that the maximum ratio of 0.32 mol glucose per mol glycerol was needed to convert glycerol completely to 1,3-propanediol under anaerobic conditions if glycerol neither entered oxidation pathways nor formed biomass. The theoretical analysis of glycerol-glucose cometabolism to 1,3-PD and 2,3-BD revealed that the ratio of 1.13 mol glucose per mol glycerol was needed to convert glycerol completely to 1,3-PD under anaerobic conditions if glucose was used for cell growth and reducing equivalent formation, whereas the yield of 2,3-BD to glucose was 0.88mol/mol. The optimal theoretical mass yield of 2,3-butanediol and hydrogen to glucose could reach to 0.50 g/g and 0.008 g/g at the respiratory quotient value of 14, respectively. Supposed that substrate was glucose or xylose alone, the molar yield of hydrogen to substrate was 0.71 mol/mol and 0.60mol/mol, respectively, whereas the optimal theoretical molar yield of hydrogen to glucose by Klebsiella pneumoniae could reach 6.68 mol/mol at the respiratory quotient value of 2.26 if no formation of 2,3-butanediol under microaerobic condition. The theoretical analysis could help us understand the metabolic principles and control the bioprocess.
引文
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