乙醇和青霉素工业生物过程中微生物的代谢组学研究
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摘要
大规模发酵过程中细胞行为和生产特性与其所处的环境因素关系密切，细胞的环境响应行为是涉及转录、蛋白、代谢及相互作用的一个基于生化反应和物质传递的复杂、非线性的多层次网络体系，传统研究方法和手段难以全面揭示其规律性。本文以乙醇和青霉素两个工业生物过程为研究体系，从代谢组学和磷脂组学的角度系统地比较分析了不同工业模式、不同规模工业过程中微生物细胞的代谢差异。试图在分子水平上更好的理解不同模式、不同规模工业生物过程中细胞对复杂工业环境的响应行为，为工业生物过程优化与放大提供科学依据。
首先选取大规模乙醇工业分批过程和连续过程作为研究体系，分析了酿酒酵母在不同工业模式中细胞响应行为的差异性。分批过程发酵前期的细胞活力和乙醇的产量明显低于连续过程。代谢组学分析表明，渗透压和氧胁迫是引起酵母细胞在两个过程中响应行为差异的两个主要环境因素。连续过程发酵初期甘油的大量积累表明高糖浓度形成渗透压，在高渗刺激下甘油积累以调节细胞渗透压。分批过程发酵后期乳酸的积累显示在这个过程细胞受到的氧胁迫逐渐增加。环境胁迫响应行为的不同也造成了细胞在两个过程中氨基酸代谢和三羧酸循环代谢的差异。进一步分析了两种工业过程细胞磷脂组成和含量变化情况。细胞磷脂链长的变化可能是酵母细胞对复杂工业环境的一个重要响应。PS和PG的LCUFA含量在分批过程中明显高于连续过程；对于连续过程胞内LCUFA磷脂含量在发酵初期明显高于其他两个阶段，并且随发酵进行含量呈显著下降的趋势。
其次以青霉素中试过程和大规模工业过程为研究对象，系统比较分析了产黄青霉胞内小分子代谢、磷脂组代谢以及次生代谢在工业生物放大过程中的表达差异。探索了产黄青霉在放大过程中的适应性响应过程。工业放大过程中青霉素的生产与胞内氨基酸的代谢密切相关，在发酵中期氨基酸的显著积累促进了青霉素的合成。不同规模青霉素发酵过程中产黄青霉糖酵解和TCA循环路径的代谢特征差异显著，这种差异和青霉素的产量具有一定的相关性，工业放大过程中次级代谢的生物合成受到初级代谢的影响显著。在中试过程发酵前期产黄青霉的初级代谢更为活跃，导致发酵过程中青霉素合成速率的降低。通过比较不同规模发酵过程中次级代谢产物表达的差异，表明次生代谢产物的相互转化和对合成酶的影响导致青霉素工业放大过程中代谢的差异。进一步磷脂组学研究显示多不饱和磷脂分子在中试过程表达明显高于工业过程。磷脂分子的不饱和度变化直接反应出在发酵过程中菌丝体形态的差异性；相比中试过程，工业过程受到的较大环境胁迫造成菌丝分裂的加剧，放大过程适当的环境胁迫更有利于青霉素产量的提高。
In large-scale fermentation process, cells behaviour and producing characters areclosely related with the environment factors. The behaviours of cells in environmentresponse are a process of involved in transcription, protein metabolism and interactioncomplex, multi-level network system based on biochemical reaction and mass transfer.Traditional research methods and tools are difficulty to fully reveal its regularity. Inthis paper, we choose ethanol and penicillin of industrial biological processes forstudy systems. From the point of phospholipids and metabolomics, we systematicallycompare and analyse the differences of the microbial cells in different industrialmodels and different industrial scales. We try to get a better understanding of cellsbehaviour to the complex industrial environment in different industrial models anddifferent industrial scales on molecular level and provide a scientific basis foroptimizing and amplificating the bio-process.
First, choosing the batch process and continuous process in large-scale ethanolindustry as study system, we analyse the similarities and differences of cells responsebehaviour of yeast fermentation patterns in different industry fermentation scales.Although, the trend of reducing sugar was similar in the two processes, the cellsviability and ethanol production in the pre-fermentation are significantly lower thanthese in continuous process. Metabolomics analysis shows that osmotic and oxidativestresses are two main environmental factors of causing yeast cells response behaviourdifferences between the two processes. In continuous per-fermentation process,massive accumulation of glycerol shows that high sugar concentration forms osmoticpressure. In hypersonic stimulation, glycerol accumulation adjusts cell osmoticpressure. In the later stage of batch fermentation process, the lactic acid accumulationshows that cellular oxidative stress is increasing. Different environmental stressresponse behaviour causes the differences of amino acid metabolism and TCA cyclemetabolic in the two processes. We further analyse the changes of cell phospholipidcomposition and content in the two processes. The synthetization of Phospholipid inLCUFA in industrial yeast shows the extension of Intracellular enzymes inpolyunsaturated fats, enzymes. The length changes of cellular phospholipid chain maybe an important response of yeast cells to complex industrial environment. Thecontents of PS and PG of LCUFA in batch process are higher than these in continuousprocess. In continuous process, the contents of intracellular phospholipid in LCUFAin early fermentation are higher than the other two stages and show a downward trend with the process of fermentation.
Secondly, choosing penicillin processes in pilot and large-scale industrial processfor study, we analyse the expression differences in biomagnification in the industrialprocess of Penicillium chrysogenum intracellular small-molecule metabolism,phospholipid metabolism and secondary metabolism group comparatively andsystematically. We get a further research response process of penicillin chrysogenumin amplification process. Studies show that the early fermentation and mediumfermentation are critical for the accumulation of penicillin. In the industrialamplification process, penicillin production is closely related to intracellular aminoacid metabolism. In the medium fermentation, amino acid significantly accumulationpromotes the synthesis of penicillin. The results also show that Penicilliumchrysogenum glycolysis and TCA cycle paths have significantly different metaboliccharacteristics in different scales of penicillin fermentation. These differences arerelated to penicillin production and in the industrial amplification process thebiosynthesis of secondary metabolism is significantly influenced by primarymetabolism. In the early stage of pilot process, the primary metabolism of penicilliumchrysogenum is more active which leads to the rate reducing of penicillin synthesis inthe fermentation process. By comparing the differences of secondary metabolites indifferent scales of fermentation processes, we found that the mutual transformation ofsecondary metabolites and the influence of synthetic enzymes are the reasons ofcausing penicillin metabolic differences in industrial amplification process. Furtherstudies of phospholipid show that polyunsaturated phospholipids in the pilot processwere higher than that in industrial process. The changes of unsaturated phospholipidmolecules directly show the differences of mycelium patterns in fermentationprocesses. In the early pilot process, the high unsaturated reduces the cells viscosityand increases the rate of gas-liquid oxygen transfer which can promote more myceliliagrowth and also lead to the rate reducing of penicillin synthesis in fermentationprocess. Compared with pilot process, the industry process suffers heavierenvironmental stresses and cause mycelium divided. And in amplification process theenvironmental stress make for the increasing of penicillin production.
首先选取大规模乙醇工业分批过程和连续过程作为研究体系，分析了酿酒酵母在不同工业模式中细胞响应行为的差异性。分批过程发酵前期的细胞活力和乙醇的产量明显低于连续过程。代谢组学分析表明，渗透压和氧胁迫是引起酵母细胞在两个过程中响应行为差异的两个主要环境因素。连续过程发酵初期甘油的大量积累表明高糖浓度形成渗透压，在高渗刺激下甘油积累以调节细胞渗透压。分批过程发酵后期乳酸的积累显示在这个过程细胞受到的氧胁迫逐渐增加。环境胁迫响应行为的不同也造成了细胞在两个过程中氨基酸代谢和三羧酸循环代谢的差异。进一步分析了两种工业过程细胞磷脂组成和含量变化情况。细胞磷脂链长的变化可能是酵母细胞对复杂工业环境的一个重要响应。PS和PG的LCUFA含量在分批过程中明显高于连续过程；对于连续过程胞内LCUFA磷脂含量在发酵初期明显高于其他两个阶段，并且随发酵进行含量呈显著下降的趋势。
其次以青霉素中试过程和大规模工业过程为研究对象，系统比较分析了产黄青霉胞内小分子代谢、磷脂组代谢以及次生代谢在工业生物放大过程中的表达差异。探索了产黄青霉在放大过程中的适应性响应过程。工业放大过程中青霉素的生产与胞内氨基酸的代谢密切相关，在发酵中期氨基酸的显著积累促进了青霉素的合成。不同规模青霉素发酵过程中产黄青霉糖酵解和TCA循环路径的代谢特征差异显著，这种差异和青霉素的产量具有一定的相关性，工业放大过程中次级代谢的生物合成受到初级代谢的影响显著。在中试过程发酵前期产黄青霉的初级代谢更为活跃，导致发酵过程中青霉素合成速率的降低。通过比较不同规模发酵过程中次级代谢产物表达的差异，表明次生代谢产物的相互转化和对合成酶的影响导致青霉素工业放大过程中代谢的差异。进一步磷脂组学研究显示多不饱和磷脂分子在中试过程表达明显高于工业过程。磷脂分子的不饱和度变化直接反应出在发酵过程中菌丝体形态的差异性；相比中试过程，工业过程受到的较大环境胁迫造成菌丝分裂的加剧，放大过程适当的环境胁迫更有利于青霉素产量的提高。
In large-scale fermentation process, cells behaviour and producing characters areclosely related with the environment factors. The behaviours of cells in environmentresponse are a process of involved in transcription, protein metabolism and interactioncomplex, multi-level network system based on biochemical reaction and mass transfer.Traditional research methods and tools are difficulty to fully reveal its regularity. Inthis paper, we choose ethanol and penicillin of industrial biological processes forstudy systems. From the point of phospholipids and metabolomics, we systematicallycompare and analyse the differences of the microbial cells in different industrialmodels and different industrial scales. We try to get a better understanding of cellsbehaviour to the complex industrial environment in different industrial models anddifferent industrial scales on molecular level and provide a scientific basis foroptimizing and amplificating the bio-process.
First, choosing the batch process and continuous process in large-scale ethanolindustry as study system, we analyse the similarities and differences of cells responsebehaviour of yeast fermentation patterns in different industry fermentation scales.Although, the trend of reducing sugar was similar in the two processes, the cellsviability and ethanol production in the pre-fermentation are significantly lower thanthese in continuous process. Metabolomics analysis shows that osmotic and oxidativestresses are two main environmental factors of causing yeast cells response behaviourdifferences between the two processes. In continuous per-fermentation process,massive accumulation of glycerol shows that high sugar concentration forms osmoticpressure. In hypersonic stimulation, glycerol accumulation adjusts cell osmoticpressure. In the later stage of batch fermentation process, the lactic acid accumulationshows that cellular oxidative stress is increasing. Different environmental stressresponse behaviour causes the differences of amino acid metabolism and TCA cyclemetabolic in the two processes. We further analyse the changes of cell phospholipidcomposition and content in the two processes. The synthetization of Phospholipid inLCUFA in industrial yeast shows the extension of Intracellular enzymes inpolyunsaturated fats, enzymes. The length changes of cellular phospholipid chain maybe an important response of yeast cells to complex industrial environment. Thecontents of PS and PG of LCUFA in batch process are higher than these in continuousprocess. In continuous process, the contents of intracellular phospholipid in LCUFAin early fermentation are higher than the other two stages and show a downward trend with the process of fermentation.
Secondly, choosing penicillin processes in pilot and large-scale industrial processfor study, we analyse the expression differences in biomagnification in the industrialprocess of Penicillium chrysogenum intracellular small-molecule metabolism,phospholipid metabolism and secondary metabolism group comparatively andsystematically. We get a further research response process of penicillin chrysogenumin amplification process. Studies show that the early fermentation and mediumfermentation are critical for the accumulation of penicillin. In the industrialamplification process, penicillin production is closely related to intracellular aminoacid metabolism. In the medium fermentation, amino acid significantly accumulationpromotes the synthesis of penicillin. The results also show that Penicilliumchrysogenum glycolysis and TCA cycle paths have significantly different metaboliccharacteristics in different scales of penicillin fermentation. These differences arerelated to penicillin production and in the industrial amplification process thebiosynthesis of secondary metabolism is significantly influenced by primarymetabolism. In the early stage of pilot process, the primary metabolism of penicilliumchrysogenum is more active which leads to the rate reducing of penicillin synthesis inthe fermentation process. By comparing the differences of secondary metabolites indifferent scales of fermentation processes, we found that the mutual transformation ofsecondary metabolites and the influence of synthetic enzymes are the reasons ofcausing penicillin metabolic differences in industrial amplification process. Furtherstudies of phospholipid show that polyunsaturated phospholipids in the pilot processwere higher than that in industrial process. The changes of unsaturated phospholipidmolecules directly show the differences of mycelium patterns in fermentationprocesses. In the early pilot process, the high unsaturated reduces the cells viscosityand increases the rate of gas-liquid oxygen transfer which can promote more myceliliagrowth and also lead to the rate reducing of penicillin synthesis in fermentationprocess. Compared with pilot process, the industry process suffers heavierenvironmental stresses and cause mycelium divided. And in amplification process theenvironmental stress make for the increasing of penicillin production.
引文
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