适应性进化策略强化VC生产两菌相互作用的代谢水平分析
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摘要
维生素C生产菌株酮古龙酸杆菌与蜡状芽孢杆菌存在较为复杂的两菌关系，为系统优化发酵过程带来困难，本研究以强化两菌相互作用作为切入点，采用混菌适应性进化手段成功的实现了提高2-酮基-L-古龙酸产率的目标，为进一步改造维生素C生产菌株提供了新思路。
混菌体系在为期150天的适应性进化过程中快速进化达到稳定状态，表现为2-KGA转化率、pH值、酮古龙酸杆菌菌数和蜡状芽孢杆菌菌数在前50天中较大波动后达到相对稳定的状态。通过对分纯后的酮古龙酸杆菌和蜡状芽孢杆菌单菌进行分析可以发现，经历适应性进化的酮古龙酸杆菌和蜡状芽孢杆菌，对培养基环境的适应能力及生长能力有很大提高，且酮古龙酸杆菌产酸能力有了显著提高，进化150天的酮古龙酸杆菌产酸能力比原始菌株提高了106.4%。对进化后菌株经交叉搭配发酵，表现为最佳混菌组合2-KGA转化率达到了93%，远高于原始菌株的77%。
通过代谢水平分析发现，进化后酮古龙酸杆菌、蜡状芽孢杆菌与原始菌株相比存在明显的代谢差异，进化后两菌相互配合更加协调，对胞内营养物质的利用能力逐渐提高，有助于目标产物2-KGA的生成；蜡状芽孢杆菌的细胞膜通透性随进化时间的增长不断提高，显示出对酮古龙酸杆菌产物2-KGA产生的胁迫逐渐适应，而酮古龙酸杆菌的细胞膜通透性在进化过程中没有变化。两菌的磷脂分子组成随进化也发生显著变化，且其变化规律与两菌生长、产酸的变化存在一致性，表明细胞磷脂组成和代谢模式能够表征菌株性状的变化。在适应性进化过程中，蜡状芽孢杆菌的细胞膜通透性变化与磷脂变化趋势相一致（如LPE、PA的增加、链长和不饱和度的变化等），表明物质交换能力的变化可能是影响酮古龙酸杆菌提高2-KGA产量的关键因素。
进化后的蜡状芽孢杆菌在酮古龙酸杆菌上的爬动能力有所下降。在氨基酸代谢、嘌呤核苷酸代谢、糖酵解途径和TCA循环等方面的结果分析表明，进化后蜡状芽孢杆菌和酮古龙酸杆菌在代谢水平上互动交流能力明显提高，蜡状芽孢杆菌抵抗酮古龙酸杆菌产生的有害物质的能力进一步提高，表现为受环境胁迫产孢的趋势减弱。这些结果进一步表明两菌关系在进化后发生了明显改变，由不同阶段的互利和偏利关系转化为趋于完全互利共生关系。
Due to the complexity of the relationship between Ketogulonigenium vulgareand Bacillus cereus, Vitamin C productive strains, it brings many difficulties tosystemically optimize the fermentation process. To intensify the interaction as anentry point, this study of adaptive evolution method applied in the mixed cultureprovides a new example to improve the productivity of the target product, and a newway of thinking for further modification of vitamin C productive strains.
The mixed culture attained steady state in the process of the150-day adaptiveevolution, characterized that2-KGA conversion rate, pH, the population of K. vulgareand B. cereus underwent dramatic fluctuations in the beginning50days and thenreached a relatively stable state. Evolution improved the adaptive capacity of themedium environment, the growth rate of K. vulgare and B. cereus, and the yield of2-KGA by K. vulgare evolved150days enhanced106.4%compared to ancestral K.vulgare. Cross-collocation of the evolved and ancestral species in an industrialfermentation medium dramatically increased the2-KGA conversion rate, and theyield of most efficient mixed culture reached93%compared to77%of ancestralstrains.
Metabolism analysis found that evolved K. vulgare and B. cereus were differentfrom ancestral strains apparently, evolved strains cooperated more harmoniously andutilized the intracellular nutrients more efficiently, contributing to the synthesis of theobjective product2-KGA. Cell membrane permeability of B. cereus increased alongwith the evolution process, implying that B. cereus gradually adapted to the stress of2-KGA produced by K. vulgare. The cell membrane permeability of K. vulgare didnot change in the process of evolution. Phospholipid molecules of K. vulgare and B.cereus have changed significantly along with the evolution process, and the changerule consisted with the change of the growth of2-KGA production of both species,which manifested that the phospholipid composition and metabolic model cancharacterize changes of strain properties. In the process of adaptive evolution,phospholipid changes of B. cereus consistented with the changes of cell membranepermeability (e.g., the increase of LPE, PA, the change of chain length and degree of saturation, etc.), indicating that changes in exchange capacity of nutrients could be thekey factor in raising the yield of2-KGA.
The swarm capacity of evolved B. cereus on K. vulgare significantly declined. Onthe amino acid metabolism, purine nucleotide metabolism, glycolysis pathway and theTCA cycle metabolism level, evolved K. vulgare and B. cereus showed higher abilityof cell-cell communication on the metabolic level. Evolved B. cereus displayed highercapacity of resistance to the harmful material produced by K. vulgare andcharacterized the deficiency of sporation. It further showed that relationships of K.vulgare and B. cereus significantly changed, from the relationship of mutualism andamensalism in different stages into the completely mutualism.
混菌体系在为期150天的适应性进化过程中快速进化达到稳定状态，表现为2-KGA转化率、pH值、酮古龙酸杆菌菌数和蜡状芽孢杆菌菌数在前50天中较大波动后达到相对稳定的状态。通过对分纯后的酮古龙酸杆菌和蜡状芽孢杆菌单菌进行分析可以发现，经历适应性进化的酮古龙酸杆菌和蜡状芽孢杆菌，对培养基环境的适应能力及生长能力有很大提高，且酮古龙酸杆菌产酸能力有了显著提高，进化150天的酮古龙酸杆菌产酸能力比原始菌株提高了106.4%。对进化后菌株经交叉搭配发酵，表现为最佳混菌组合2-KGA转化率达到了93%，远高于原始菌株的77%。
通过代谢水平分析发现，进化后酮古龙酸杆菌、蜡状芽孢杆菌与原始菌株相比存在明显的代谢差异，进化后两菌相互配合更加协调，对胞内营养物质的利用能力逐渐提高，有助于目标产物2-KGA的生成；蜡状芽孢杆菌的细胞膜通透性随进化时间的增长不断提高，显示出对酮古龙酸杆菌产物2-KGA产生的胁迫逐渐适应，而酮古龙酸杆菌的细胞膜通透性在进化过程中没有变化。两菌的磷脂分子组成随进化也发生显著变化，且其变化规律与两菌生长、产酸的变化存在一致性，表明细胞磷脂组成和代谢模式能够表征菌株性状的变化。在适应性进化过程中，蜡状芽孢杆菌的细胞膜通透性变化与磷脂变化趋势相一致（如LPE、PA的增加、链长和不饱和度的变化等），表明物质交换能力的变化可能是影响酮古龙酸杆菌提高2-KGA产量的关键因素。
进化后的蜡状芽孢杆菌在酮古龙酸杆菌上的爬动能力有所下降。在氨基酸代谢、嘌呤核苷酸代谢、糖酵解途径和TCA循环等方面的结果分析表明，进化后蜡状芽孢杆菌和酮古龙酸杆菌在代谢水平上互动交流能力明显提高，蜡状芽孢杆菌抵抗酮古龙酸杆菌产生的有害物质的能力进一步提高，表现为受环境胁迫产孢的趋势减弱。这些结果进一步表明两菌关系在进化后发生了明显改变，由不同阶段的互利和偏利关系转化为趋于完全互利共生关系。
Due to the complexity of the relationship between Ketogulonigenium vulgareand Bacillus cereus, Vitamin C productive strains, it brings many difficulties tosystemically optimize the fermentation process. To intensify the interaction as anentry point, this study of adaptive evolution method applied in the mixed cultureprovides a new example to improve the productivity of the target product, and a newway of thinking for further modification of vitamin C productive strains.
The mixed culture attained steady state in the process of the150-day adaptiveevolution, characterized that2-KGA conversion rate, pH, the population of K. vulgareand B. cereus underwent dramatic fluctuations in the beginning50days and thenreached a relatively stable state. Evolution improved the adaptive capacity of themedium environment, the growth rate of K. vulgare and B. cereus, and the yield of2-KGA by K. vulgare evolved150days enhanced106.4%compared to ancestral K.vulgare. Cross-collocation of the evolved and ancestral species in an industrialfermentation medium dramatically increased the2-KGA conversion rate, and theyield of most efficient mixed culture reached93%compared to77%of ancestralstrains.
Metabolism analysis found that evolved K. vulgare and B. cereus were differentfrom ancestral strains apparently, evolved strains cooperated more harmoniously andutilized the intracellular nutrients more efficiently, contributing to the synthesis of theobjective product2-KGA. Cell membrane permeability of B. cereus increased alongwith the evolution process, implying that B. cereus gradually adapted to the stress of2-KGA produced by K. vulgare. The cell membrane permeability of K. vulgare didnot change in the process of evolution. Phospholipid molecules of K. vulgare and B.cereus have changed significantly along with the evolution process, and the changerule consisted with the change of the growth of2-KGA production of both species,which manifested that the phospholipid composition and metabolic model cancharacterize changes of strain properties. In the process of adaptive evolution,phospholipid changes of B. cereus consistented with the changes of cell membranepermeability (e.g., the increase of LPE, PA, the change of chain length and degree of saturation, etc.), indicating that changes in exchange capacity of nutrients could be thekey factor in raising the yield of2-KGA.
The swarm capacity of evolved B. cereus on K. vulgare significantly declined. Onthe amino acid metabolism, purine nucleotide metabolism, glycolysis pathway and theTCA cycle metabolism level, evolved K. vulgare and B. cereus showed higher abilityof cell-cell communication on the metabolic level. Evolved B. cereus displayed highercapacity of resistance to the harmful material produced by K. vulgare andcharacterized the deficiency of sporation. It further showed that relationships of K.vulgare and B. cereus significantly changed, from the relationship of mutualism andamensalism in different stages into the completely mutualism.
引文
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