ε-聚赖氨酸生物合成及代谢调控研究
|
摘要
ε-聚赖氨酸(ε-poly-L-lysine, ε-PL)是链霉菌(Streptomyces)合成的L-赖氨酸(L-lysine)聚合物，通常由25-35个L-赖氨酸残基组成。本研究以本课题组以亚甲基蓝(methylene blue)法分离到的1株产ε-聚赖氨酸的不吸水链霉菌(Streptomycesahygroscopicus GIM8)为实验菌株，对其合成产物进行确证，并确定其分子量和聚合度；主要研究ε-聚赖氨酸生物合成及代谢调控，包括：ε-聚赖氨酸的产生菌细胞效应研究；生物过程细胞活性研究；L-赖氨酸及D-赖氨酸对ε-聚赖氨酸生物合成影响差异研究；原位分离发酵研究；固定化细胞原位分离发酵研究；调控细胞活性的补料分批发酵研究，主要结果如下：
德拉根夫(Dragendorff)试剂反应显示菌株GIM8发酵产物不同于α-聚赖氨酸；经离子交换、葡聚糖过柱等步骤获得的纯化产物RG经6mol/L HCl水解后的薄层层析表明赖氨酸(lysine)是分离纯化产物的惟一组分；经红外光谱、1H-NMR、13C-NMR和HMBC谱确证分离产物RG为ε-聚赖氨酸，因此，菌株GIM8为ε-聚赖氨酸产生菌。Tricine-SDS-PAGE电泳显示菌株GIM8生物合成的ε-聚赖氨酸分子量约为3300Da；基质辅助激光解析电离质谱(MALDI-TOF-MS)表明其聚合度主要在28-34间，可见菌株GIM8所合成ε-聚赖氨酸适合作为食品工业用防腐剂。
生理条件下(pH7.0) ε-聚赖氨酸大量吸附至产生菌细胞，酸性pH4.0时极少量吸附细胞；荧光显微镜分析表明异硫氰酸荧光素(Fluorescein isothiocyanate, FITC)标记的ε-聚赖氨酸吸附至细胞表面，未进入细胞内；pH7.0时ε-聚赖氨酸对产生菌细胞具有膜破坏活性，致使膜通透性增加、细胞质膜损伤及代谢活性降低；透射电子显微镜镜(Tranmission electron microscopy, TEM)显示细胞质膜是主要作用位点；pH4.0时ε-聚赖氨酸抑制胞内物质泄漏，但仍然能使细胞活性降低，推测其进入胞内发生作用。基于ε-聚赖氨酸生物合成发生于酸性条件，而酸性条件下ε-聚赖氨酸仍显著降低合成细胞活性，研究以D152为吸附剂的原位分离发酵，显示ε-聚赖氨酸合成阶段置入树脂的原位分离发酵产率达2.86g/L，与对照的0.81g/L增长253%；将尼龙布包裹的树脂系于5L生物反应器支架上的原位分离补料分批发酵，产率从3.76g/L增长至23.4g/L。
考虑到ε-聚赖氨酸生物合成强烈依赖于细胞密度以及其作为终端代谢产物和所具有的强抑菌活性，将细胞固定化及原位分离发酵技术优化整合，即采用丝瓜络为固定化材料，发酵过程以自然吸附的方式达到细胞固定的固定化发酵，以提高细胞生长量；以D152为原位分离吸附剂避免产物的抑菌活性和/或反馈抑制效应的原位分离发酵，结果显示固定化细胞原位分离发酵摇瓶产量达3.64g/L，显著高于单一的发酵技术（原位分离的2.73g/L和固定化细胞发酵的0.54g/L），且固定化细胞可重复利用3次，细胞总生产能力达8.05g/L。
BacLight Live/Dead染色的共聚焦图片显示ε-聚赖氨酸发酵前期(0-12h)大部分细胞具有活性；发酵中后期(18-72h)得不到典型的BacLight图片。 CTC(5-cyano-2,3-ditolyl tetrazolium chloride)染色的共聚焦图片显示0-18h细胞代谢活性逐渐增强，后开始下降；培养至48h时，此时ε-聚赖氨酸生物合成停止，细胞仅显示微弱活性；比色法显示接种6h后细胞活性略有降低，后逐渐上升(6-18h)，ε-聚赖氨酸的合成阶段(18-24h)活性快速下降，后以较低速度持续下降，48h时，此时ε-聚赖氨酸生物合成已经终止，细胞代谢活性仅为起始活性15.9%。从产物合成及细胞活性变化可知高细胞代谢活性有利于ε-聚赖氨酸合成，基于此研究调控细胞代谢活性的发酵工艺，发现在摇瓶培养ε-聚赖氨酸合成阶段补加0.5%酵母抽提物，细胞密度、细胞活性及细胞生产力可得到显著提高；间断补加酵母抽提物的补料分批发酵，在30L生物反应器中的产率从16.3g/L增长至28.2g/L，提高73%。
ε-聚赖氨酸生物合成阶段L-赖氨酸大都直接参与生物合成，从而提高产率；D-赖氨酸主要被细胞分解利用提高了细胞密度，由此生物合成得到增强，显见两对映异构体促进ε-聚赖氨酸生物合成的机制明显不同；薄层层析表明L-赖氨酸和D-赖氨酸在产生菌细胞内均不形成有毒物质尸胺(cadaverine)；液相色谱-质谱联用(LC-MS)显示L-赖氨酸在胞内分解代谢为5-氨基戊酸(5-aminovalerate)、甲基哌啶(pipecolate)及L-α-氨基已二酸(L-α-aminoadipate)；D-lysine代谢为L-α-氨基已二酸；在化学合成培养基中L-赖氨酸不是细胞适合的有机氮源；这些研究结果为以L-赖氨酸为底物生物转化法生产ε-聚赖氨酸提供了理论依据。
本论文研究结果有助于提升对ε-聚赖氨酸生物合成的进一步认识，可为ε-聚赖氨酸生物过程优化及控制提供一定理论依据，为大规模工业化发酵生产ε-聚赖氨酸打下了一定的基础。
ε-Poly-L-lysine (ε-PL), produced by Streptomyces strains, is a homopolymer of L-lysinewith a pomerization degree of25-35. Due to its highly safety, ε-PL is being receivedincreasing interest as a natural food preservation. In this paper, the product isolated fromStreptomyces ahygroscopicus GIM8fermentation broth was identified and its molecularweight was determined for assessing as a suitable food preservative. With the main aim ofimproving ε-PL production, study emphasis was paid on ε-PL biosynthesis and metabolicregulation. The main results obtained were summarized in the following.
The product isolated from Streptomyces ahygroscopicus GIM8was confirmed as ε-PLafter TLC, ultraviolet spectrum, infrared spectrum (IR) and nuclear magnetic resonance(NMR) analysis. Tricine-SDS-PAGE demonstrated that the molecular weight of ε-PLproduced by this strain was about3300kDa, and this polymer has a pomerization degree ofranging from28to34obtained from MALDI-TOF-MS spectrum. On the basis of thesefindings, S. ahygroscopicus is a strain capable of producing ε-PL and the product is suitablefor using in the food industry as a food preservative.
In a neutral buffer, large amounts of ε-PL adsorbed onto the cells, and declined with adecrease in pH value. When the pH was at4.0, which pH is required for ε-PL biosynthesis,there was minimal adsorption of ε-PL on the cells. The adsorption was also confirmed byfluorescence microscopy through labeling ε-PL with FITC. Treatment of the cells with ε-PL atpH7.0, increased membrane permeability, cell membrane damage, and decreased cell activitywere observed. However, ε-PL inhibited the intracellular materials leakage in the pH4.0buffer even though minimal adsorption of ε-PL onto the cells occurred, and decreased cellactivity considerably. From these findings, it was reasonably postulated that ε-PL could enterthe cells at pH4.0, thereby exerting its function. The entrance of ε-PL into the cells may bedue to the increase in membrane permeability and ε-PL conformation change caused by lowpH.
As ε-PL could significantly decrease metabolic activity of the cells, it is necessary toseparate ε-PL from fermentation broth as it was produced by the cells. For development of insitu removal of ε-PL, adsorption experiments were performed. Among Amberlite IRC-76,Amberlite IRC-50, and Amberlite IR-120, D152was chosen using adsorption capactity anddesoprtion rate as bases. Inclusion of D152in shaken cultures grown in the production phase,the production of ε-PL was increased to2.86g/L from0.81g/L. In a5L fermentor, ε-PLconcentration as high as23.4g/L, with an increase of522%relative to the control (3.76g/L), was obtained by affixing two bags of D152resin to the probes and baffles of the fermentor,indicating in situ product removal an efficient technique for the production of ε-PL.
To significantly improve cell density and overcome the inhibitory effect of ε-PL, acombination of cell immobilization and in situ adsorption was developed to test in improvingfermentation efficiency in shaken flasks. Among loofah sponge, sugarcane bagasse andsynthetic sponge, loofah sponge-immobilzed S. ahygroscopicus GIM8behaved the best on thebasis of ε-PL productivity and cell growth. Using loofah sponge as cell carrier forimmobilization and D152resin as an adsorbent for in situ adsorption of ε-PL, a final ε-PL titreof3.64g/L was achieved, signficantly higher than those obtained by the single technique(immobilization,0.54g/L; in situ product removal,2.73g/L). Furthermore, the immobilizedcells could be repeatedly used three times, with a total ε-PL amount of8.05g/L at flask level.
Using BacLight Live/Dead as a viability dye, laser scanning confocal microsocpy(LSCM) data demonstrated that most of the cells was active from0to12h. At18h andwhereafter, typical BacLight images could not be observed. This may be related to the changein membrane permeability and DNA conformation. With CTC as a dye based on metabolicactivity, it was found that cell activity increased from0to18h, and thereafter it began todecline. At48h, when ε-PL biosynthesis ceased, the cells exhibited little metabolic activity.With a colorimetric procedure, lower metabolic activity was observed after6h inoculation,and increased gradually to18h. However, a sharp decline was observed between18to24hcultivation. In the later cultivation, the decline trend continued, and at48h only15.9%ofinitial activity remained. From the evolutionary of ε-PL formation and cell activity, it could beconcluded that the ε-PL biosynthesis was closely related to metabolic activity of the cells.
Based on the correlation between ε-PL biosynthesis and metabolic activity, enhancingcell activity is very necessary for efficient ε-PL production. Therefore, malt, beef extract, andyeast extract were tested in improving ε-PL production in the flask culture of S.ahygroscopicus GIM8. The results indicated that yeast extract stimulated ε-PL biosynthesisthe most. Further studies indicated that enhancement of cell activity and production capacityof the cells was observed. By intermittently feeding yeast extract to fed-batch cultures in30Lfermenters grown in the production phase, both the ε-PL production time and biomass hadsignificant improvement as compared with those of the control cultures. ε-PL concentration ashigh as28.2g/L was achieved—73%higher than the concentration of the control culture(16.3g/L).
Considering that lysine is a precursor for the biosynthesis of ε-PL, its effect on ε-PLproduction in a fermentation medium was examined. The results demonstrated that L-lysine added in the production phase mainly served as a precursor for ε-PL biosynthesis, leading togreater ε-PL production. At an optimum level of3mM L-lysine, a ε-PL yield of1.16g/L wasattained, with a41.4%increment relative to the control (0.78g/L). Interestingly, ε-PLproduction was also enhanced considerably when D-lysine at3mM was supplemented intothe initial fermentation medium in flasks, even higher than that of L-lysine initial addition (3mM). The mechanism by which D-lysine improves ε-PL biosynthesis is that its utilization ledto greater biomass and, consequently, greater ε-PL production.
When S. ahygroscopicus GIM8was cultivated in the defined medium containing L-lysine,several key metabolites of lysine metabolism including5-aminovalerate, pipecolate, andL-2-aminoadipate were identified in the cells by the LC-MS analysis; whereas onlyL-2-aminoadipate was detected after D-lysine metabolism. Apparently, L-lysine and D-lysinehave different catabolism pathways in the cells. On the other hand, cadaverine, a toxiccompound, was not formed in the cells after metabolism of both L-lysine and D-lysine. Theresults are expected to aid the understanding of ε-PL biosynthesis, and serve as reference forthe formulation of an alternative approach to improve ε-PL productivity using L-lysine as anadditional substrate in fermentation medium.
The results of this paper provide insights on ε-PL biosynthesis and could serve forfermentation control and optimization in industrial fermentation processes.
德拉根夫(Dragendorff)试剂反应显示菌株GIM8发酵产物不同于α-聚赖氨酸；经离子交换、葡聚糖过柱等步骤获得的纯化产物RG经6mol/L HCl水解后的薄层层析表明赖氨酸(lysine)是分离纯化产物的惟一组分；经红外光谱、1H-NMR、13C-NMR和HMBC谱确证分离产物RG为ε-聚赖氨酸，因此，菌株GIM8为ε-聚赖氨酸产生菌。Tricine-SDS-PAGE电泳显示菌株GIM8生物合成的ε-聚赖氨酸分子量约为3300Da；基质辅助激光解析电离质谱(MALDI-TOF-MS)表明其聚合度主要在28-34间，可见菌株GIM8所合成ε-聚赖氨酸适合作为食品工业用防腐剂。
生理条件下(pH7.0) ε-聚赖氨酸大量吸附至产生菌细胞，酸性pH4.0时极少量吸附细胞；荧光显微镜分析表明异硫氰酸荧光素(Fluorescein isothiocyanate, FITC)标记的ε-聚赖氨酸吸附至细胞表面，未进入细胞内；pH7.0时ε-聚赖氨酸对产生菌细胞具有膜破坏活性，致使膜通透性增加、细胞质膜损伤及代谢活性降低；透射电子显微镜镜(Tranmission electron microscopy, TEM)显示细胞质膜是主要作用位点；pH4.0时ε-聚赖氨酸抑制胞内物质泄漏，但仍然能使细胞活性降低，推测其进入胞内发生作用。基于ε-聚赖氨酸生物合成发生于酸性条件，而酸性条件下ε-聚赖氨酸仍显著降低合成细胞活性，研究以D152为吸附剂的原位分离发酵，显示ε-聚赖氨酸合成阶段置入树脂的原位分离发酵产率达2.86g/L，与对照的0.81g/L增长253%；将尼龙布包裹的树脂系于5L生物反应器支架上的原位分离补料分批发酵，产率从3.76g/L增长至23.4g/L。
考虑到ε-聚赖氨酸生物合成强烈依赖于细胞密度以及其作为终端代谢产物和所具有的强抑菌活性，将细胞固定化及原位分离发酵技术优化整合，即采用丝瓜络为固定化材料，发酵过程以自然吸附的方式达到细胞固定的固定化发酵，以提高细胞生长量；以D152为原位分离吸附剂避免产物的抑菌活性和/或反馈抑制效应的原位分离发酵，结果显示固定化细胞原位分离发酵摇瓶产量达3.64g/L，显著高于单一的发酵技术（原位分离的2.73g/L和固定化细胞发酵的0.54g/L），且固定化细胞可重复利用3次，细胞总生产能力达8.05g/L。
BacLight Live/Dead染色的共聚焦图片显示ε-聚赖氨酸发酵前期(0-12h)大部分细胞具有活性；发酵中后期(18-72h)得不到典型的BacLight图片。 CTC(5-cyano-2,3-ditolyl tetrazolium chloride)染色的共聚焦图片显示0-18h细胞代谢活性逐渐增强，后开始下降；培养至48h时，此时ε-聚赖氨酸生物合成停止，细胞仅显示微弱活性；比色法显示接种6h后细胞活性略有降低，后逐渐上升(6-18h)，ε-聚赖氨酸的合成阶段(18-24h)活性快速下降，后以较低速度持续下降，48h时，此时ε-聚赖氨酸生物合成已经终止，细胞代谢活性仅为起始活性15.9%。从产物合成及细胞活性变化可知高细胞代谢活性有利于ε-聚赖氨酸合成，基于此研究调控细胞代谢活性的发酵工艺，发现在摇瓶培养ε-聚赖氨酸合成阶段补加0.5%酵母抽提物，细胞密度、细胞活性及细胞生产力可得到显著提高；间断补加酵母抽提物的补料分批发酵，在30L生物反应器中的产率从16.3g/L增长至28.2g/L，提高73%。
ε-聚赖氨酸生物合成阶段L-赖氨酸大都直接参与生物合成，从而提高产率；D-赖氨酸主要被细胞分解利用提高了细胞密度，由此生物合成得到增强，显见两对映异构体促进ε-聚赖氨酸生物合成的机制明显不同；薄层层析表明L-赖氨酸和D-赖氨酸在产生菌细胞内均不形成有毒物质尸胺(cadaverine)；液相色谱-质谱联用(LC-MS)显示L-赖氨酸在胞内分解代谢为5-氨基戊酸(5-aminovalerate)、甲基哌啶(pipecolate)及L-α-氨基已二酸(L-α-aminoadipate)；D-lysine代谢为L-α-氨基已二酸；在化学合成培养基中L-赖氨酸不是细胞适合的有机氮源；这些研究结果为以L-赖氨酸为底物生物转化法生产ε-聚赖氨酸提供了理论依据。
本论文研究结果有助于提升对ε-聚赖氨酸生物合成的进一步认识，可为ε-聚赖氨酸生物过程优化及控制提供一定理论依据，为大规模工业化发酵生产ε-聚赖氨酸打下了一定的基础。
ε-Poly-L-lysine (ε-PL), produced by Streptomyces strains, is a homopolymer of L-lysinewith a pomerization degree of25-35. Due to its highly safety, ε-PL is being receivedincreasing interest as a natural food preservation. In this paper, the product isolated fromStreptomyces ahygroscopicus GIM8fermentation broth was identified and its molecularweight was determined for assessing as a suitable food preservative. With the main aim ofimproving ε-PL production, study emphasis was paid on ε-PL biosynthesis and metabolicregulation. The main results obtained were summarized in the following.
The product isolated from Streptomyces ahygroscopicus GIM8was confirmed as ε-PLafter TLC, ultraviolet spectrum, infrared spectrum (IR) and nuclear magnetic resonance(NMR) analysis. Tricine-SDS-PAGE demonstrated that the molecular weight of ε-PLproduced by this strain was about3300kDa, and this polymer has a pomerization degree ofranging from28to34obtained from MALDI-TOF-MS spectrum. On the basis of thesefindings, S. ahygroscopicus is a strain capable of producing ε-PL and the product is suitablefor using in the food industry as a food preservative.
In a neutral buffer, large amounts of ε-PL adsorbed onto the cells, and declined with adecrease in pH value. When the pH was at4.0, which pH is required for ε-PL biosynthesis,there was minimal adsorption of ε-PL on the cells. The adsorption was also confirmed byfluorescence microscopy through labeling ε-PL with FITC. Treatment of the cells with ε-PL atpH7.0, increased membrane permeability, cell membrane damage, and decreased cell activitywere observed. However, ε-PL inhibited the intracellular materials leakage in the pH4.0buffer even though minimal adsorption of ε-PL onto the cells occurred, and decreased cellactivity considerably. From these findings, it was reasonably postulated that ε-PL could enterthe cells at pH4.0, thereby exerting its function. The entrance of ε-PL into the cells may bedue to the increase in membrane permeability and ε-PL conformation change caused by lowpH.
As ε-PL could significantly decrease metabolic activity of the cells, it is necessary toseparate ε-PL from fermentation broth as it was produced by the cells. For development of insitu removal of ε-PL, adsorption experiments were performed. Among Amberlite IRC-76,Amberlite IRC-50, and Amberlite IR-120, D152was chosen using adsorption capactity anddesoprtion rate as bases. Inclusion of D152in shaken cultures grown in the production phase,the production of ε-PL was increased to2.86g/L from0.81g/L. In a5L fermentor, ε-PLconcentration as high as23.4g/L, with an increase of522%relative to the control (3.76g/L), was obtained by affixing two bags of D152resin to the probes and baffles of the fermentor,indicating in situ product removal an efficient technique for the production of ε-PL.
To significantly improve cell density and overcome the inhibitory effect of ε-PL, acombination of cell immobilization and in situ adsorption was developed to test in improvingfermentation efficiency in shaken flasks. Among loofah sponge, sugarcane bagasse andsynthetic sponge, loofah sponge-immobilzed S. ahygroscopicus GIM8behaved the best on thebasis of ε-PL productivity and cell growth. Using loofah sponge as cell carrier forimmobilization and D152resin as an adsorbent for in situ adsorption of ε-PL, a final ε-PL titreof3.64g/L was achieved, signficantly higher than those obtained by the single technique(immobilization,0.54g/L; in situ product removal,2.73g/L). Furthermore, the immobilizedcells could be repeatedly used three times, with a total ε-PL amount of8.05g/L at flask level.
Using BacLight Live/Dead as a viability dye, laser scanning confocal microsocpy(LSCM) data demonstrated that most of the cells was active from0to12h. At18h andwhereafter, typical BacLight images could not be observed. This may be related to the changein membrane permeability and DNA conformation. With CTC as a dye based on metabolicactivity, it was found that cell activity increased from0to18h, and thereafter it began todecline. At48h, when ε-PL biosynthesis ceased, the cells exhibited little metabolic activity.With a colorimetric procedure, lower metabolic activity was observed after6h inoculation,and increased gradually to18h. However, a sharp decline was observed between18to24hcultivation. In the later cultivation, the decline trend continued, and at48h only15.9%ofinitial activity remained. From the evolutionary of ε-PL formation and cell activity, it could beconcluded that the ε-PL biosynthesis was closely related to metabolic activity of the cells.
Based on the correlation between ε-PL biosynthesis and metabolic activity, enhancingcell activity is very necessary for efficient ε-PL production. Therefore, malt, beef extract, andyeast extract were tested in improving ε-PL production in the flask culture of S.ahygroscopicus GIM8. The results indicated that yeast extract stimulated ε-PL biosynthesisthe most. Further studies indicated that enhancement of cell activity and production capacityof the cells was observed. By intermittently feeding yeast extract to fed-batch cultures in30Lfermenters grown in the production phase, both the ε-PL production time and biomass hadsignificant improvement as compared with those of the control cultures. ε-PL concentration ashigh as28.2g/L was achieved—73%higher than the concentration of the control culture(16.3g/L).
Considering that lysine is a precursor for the biosynthesis of ε-PL, its effect on ε-PLproduction in a fermentation medium was examined. The results demonstrated that L-lysine added in the production phase mainly served as a precursor for ε-PL biosynthesis, leading togreater ε-PL production. At an optimum level of3mM L-lysine, a ε-PL yield of1.16g/L wasattained, with a41.4%increment relative to the control (0.78g/L). Interestingly, ε-PLproduction was also enhanced considerably when D-lysine at3mM was supplemented intothe initial fermentation medium in flasks, even higher than that of L-lysine initial addition (3mM). The mechanism by which D-lysine improves ε-PL biosynthesis is that its utilization ledto greater biomass and, consequently, greater ε-PL production.
When S. ahygroscopicus GIM8was cultivated in the defined medium containing L-lysine,several key metabolites of lysine metabolism including5-aminovalerate, pipecolate, andL-2-aminoadipate were identified in the cells by the LC-MS analysis; whereas onlyL-2-aminoadipate was detected after D-lysine metabolism. Apparently, L-lysine and D-lysinehave different catabolism pathways in the cells. On the other hand, cadaverine, a toxiccompound, was not formed in the cells after metabolism of both L-lysine and D-lysine. Theresults are expected to aid the understanding of ε-PL biosynthesis, and serve as reference forthe formulation of an alternative approach to improve ε-PL productivity using L-lysine as anadditional substrate in fermentation medium.
The results of this paper provide insights on ε-PL biosynthesis and could serve forfermentation control and optimization in industrial fermentation processes.
引文
[1] Shima S, Sakai H. Polylysine produced by Streptomyces[J]. Agricultural andBiological Chemistry,1977,41:1807-1809.
[2] Hiraki J, Ichikawa T, Ninomiya SI, et al. Use of ADME studies to confirm thesafety of ε-polylysine as a preservative in food[J]. Regulatory Toxicology andPharmacology,2003,37:328–340.
[3] Hiraki J. Basic and applied studies on ε-polylysine[J]. Journal of AntibactAntifungal Agents,1995,23:349-354.
[4] Shima S, Sakai H. Poly-L-lysine produced by Streptomyces. Part Ⅲ. Chemicalstudies[J]. Agricultural and Biological Chemistry,1981,45:2503-2508.
[5] Maeda S, Kunimoto KK, Sasaki C, et al. Characterization of microbialpoly(ε-L-lysine) by FT-IR, Raman, and solid state13C NMR spectroscopies[J].Journal of Molecular Structure,2003,655:149-155.
[6]孙群，阚建全，赵国华，等.活性多糖构效关系研究进展[J].广州食品工业科技,2004,(1):104-107.
[7]诸葛健，赵振峰，方慧英.功能性多糖的构效关系[J].无锡轻工大学学报,2002,21(2):209-212.
[8] Bohn JA, Bemiller JN.(1,3)-β-D-Glucans as biological response modifiers: areview of structure-functional activity relationships[J]. Carbohydrate Polymers,1995,28:3-14.
[9] Ploug M. Structure-function relationships in the interaction between theurokinase-tape plasminogen activator and its receptor[J]. Current PharmaceuticalDesign,2003,9:1499-1528(30).
[10] Eisenberg D, Gill HS, Pfluegl GMU, et al. Structure-function relationships ofglutamine synthetases[J]. Biochimica et Biophysica Acta,2000,1477:122-145.
[11] Fukushi H, Oyama K, Hatakeyama M, et al. HPLC fractionation ofoligo(ε-L-lysine)mers and their1H NMR characteristics[J]. Chemistry Express,1993,8:745-748.
[12] Kushwaha DR, Mathur KB, Balasubramanian D. Poly(ε-L-lysine): synthesis andconformation[J]. Biopolymers,1980,19:219-229.
[13] Lee HH, Oyama K, Hiraki J, et al. Microbial production and conformation ofpoly(ε-L-lysine)[J]. Chemistry Express,1991,6:683-686.
[14] Shima S, Matsuoka H, Iwanoto T, et al. Antimicrobial action ofε-poly-L-lysine[J]. Journal of antibiotics,1984,37:1445-1449.
[15] Shima S, Fukuhara Y, Sakai H. Inactivation of bacteriophages by ε-poly-L-lysineproduced by Streptomyces[J]. Agricultural and Biological Chemistry,1982,46:1917-1919.
[16]张东荣，王正刚，毛忠贵. ε-聚赖氨酸的研究进展[J].氨基酸和生物资源,2005,27(2):48-51.
[17] Najjar MB, Kashtanov D, Chikindas ML. ε-Poly-L-lysine and nisin A actsynergistically against Gram-positive food-borne pathogens Bacillus cereus andListeria monocytogenes[J]. Letters in Applied Microbiology,2007,45:13-18.
[18]侯晓姝，胡宗利，陈国平，等.抗菌肽的抗菌机制及其临床应用[J].微生物学通报，2009，36(1):97-105.
[19] Chen FY, Lee MT, Huang HW. Sigmoidal concentration dependence ofantimicrobial peptide activities: a case study on alamethicin[J]. Biophysical Journal,2002,82:908-914.
[20] Brogden KA. Antimicrobial peptides: pore formers or metabolic inhibitors inbacteria? Nature Reviews Microbiology,2005,3:238-250.
[21] Zorko M, Langel U. Cell-penetrating peptides: mechanism and kinetics of cargodelivery. Advanced Drug Delivery Reviews,2005,57:529-545.
[22] Moll GN, Roberts, GCK, Konings WN, et al. Mechanisms of lantibiotic-inducedpore-formation[J]. Antonie van Leuwenhoek,1996,69:185-191.
[23] Winkowski K, Ludescher RD, Montville TJ. Physicochemical characterization ofthe nisin-membrane interaction with liposomes derived from Listeriamonocytogenes[J]. Applied and Environmental Microbiology,1996,62:323-327.
[24] Reddy KVR, Yedery RD, Aranha C. Antimicrobial peptides: premises andpromises[J]. International Journal of Antimicrobial Agents,2004,24:536-547.
[25] Neda K, Sakurai T, Stakahashi M, et al. Two-generation reproduction study withteratology test of ε-poly-L-lysine by dietary administration in rats. JapanesePharmcology and Therapeutics,1999,27:1139-1159.
[26] Hiraki J. ε-polylysine, its development and utilization[J]. Fine Chemistry,2000,29:25-28.
[27] Shih IL, Shen MH, Van YT. Microbial synthesis of poly(ε-lysine) and its variousapplications[J]. Bioresource Technology,2006,97:1148–1159.
[28] Otsuka N, Kuwahara Y, Manabe K. Effect of ε-poly-lysine on preservation ofboiled noodles[J]. Nippon Shokuhin Kogyo Gakkaishi,1992,39:344-347.
[29] Chang SS, Wendy Lu WY, Park SH, et al. Control of foodborne pathogens onready-to-eat roast beef slurry by ε-polylysine[J]. International Journal of FoodMicrobiology,2010,141:236-241.
[30] Ho YT, Ishizaki S, Tanaka M. Improving emulsifying activity of ε-polylysine byconjugation with dextran through the Maillard reaction[J]. Food Chemistry,2000,68:449-455.
[31]谢建飞，杨玉红，陈红漫，等.防腐型乳化剂葡聚赖氨酸的研究[J].食品科学，2009,30(11):131-133.
[32] Ting HY, Ishizaki S, Tanaka M. Effect of the maillard reaction on the bactericidalactivity of ε-polylysine[J]. Journal of Tokyo University of Fisheries,1997,84:25-30.
[33] Kido Y, Hiramoto S, Murao M, et al. ε-Poly-L-lysine inhibits pancreatic lipaseactivity and suppresses postprandial hypertriacylglyceridemia in rats[J]. The Journalof Nutrition,2003,1887-1891.
[34] Tsujita T, Takaichi H, Takaku T, et al, Hiraki J. Antiobesity action of ε-polylysine,a potent inhibitor of pancreatic lipase[J]. Journal of Lipid Research,2006,47:1852-1858.
[35] Friemann T, Robin R. Gene therapy for human genetic disease. Science,1972,175:949-955.
[36] Mulligan RC. The basic science of gene therapy[J]. Science,1993,260:926-932.
[37] Hanania EG, Kavanagh J, Hortovagyl G, et al. Recent advances in the applicationof gene therapy to human disease[J]. The Americian Journal of Medicine,1995,99,537-552.
[38] Chiou HC, Tangco MV, Levine SM, et al. Enhanced resistance to nucleasedegradation of nucleic acids complexed to asialoglycoprotein-polylysine carriers[J].Nucleic Acids Research,1994,22:5439-5446.
[39] Dorudi S, Northover JM, Vile RG. Gene transfer therapy in cancer[J]. BritishJournal of Surgery,1993,80:566-572.
[40] Choi JS, Joo DK, Kim CH, et al. Synthesis of a barbell-like triblock copolymer,poly(L-lysine) dendrimer-block-poly(ethylene glycol)-block-poly(L-lysine) dendrimer,and its self-assembly with plasmid DNA[J]. The Journal of American ChemicalSociety.2000,122:474-480.
[41] Shen WC，Ryser HJP. Conjugation of poly-L-lysine to albumin and horseradishperoxidase: a novel method of enhancing the cellular uptake of protein[J].Proceedings of the National Academy of Sciences USA,1978,75:1872-1876.
[42] Shen WC, Ryser HJP. Poly(L-lysine) and poly(D-lysine) conjugates ofmethotrexate: different inhibitory effect on drug resistant cells[J]. MolecularPharmacology,1979,16:614-622.
[43] Ryser HJP, Shen WC. Conjugation of methotrexate to poly(L-lysine) increasedrug transport and overcome drug resistance in cultured cells[J]. Proceedings of theNational Academy of Sciences USA,1978,75:3867-3870.
[44] Dubrovskii SA, Afanaseva MV, Lagutina, MA, et al. Comprehensivecharacterization of superabsorbent polymer hydrogels[J]. Polymer Bulletin,1990,24:107-110.
[45] Park TG, Hoffman AS. Synthesis and characterization of pH-and/or temperaturesensitive hydrogels[J]. Journal of Applied Polymer Science,1992,46:659-664.
[46] Choi HJ, Yang R, Kunioka M. Synthesis and characterization of pH-sensitive andbiodegradable hydrogels prepared by γ-irradiation using microbial poly(γ-glutamicacid) and poly(ε-lysine)[J]. Journal of Applied Polymer Science,1995,58:807-814.
[47] Salick DA, Kretsinger JK, Pochan DJ, et al. Inherent antibacterial activity of apeptide-based-hairpin hydrogel[J]. The Journal of American Chemical Society,2007,129:14793-14799.
[48] Yoshida T, Nagasawa T. ε-Poly-L-lysine: microbial production, biodegradationand application potential[J]. Applied Microbiology and Biotechnology,2003,62:21-26.
[49] Cai L, Tabata H, Kawai T. Probing electrical properties of oriented DNA byconducting atomic force microscopy[J]. Nanotechnology,2002,12:211-216.
[50] Ostuni E, Yan L, Whitesides GM. The interaction of proteins and cells withself-assembled monolayers of alkanethiolates on gold and silver[J]. Colloids andSurfaces B: Biointerfaces,1999,15:3-30.
[51] Wallace E, Walton A, Bathia G, et al. Photoisomeization and aggregationbehavior of DNA/polylysine/azobenzene (DR80) dye ultrathin film: substrate foroptobioelectronics applications[J]. Polymer Prints,2000,41:1016-1017.
[52] Nishikawa M, Ogawa K. Distribution of microbes producing antimicrobialε-poly-L-lysine polymers in soil microflora determined by a novel method[J]. Appliedand Environmental Microbiology,2002,68:3575-3581.
[53] Nishikawa M, Kobayashi K. Streptomyces roseoverticillatus produces twodifferent poly(amino acid)s: lariat-shaped γ-poly(L-glutamic acid) andε-poly(L-lysine)[J]. Microbiology,2009,155:2988-2993.
[54] Takehara M, Saimura M, Inaba H, et al. Poly(γ-L-diaminobutanoic acid), a novelpoly(amino acid), coproduced with poly(ε-L-lysine) by two strains of Streptomycescelluloflavus[J]. FEMS Microbiology Letters,2008,286:110-117.
[55] Hirohara H, Saimura M, Takehara M, et al. Substantially monodispersedpoly(ε-L-lysine)s frequently occurred in newly isolated strains of Streptomyces sp.[J].Applied Microbiology and Biotechnology,2007,76:1009-1016.
[56]朱宏阳,徐虹,吴群,等. ε-聚赖氨酸菌的筛选和鉴定[J].微生物学通报，2005,32(5):127-130.
[57]段杉,朱伟珊. ε-聚赖氨酸的筛选[J].食品与发酵工业，2007,33(8):14-16.
[58]贾士儒,许春英,谭之磊，等. ε-聚赖氨酸产生菌TUST-2的分离鉴定[J].微生物学报，2010,50(2):191-196.
[59]李树,陈旭升,廖莉娟,等. ε-聚赖氨酸产生菌的筛选方法改进[J].食品与生物技术学报，2010,29(2):282-287.
[60] Li S, Tang L, Chen XS, et al. Isolation and characterization of a novelε-poly-L-lysine producing strain: Streptomyces griseofuscus[J]. Journal of IndustrialMicrobiology and Biotechnology,2011,38:557-563.
[61] EI-Sersy NA, Abdelwahab AE, Abouelkhiir SS, et al. Antibacterial andanticancer activity of ε-poly-L-lysine (ε-PL) produced by a marine Bacillus subtilis sp[J]. Journal of Basic Microbiology,2012,52:1-10.
[62] Shima S, Oshima S, Sakai H. Biosynthesis of ε-poly-L-lysine by washedmycelium of Streptomyces albulus No346[J]. Nippon Nogeikagaku Kaishi,1983,57:221-226.
[63] Hiraki J, Hatakeyama M, Morita S, et al. Improved poly-L-lysine production ofan S-(2-aminoethyl)-L-cysteine resistance mutant of Streptomyces albulus[J]. SeibutsuKogaku,1998,76:487-493.
[64] Hamano Y, Nicchu I, Shimizu T, et al. ε-Poly-L-lysine producer, Streptomycesalbulus, has feedback-inhibition resistant aspartokinase[J]. Applied Microbiology andBiotechnology,2007,76:873-882.
[65] Hirohara H, Takehara M, Saimura M. Biosynthesis of poly(ε-L-lysine)s in twonewly isolated strains of Streptomyces sp.[J]. Applied Microbiology andBiotechnology,2006,73:321-331.
[66] Yamanaka K, Maruyama C, Takagi H, et al. ε-Poly-L-lysine dispersity iscontrolled by a highly unusual nonribosomal peptide synthetase. Nature ChemicalBiology,2008,4:766-772.
[67] Kobayashi K, Nishikawa M. Promotion of ε-poly-L-lysine by iron inKitasatospora kifunense[J]. World Journal of Microbiology and Biotechnology,2007,23:1033-1036.
[68] Wang GL, Jia SR, Wang T, et al. Effect of ferrous ion on ε-poly-L-lysinebiosynthesis by Streptomyces diastatochromogenes CGMCC3145[J]. CurrentMicrobiology,2011,62:1062-1067.
[69] Kawai T, Takaaki K, Hiraki J, et al. Biosynthesis of ε-poly-L-Lysine in a cell-freesystem of Streptomyces albulus[J]. Biochemical and Biophysical ResearchCommuniations,2003,311:635-640.
[70] Kito M, Takimoto R, Yoshida T, et al. Purification and characterization of anε-poly-L-lysine-degrading enzyme from an ε-poly-L-lysine-producing strain ofStreptomyces albulus[J]. Archives Microbiology,2002,178:325-330.
[71] Feng XH, Xu H, Xu XY, et al. Purification and some properties ofε-poly-L-lysine-degrading enzyme from Kitasatospora sp. CCTCC M205012[J].Process Biochemistry,2008,43:667-672.
[72] Kito M, Onji Y, Yoshida T, et al. Ocurrence of ε-poly-L-lysine-degradingenzyme in ε-poly-L-lysine-tolerant Shingobacterium multivorum OJ10: purificationand characterization[J]. FEMS Microbiology Letters,2002,207:147-151.
[73] Kito M, Takimoto R, Onji Y, et al. Purification and characterization of anε-poly-lysine-degrading enzyme from the ε-poly-L-lysine-tolerant Chryseobacteriumsp. OJ7[J]. Journal of Bioscience and Bioengineering,2003,96:92-94.
[74] Hamano Y, Yoshida T, Kito M, et al. Biological function of the pld gene productthat degrades ε-poly-L-lysine in Streptomyces albulus[J]. Applied Microbiology andBiotechnology,2006,72:173-181.
[75] Yamanaka K, Kito N, Imokawa Y, et al. Mechanism of ε-poly-L-lysineproduction and accumulation revealed by identification and analysis of anε-poly-L-lysine-degrading enzyme[J]. Applied and Environmental Microbiology,2010,76:5669-5675.
[76]李树，陈旭升，廖莉娟，等. ε-聚赖氨酸产生菌的筛选方法改进[J].食品与生物技术学报,2010,29(2):282-287.
[77]李荣杰.微生物诱变育种方法研究进展[J].河北农业科学，2009，13(10):73-76,78.
[78]贾红华，周华，韦萍.微波诱变育种研究及应用进展[J].工业微生物，2003，33(2):46-50.
[79]宫春波，刘鹭，谢丽琼，等.离子注入微生物诱变育种研究进展[J].生物技术，2003，13(2):47-49.
[80]张玲华，田兴山.微生物空间诱变育种的研究进展[J].核农学报，2004,18(4):294-294.
[81]田丰伟，程传荣，袁维涵，等.原生质体诱变选育ε-聚赖氨酸高产菌株[J].微生物学通报，2010,37(10)：1457-1461.
[82]张超，王正刚，段作营，等.大量紫外诱变选育ε-聚赖氨酸高产菌[J].生物加工过程，2007,5(3):64-68.
[83]张海涛，李燕，欧杰，等.诱变选育ε-聚赖氨酸菌产生菌突变株[J].食品科学，2007,28(09):398-401.
[84] Itzhaki FR. Colorimetric method for estimating polylysine and polyarginine[J].Analytical Biochemistry,1972,50:569-574.
[85] Kahar P, Iwata T, Hiraki J, et al. Enhancement of polylysine production byStreptomyces albulus strain410using pH control[J]. Journal of Bioscience andBioengineering,2001,91:190-194.
[86]骆健美，成永新，李培君，等.基于抑菌活性的ε-聚赖氨酸的微孔板生物检测法[J].微生物学通报，2011,38(7):976-981.
[87]刘双燕，贾士儒，王国良，等.荧光淬灭法测定ε-聚赖氨酸含量研究[J].现代食品科技，2010,26(11):1267-1270.
[88]程传荣，田丰伟，张灏，等.一种快速测定发酵液中ε-聚赖氨酸的方法[J].食品与发酵工业，2009,35(11):133-136.
[89]张超，张克峰，侯书国，等.利用响应面法优化ε-聚赖氨酸发酵培养基[J].微生物学通报，2011,38(5):641-646.
[90] Shih IL, Shen MH. Application of response surface methodology to optimizeproduction of poly-ε-lysine by Streptomyces albulus IFO14147[J]. Enzyme andMicrobial Technology,2006,39:15-21.
[91] Chen XS, Tang L, Li S, et al. Optimization of medium for enhancement ofε-poly-L-lysine production by Streptomyces sp. M-Z18with glycerol as carbonsource[J]. Bioresource Technology,2011,102:1727-1732.
[92] Bankar SB, Singhal RS. Optimization of ε-poly-L-lysine production byStreptomyces noursei NRRL5126[J]. Bioresource Technology,2010,101:8370-8375.
[93] EI-Naggar MY, Hassan MA, Said WY, et al. Effect of support materials onantibiotic MSW2000production by immobilized Streptomyces violatus[J]. Journal ofGeneral Applied Microbiology,2003,49:235-243.
[94] Srinivasulu B, Prakasham RS, Jetty A, et al. Neomycin production with free andimmobilized cells of Streptomyces marinensis in an airlift reactor[J]. ProcessBiochemistry,2002,38:593-598.
[95] Ogaki M, Sonomoto K, Nakajima H, et al. Continuous production ofoxytetracycline by immobilized growing Streptomyces rimosus cells[J]. AppliedMicrobiology and Biotechnology,1986,24:6-11.
[96] Devi S, Sridhar P. Production of cephamycin C in repeated batch operations fromimmobilized Streptomyces clavuligerus[J]. Process Biochemistry,2000,36:225-231.
[97] Hiraki J, Suzuki E. Process for producing ε-poly-L-lysine with immobilizedStreptomyces albulus[P]. US. Patent.1999, US5900363.
[98] Zhang Y, Feng XH, Xu H, et al. ε-Poly-L-lysine production by immobilized cellsof Kitasatospora sp. MY5-36in repeated fed-batch cultures[J]. BioresourceTechnology,2010,101:5523-5527.
[99] Teodoro JC, Baptista-Neto A, Cruz-Hernández IL, et al. Influence of feedingconditions on clavulanic acid production in fed-batch cultivation with mediumcontaining glycerol[J]. Applied Microbiology and Biotechnology,2006,72:450-455.
[100] Kim IC, Kim CH, Hong SI, et al. Fed-batch cultivation for the production ofclavulanic acid by an immobilized Streptomyces clavuligerus mutant[J]. WorldJournal of Microbiology and Biotechnology,2001,17:869-872.
[101] Lai LST, Pan CC, Tzeng BK. The influence of medium design on lovastatinproduction and pellet formation with a high-producing mutant of Aspergillus terreusin submerged cultures [J]. Process Biochemistry,2003,38:1317-1326.
[102] Kim YS, Lee JH, Kim NH, et al. Increase of lycopene production bysupplementing auxiliary carbon sources in metabolically engineered Escherichiacoli[J]. Applied Microbiology and Biotechnology,2011,90:489-497.
[103] Saint-amans S, Girbal L, Andrade J, et al. Regulation of carbon and electronflow in Clostridium butyricum VPI3266grown on glucose-glycerol mixtures[J].Journal of Bacteriology,183:1748-1754.
[104] Chen XS, Ren XD, Dong N, et al. Culture medium containing glucose andglycerol as a mixed carbon source improves ε-poly-L-lysine production byStreptomyces sp. M-Z18. Bioprocess Biosystems Engineering,2011,34:561-567
[105] Shih IL, Shen MH. Optimization of cell growth and poly(ε-lysine) production inbatch and fed-batch cultures by Streptomyces albulus IFO14147[J]. ProcessBiochemistry,2006,41:1644-1649.
[106] Nishikawa M, Ogawa K. Inhibition of epsilon-poly-L-lysine biosynthesis inStreptomycetaceae bacteria by short-chain polyols[J]. Applied and EnvironmentalMicrobiology,2006,72:2306-2312.
[107] Nishikawa M. Molecular mass control using polyanionic cyclodextrinderivatives for the epsilon-poly-L-lysine biosynthesis by Streptomyces[J]. Enzyme andMicrobial Technology,2009,45:295-298.
[108] Chen XS, Li S, Liao LJ, et al. Production of ε-poly-L-lysine using a noveltwo-stage pH control strategy by Streptomyces sp. M-Z18from glycerol[J].Bioprocess Biosystems Engineering,2011,34:561-567.
[109] Jia SR, Chen GB, Kahar P, et al. Effect of soybean oil on oxygen transfer in theproduction of tetracycline with an airlift bioreactor[J]. Journal of Bioscience andBioengineering,1999,87:825-827.
[110] Kahar P, Kobayashi K, Iwata T, et al. Production of ε-polylysine in an airliftbioreactor (ABR)[J]. Journal of Bioscience and Bioengineering,2002,93:274-280.
[111] Bankar SB, Singhal RS. Improved poly-ε-lysine biosynthesis usingStreptomyces noursei NRRL5126by controlling dissolved oxygen duringfermentation[J]. Journal of Microbiology and Biotechnology,2011,21:652-658.
[112]姜俊云，贾士儒，董惠钧，等.搅拌转速和pH对ε-聚赖氨酸发酵的影响[J].生物加工过程，2004,2(2):60-63.
[113] Ouyang J, Xu H, Li S, et al. Production of ε-poly-L-lysine by newly isolatedKitasatospora sp. PL6-3[J]. Biotechnology Journal,2006,1:1459-1463.
[114] Shirling EB, Gottlieb D. Methods for characterization of Streptomycesspecies[J]. International Journal of System Bacteriology,1966,16:313-340.
[115]邢芳芳，黄瑞林，张友明，等.改进Tricine-SDS-PAGE法分析重组牛乳铁蛋白肽[J].饲料工业，2007,28(9):10-13.
[116]王旭，何冰芳，李霜，等. Tricine-SDS-PAGE电泳分析小分子多肽[J].南京工业大学学报,2003,25(2):79-81.
[117]徐小华，陈天豹，李珑，等.一种改进的小分子多肽SDS-PAGE方法[J].福州大学学报(自然科学版)，2001,29(3):113-115.
[118]向弘，朱斌，徐昕荣，等.基质辅助激光解析电离-飞行时间质谱在高分子聚合物研究应用中的样品制备方法[J].广东化工，2009,36(196):85-86.
[119]徐昕荣，朱斌，马瑜璐.基质辅助激光解析电离飞行时间质谱快速测定水解胶原蛋白粉分子量[J].分析科学学报,2011,27(3):397-399.
[120]杨博，郭丽琼，郑冰昕，等. ε-聚赖氨酸产生菌的鉴定及产物特性研究[J].中国食品学报，2011,11(6):163-169.
[121]周俊，徐虹，王军，等.北里孢菌PL6-3产ε-聚赖氨酸的分离纯化和结构表征[J].化工学报，2006,57(8):1957-1961.
[122]顾觉奋主编.抗生素[M].上海：上海科学技术出版社,2001:13-20.
[123] Takagi H, Hoshino Y, Nakamori S, et al. Isolation and sequence analysis ofplasmid pNO33in the ε-poly-L-lysine-producing actinomycete Streptomyces albulusIFO14147[J]. Journal of Bioscience and Bioengineering,2000,89:94-96.
[124] Helander IM, Nurmiaho-Lassila EL, Ahvenainen R, et al. Chitosan disrupts thebarrier properties of the outer membrane of Gram-negative bacteria[J]. InternationalJournal of Food Microbiology,2001,71:235-244.
[125] Johnston MD, Hanlon GW, Denyer SP, et al. Membrane damage to bacteriacaused by single and combined biocides[J]. Journal of Applied Microbiology,2003,94:1015-1023.
[126] Hancock REW. Alterations in outer membrane permeability. Annual ReviewMicrobiology,1984,38:237-264.
[127] Kroll RG, Anagnostopoulos GD. Potassium leakage as a lethality index ofphenol and the effect of solute and water activity[J]. Journal of Applied Microbiology,1981,50:139-147.
[128] Hatzinger PB, Palmer P, Smith RL, et al. Applicability of tetrazolium salts forthe measurement of respiratory activity and viability of groundwater bacteria[J].Journal of Microbiology Methods,2003,52:47-58.
[129] Rodriguez GG, Phipps D, Ishiguro K, et al. Use of a fluorescent redox probe fordirect visualization of actively respiring bacteria[J]. Applied EnvironmentalMicrobiology,1992,58:1801-1808.
[130] Dufour P, Colon M. The tetrazolium reduction method for assessing theviability of individual bacterial cells in aquatic environments: improvements,performance and application[J]. Hydrobiologia,1992,232:211-218.
[131] Cundliffe E. How antibiotic-producing organisms avoid suicide[J]. AnnualReview. Microbiology,1989,43:207-233.
[132] Noda M, Kawahara Y, Ichikawa A, et al. Self-protection mechanism inD-cycloserine-producing Streptomyces lavendulae. Gene cloning, characterization,and kinetics of its alanine racemase and D-alanyl-D-alanine ligase, which are targetenzymes of D-cycloserine[J]. Journal of Biology Chemistry,2004,279:46143-46152.
[133] Sugiyama M, Kumagai T, Shionoya M, et al. Inactivation of bleomycin by anN-acetyltransferase in the bleomycin-producing strain Streptomyces verticillus[J].FEMS Microbiology Letters,1994,121:81-85.
[134] Zalacain M, Cundliffe E. Cloning of tlrD, a fourth resistance gene, from thetylosin producer, Streptomyces fradiae[J]. Gene,1991,97:137-142.
[135] Berney M, Hammes F, Bosshard F, et al. Assessment and interpretation ofbacterial viability by using the LIVE/DEAD BacLight kit in combination with flowcytometry[J]. Applied and Environmental Microbiology,2007,73:3283-3290.
[136] Boulos L, Prévost M, Barbeau B, et al. LIVE/DEAD BacLightTM: applicationof a new rapid staining method for direct enumeration of viable and total bacteria indrinking water[J]. Journal of Microbiology Methods,1999,37:77-86.
[137] Stocks SM. Mechanism and use of the commercially available viability stain,BacLight[J]. Cytometry A2004,61:189-195.
[138] Manteca A, Fernandez M, Sanchez J. Mycelium development in Streptomycesantibioticus ATCC11891occurs in an orderly pattern which determines multiphasegrowth curves[J]. BMC Microbiology,2005,5:51-60.
[139] Yagüe P, Manteca A, Simon A, et al. New method for monitoring programmedcell death and differentiation in submerged Streptomyces cultures[J]. Applied andEnvironmental Microbiology,2010,76:3401-3404.
[140] Diaper JP, Tither K, Edwards C. Rapid assessment of bacterial viability by flowcytometry[J]. Applied Microbiology and Biotechnology,1992,38:268-272.
[141] Smith JJ, McFeters GA. Mechanisms of INT(2-(4-iodophenyl)-3-(4-nitrophenyl)-5-phenyl tetrazolium chloride), and CTC(5-cyano-2,3-ditolyl tetrazolium chloride) reduction in Escherichia coli K-12[J].Journal of Microbiological Methods,1997,29:161-175.
[142] Miller GL. Use of dinitrosalicylic acid reagent for determination of reducingsugar[J]. Analytical Chemistry.1959,31:426-428.
[143] Bhupathiraju VK, Hernandez M, Landfear D, et al. Application of a tetrazoliumdyes as an indicator of viability in anaerobic bacteria[J]. Journal of MicrobiologicalMethods1999,37:231-243.
[144] Créach V, Baudoux AC, Bertru G, et al. Direct estimate of active bacteria: CTCuse and limitations[J]. Journal of Microbiological Methods,2003,52:19-28.
[145] Berney M, Hammes F, Bosshard F, et al. Assessment and interpretation ofbacterial viability by using the LIVE/DEAD BacLight Kit in combination with flowcytometry[J]. Applied and Environmental Microbiology,2007,73:3283-3290.
[146] Sebastine IM, Stocks SM, Cox P, et al. Characterisation of percentage viabilityof Streptomyces clavuligerus using image analysis[J]. Biotechnology Techniques,1999,13,419-423.
[147] Manteca A, Alvarez R, Salazar N, et al. Mycelium differentiation and antibioticproduction in submerged cultures of Streptomyces coelicolor[J]. Applied andEnvironmental Microbiology,2008,74:3877-3886.
[148] Pinto LS, Vieira LM, Pons MN, et al. Morphology and viability analysis ofStreptomyces clavuligerus in industrial cultivation systems[J]. Bioprocess BiosystemsEngineering,2004,26:177-184.
[149] Christiansen T, Michaelsen S, Wümpelmann M, et al. Production of savinaseand population viability of Bacillus clausii during high-cell-density fed-batchcultivations[J]. Biotechnology and Bioengineering,2003,83:344-352.
[150] Bouix M, Leveau JY. Rapid assessment of yeast viability and yeast vitalityduring alcoholic fermentation[J]. Journal of The Inistitute of Brewing,2001,107:217-225.
[151] Müller S, Hutter KJ, Bley T, et al. Dynamics of yeast cell states duringproliferation and non proliferation periods in a brewing reactor monitored bymultidimensional flow cytometry[J]. Bioprocess Engineering,1997,17:287-293.
[152] Bankar SB, Singhal RS. Metabolic precursors enhance the production ofpoly-ε-lysine by Streptomyces noursei NRRL5126[J]. Engineering in Life Sciences,2011,11:253-258.
[153] Kunioka M. Biosynthesis of poly(γ-glutamic acid) from L-glutamine, citric acidand ammonium sulfate in Bacillus subtilis IFO3335[J]. Applied Microbiology andBiotechnology,1995,44:501-506.
[154] Yoon SH, Do JH, Lee SY, et al. Production of poly-γ-glutamic acid by fed-batchculture of Bacillus licheniformis[J]. Biotechnology Letters,2000,22:585-588.
[155] Sasaki K, Tanaka T, Nishizawa Y, et al. Enhanced production of5-aminolevulinic acid by repeated addition of levulinic acid and supplement ofprecursors in photoheterotrophic culture of Rhodobacter sphaeroides[J]. Journal ofFermentation and Bioengineering,1991,71:403-406.
[156] Bajaj IB, Singhal RS. Enhanced production of poly(γ-glutamic acid) fromBacillus licheniformis NCIM2324by using metabolic precursors[J]. AppliedBiochemistry and Biotechnology,2009,159:133-141.
[157] Miller DL, Rodwell VW. Metabolism of basic amino acids in Pseudomonasputida. Catabolism of lysine by cyclic and acyclic intermediates[J]. Journal ofBiology Chemistry,1971,246:2758-2764.
[158] Fothergill JC, Guest JR. Catabolism of L-lysine by Pseudomonas aeruginosa[J].Journal of General Microbiology,1977,99:139-155.
[159] Stewart DJ. The decarboxylation of L-lysine by Pseudomonas aeruginosaisolates[J]. Journal of Applied Bacteriology,1970,33:501-504.
[160] Reitz MS, Rodwell VW. δ-Aminovaleramidase of Pseudomonas putida[J].Journal of Biology Chemistry,1970,245:3091-3096.
[161] Vandecasteele JP, Hermann M. Regulation of a catabolic pathway[J]. EuropeanJournal of Biochemistry,1972,31:80-85.
[162] Madduri K, Stuttard C, Vining LC. Lysine catabolism in Streptomyces spp. isprimarily through cadaverine: β-lactam producers also make α-aminoadipate[J].Journal of Bacteriology1989,171:299-302.
[163] Untrau S, Lebrihi A, Germain P, et al. Lysine catabolism in Streptomycesambofaciens producer of macrolide antibiotic, spiramycin[J]. Current Microbiology,1992,25:313-318.
[164] Kern BA, Hendlin D, Inamine E. L-Lysine epsilon-aminotransferase involved incephamycin C synthesis in Streptomyces lactamdurans[J]. Antimicrobial Agents andChemotherapy,1980,17:679-685.
[165] Tsueng G, Lam KS. Stabilization effect of resin on the production of potentproteasome inhibitor NPI-0052during submerged fermentation of Salinisporatropica[J]. Journal of Antibiotics,2007,60:469-472.
[166] Stark D, Von Stockar U. In situ product removal (ISPR) in whole cellbiotechnology during the last twenty years[J]. Advances in Biochemical EngineeringBiotechnology,2003,80:149-175.
[167] Kim CH, Kim SW, Hong SI. An integrated fermentation-separation process forthe production of red pigment by Serratia sp. KH-95[J]. Process Biochemistry,1999,35:485-490.
[168] Wong PL, Royce AJ, Lee-Parsons CWT. Improved ajmalicine production andrecovery from Catharanthus roseus suspensions with increased product removalrates[J]. Biochemical Engineering Journal,2004,21:253-258.
[169] Gastaldo L, Marinelli F, Acquarella C, et al. Improvement of the kirromycinfermentation by resin addition[J]. Journal of Industrial Microbiology,1996,16:305-308.
[170] Azuma S, Tsunekawa H, Okabe M, et al. Hyper-production of L-tryptophan viafermentation with crystallization[J]. Applied Microbiology and Biotechnology,1993,39:471-476.
[171] Ezeji TC, Qureshi N, Blaschek HP. Production of acetone, butanol and ethanolby Clostridium beijerinckii BA101and in situ recovery by gas stripping[J]. WorldJournal of Microbiology and Biotechnology,2003,19:595-603.
[172] Qureshi N, Hughes S, Maddox IS, et al. Energy-efficient recovery of butanolfrom model solutions and fermentation broth by adsorption[J]. Bioprocess BiosystemsEngineering,2005,27:215-222.
[173]胡红梅，蒋立科，林宇恒，等.乳酸菌肽自身免疫基因nisI的表达乳酸菌肽产量的影响[J].微生物学报,2010,50(10):1341-1346.
[174] Kim WS, Hall RJ, Dunn NW. Improving nisin production by increasing nisinimmunity/resistance genes in the producer organism Lactococcus lactis[J]. AppliedMicrobiology and Biotechnology,1998,50:429-433.
[175] Santos DT, Sarrouh BF, Rivaldi JD, et al. Use of sugarcane bagasse asbiomaterial for cell immobilization for xylitol production[J]. Journal of FoodEngineering,2008,86:542-548.
[176] Mukhopadhyay R, Chatterjee S, Chatterjee BP, et al. Production of gluconicacid from whey by free and immobilized Aspergillus niger[J]. Interational DairyJournal,2005,15:299-303.
[177] Yang SS, Yueh CY. Oxytetracycline production by immobilized Streptomycesrimosus[J]. Journal of Microbiology, Immunology and Infection,2001,34:235-242.
[178] Saudagar PS, Shaligram NS, Singhal RS. Immobilization of Streptomycesclavuligerus on loofah sponge for the production of clavulanic acid. BioresourceTechnology,2008,99:2250-2253.
[179] Evans PJ, Wang HY. Pigment production from immobilized Monascus sp.utilizing polymeric resin adsorption[J]. Applied and Environmental Microbiology,1984,47:1323-1326.
[180] Wu Z, Yang ST. Extractive fermentation for butyric acid production fromglucose by Clostridium tyrobutyricum[J]. Biotechnology and Bioengineering,2003,82:93-102.
[181] Friedl A, Qureshi N, Maddox IS. Continuous acetone-butanol-ethanol (ABE)fermentation using immobilized cells of Clostridium acetobutylicum in a packed bedreactor and integration with product removal by pervaporation[J]. Biotechnology andBioengineering,1991,38:518-527.
[182] Zeng Y, Ji XJ, Chang SM, et al. Improving arachidonic acid accumulation inMortierella alpina through B-group vitamin addition. Bioprocess BiosystemsEngineering,2011, DOI10.1007/s00449-011-0648-2.
[183] Xu GQ, Chu J, Zhuang YP, et al. Effects of vitamins on the lactic acidbiosynthesis of Lactobacillus paracasei NERCB0401[J]. Biochemical EngineeringJournal,2008,38:189-197.
[184] Nancib A, Nancib N, Meziane-Cherif D, et al. Joint effect of nitrogen sourcesand B vitamin supplementation of date juice on lactic acid production[J]. BioresourceTechnology,2005,96:63-67.
[185] Aeshlimann A, Von Stockar U. The effect of yeast extract supplementation onthe production of lactic acid from whey permeate by Lactobacillus helveticus[J].Applied Microbiology and Biotechnology,1990,32:398-402.
[186] Bizukojc M, Beata P, Stanislaw L. Supplementation of the cultivation mediawith B-group vitamins enhances lovastatin biosynthesis by Aspergillus terreus[J].Journal of Biotechnology,2007,127:258-268.
[187] Oh IJ, Kim DH, Oh EK, et al. Optimization and scale-up of succinic acidproduction by Mannheimia succiniciproducens LPK7[J]. Journal of Microbiology andBiotechnology,2009,19:167-17
[2] Hiraki J, Ichikawa T, Ninomiya SI, et al. Use of ADME studies to confirm thesafety of ε-polylysine as a preservative in food[J]. Regulatory Toxicology andPharmacology,2003,37:328–340.
[3] Hiraki J. Basic and applied studies on ε-polylysine[J]. Journal of AntibactAntifungal Agents,1995,23:349-354.
[4] Shima S, Sakai H. Poly-L-lysine produced by Streptomyces. Part Ⅲ. Chemicalstudies[J]. Agricultural and Biological Chemistry,1981,45:2503-2508.
[5] Maeda S, Kunimoto KK, Sasaki C, et al. Characterization of microbialpoly(ε-L-lysine) by FT-IR, Raman, and solid state13C NMR spectroscopies[J].Journal of Molecular Structure,2003,655:149-155.
[6]孙群，阚建全，赵国华，等.活性多糖构效关系研究进展[J].广州食品工业科技,2004,(1):104-107.
[7]诸葛健，赵振峰，方慧英.功能性多糖的构效关系[J].无锡轻工大学学报,2002,21(2):209-212.
[8] Bohn JA, Bemiller JN.(1,3)-β-D-Glucans as biological response modifiers: areview of structure-functional activity relationships[J]. Carbohydrate Polymers,1995,28:3-14.
[9] Ploug M. Structure-function relationships in the interaction between theurokinase-tape plasminogen activator and its receptor[J]. Current PharmaceuticalDesign,2003,9:1499-1528(30).
[10] Eisenberg D, Gill HS, Pfluegl GMU, et al. Structure-function relationships ofglutamine synthetases[J]. Biochimica et Biophysica Acta,2000,1477:122-145.
[11] Fukushi H, Oyama K, Hatakeyama M, et al. HPLC fractionation ofoligo(ε-L-lysine)mers and their1H NMR characteristics[J]. Chemistry Express,1993,8:745-748.
[12] Kushwaha DR, Mathur KB, Balasubramanian D. Poly(ε-L-lysine): synthesis andconformation[J]. Biopolymers,1980,19:219-229.
[13] Lee HH, Oyama K, Hiraki J, et al. Microbial production and conformation ofpoly(ε-L-lysine)[J]. Chemistry Express,1991,6:683-686.
[14] Shima S, Matsuoka H, Iwanoto T, et al. Antimicrobial action ofε-poly-L-lysine[J]. Journal of antibiotics,1984,37:1445-1449.
[15] Shima S, Fukuhara Y, Sakai H. Inactivation of bacteriophages by ε-poly-L-lysineproduced by Streptomyces[J]. Agricultural and Biological Chemistry,1982,46:1917-1919.
[16]张东荣，王正刚，毛忠贵. ε-聚赖氨酸的研究进展[J].氨基酸和生物资源,2005,27(2):48-51.
[17] Najjar MB, Kashtanov D, Chikindas ML. ε-Poly-L-lysine and nisin A actsynergistically against Gram-positive food-borne pathogens Bacillus cereus andListeria monocytogenes[J]. Letters in Applied Microbiology,2007,45:13-18.
[18]侯晓姝，胡宗利，陈国平，等.抗菌肽的抗菌机制及其临床应用[J].微生物学通报，2009，36(1):97-105.
[19] Chen FY, Lee MT, Huang HW. Sigmoidal concentration dependence ofantimicrobial peptide activities: a case study on alamethicin[J]. Biophysical Journal,2002,82:908-914.
[20] Brogden KA. Antimicrobial peptides: pore formers or metabolic inhibitors inbacteria? Nature Reviews Microbiology,2005,3:238-250.
[21] Zorko M, Langel U. Cell-penetrating peptides: mechanism and kinetics of cargodelivery. Advanced Drug Delivery Reviews,2005,57:529-545.
[22] Moll GN, Roberts, GCK, Konings WN, et al. Mechanisms of lantibiotic-inducedpore-formation[J]. Antonie van Leuwenhoek,1996,69:185-191.
[23] Winkowski K, Ludescher RD, Montville TJ. Physicochemical characterization ofthe nisin-membrane interaction with liposomes derived from Listeriamonocytogenes[J]. Applied and Environmental Microbiology,1996,62:323-327.
[24] Reddy KVR, Yedery RD, Aranha C. Antimicrobial peptides: premises andpromises[J]. International Journal of Antimicrobial Agents,2004,24:536-547.
[25] Neda K, Sakurai T, Stakahashi M, et al. Two-generation reproduction study withteratology test of ε-poly-L-lysine by dietary administration in rats. JapanesePharmcology and Therapeutics,1999,27:1139-1159.
[26] Hiraki J. ε-polylysine, its development and utilization[J]. Fine Chemistry,2000,29:25-28.
[27] Shih IL, Shen MH, Van YT. Microbial synthesis of poly(ε-lysine) and its variousapplications[J]. Bioresource Technology,2006,97:1148–1159.
[28] Otsuka N, Kuwahara Y, Manabe K. Effect of ε-poly-lysine on preservation ofboiled noodles[J]. Nippon Shokuhin Kogyo Gakkaishi,1992,39:344-347.
[29] Chang SS, Wendy Lu WY, Park SH, et al. Control of foodborne pathogens onready-to-eat roast beef slurry by ε-polylysine[J]. International Journal of FoodMicrobiology,2010,141:236-241.
[30] Ho YT, Ishizaki S, Tanaka M. Improving emulsifying activity of ε-polylysine byconjugation with dextran through the Maillard reaction[J]. Food Chemistry,2000,68:449-455.
[31]谢建飞，杨玉红，陈红漫，等.防腐型乳化剂葡聚赖氨酸的研究[J].食品科学，2009,30(11):131-133.
[32] Ting HY, Ishizaki S, Tanaka M. Effect of the maillard reaction on the bactericidalactivity of ε-polylysine[J]. Journal of Tokyo University of Fisheries,1997,84:25-30.
[33] Kido Y, Hiramoto S, Murao M, et al. ε-Poly-L-lysine inhibits pancreatic lipaseactivity and suppresses postprandial hypertriacylglyceridemia in rats[J]. The Journalof Nutrition,2003,1887-1891.
[34] Tsujita T, Takaichi H, Takaku T, et al, Hiraki J. Antiobesity action of ε-polylysine,a potent inhibitor of pancreatic lipase[J]. Journal of Lipid Research,2006,47:1852-1858.
[35] Friemann T, Robin R. Gene therapy for human genetic disease. Science,1972,175:949-955.
[36] Mulligan RC. The basic science of gene therapy[J]. Science,1993,260:926-932.
[37] Hanania EG, Kavanagh J, Hortovagyl G, et al. Recent advances in the applicationof gene therapy to human disease[J]. The Americian Journal of Medicine,1995,99,537-552.
[38] Chiou HC, Tangco MV, Levine SM, et al. Enhanced resistance to nucleasedegradation of nucleic acids complexed to asialoglycoprotein-polylysine carriers[J].Nucleic Acids Research,1994,22:5439-5446.
[39] Dorudi S, Northover JM, Vile RG. Gene transfer therapy in cancer[J]. BritishJournal of Surgery,1993,80:566-572.
[40] Choi JS, Joo DK, Kim CH, et al. Synthesis of a barbell-like triblock copolymer,poly(L-lysine) dendrimer-block-poly(ethylene glycol)-block-poly(L-lysine) dendrimer,and its self-assembly with plasmid DNA[J]. The Journal of American ChemicalSociety.2000,122:474-480.
[41] Shen WC，Ryser HJP. Conjugation of poly-L-lysine to albumin and horseradishperoxidase: a novel method of enhancing the cellular uptake of protein[J].Proceedings of the National Academy of Sciences USA,1978,75:1872-1876.
[42] Shen WC, Ryser HJP. Poly(L-lysine) and poly(D-lysine) conjugates ofmethotrexate: different inhibitory effect on drug resistant cells[J]. MolecularPharmacology,1979,16:614-622.
[43] Ryser HJP, Shen WC. Conjugation of methotrexate to poly(L-lysine) increasedrug transport and overcome drug resistance in cultured cells[J]. Proceedings of theNational Academy of Sciences USA,1978,75:3867-3870.
[44] Dubrovskii SA, Afanaseva MV, Lagutina, MA, et al. Comprehensivecharacterization of superabsorbent polymer hydrogels[J]. Polymer Bulletin,1990,24:107-110.
[45] Park TG, Hoffman AS. Synthesis and characterization of pH-and/or temperaturesensitive hydrogels[J]. Journal of Applied Polymer Science,1992,46:659-664.
[46] Choi HJ, Yang R, Kunioka M. Synthesis and characterization of pH-sensitive andbiodegradable hydrogels prepared by γ-irradiation using microbial poly(γ-glutamicacid) and poly(ε-lysine)[J]. Journal of Applied Polymer Science,1995,58:807-814.
[47] Salick DA, Kretsinger JK, Pochan DJ, et al. Inherent antibacterial activity of apeptide-based-hairpin hydrogel[J]. The Journal of American Chemical Society,2007,129:14793-14799.
[48] Yoshida T, Nagasawa T. ε-Poly-L-lysine: microbial production, biodegradationand application potential[J]. Applied Microbiology and Biotechnology,2003,62:21-26.
[49] Cai L, Tabata H, Kawai T. Probing electrical properties of oriented DNA byconducting atomic force microscopy[J]. Nanotechnology,2002,12:211-216.
[50] Ostuni E, Yan L, Whitesides GM. The interaction of proteins and cells withself-assembled monolayers of alkanethiolates on gold and silver[J]. Colloids andSurfaces B: Biointerfaces,1999,15:3-30.
[51] Wallace E, Walton A, Bathia G, et al. Photoisomeization and aggregationbehavior of DNA/polylysine/azobenzene (DR80) dye ultrathin film: substrate foroptobioelectronics applications[J]. Polymer Prints,2000,41:1016-1017.
[52] Nishikawa M, Ogawa K. Distribution of microbes producing antimicrobialε-poly-L-lysine polymers in soil microflora determined by a novel method[J]. Appliedand Environmental Microbiology,2002,68:3575-3581.
[53] Nishikawa M, Kobayashi K. Streptomyces roseoverticillatus produces twodifferent poly(amino acid)s: lariat-shaped γ-poly(L-glutamic acid) andε-poly(L-lysine)[J]. Microbiology,2009,155:2988-2993.
[54] Takehara M, Saimura M, Inaba H, et al. Poly(γ-L-diaminobutanoic acid), a novelpoly(amino acid), coproduced with poly(ε-L-lysine) by two strains of Streptomycescelluloflavus[J]. FEMS Microbiology Letters,2008,286:110-117.
[55] Hirohara H, Saimura M, Takehara M, et al. Substantially monodispersedpoly(ε-L-lysine)s frequently occurred in newly isolated strains of Streptomyces sp.[J].Applied Microbiology and Biotechnology,2007,76:1009-1016.
[56]朱宏阳,徐虹,吴群,等. ε-聚赖氨酸菌的筛选和鉴定[J].微生物学通报，2005,32(5):127-130.
[57]段杉,朱伟珊. ε-聚赖氨酸的筛选[J].食品与发酵工业，2007,33(8):14-16.
[58]贾士儒,许春英,谭之磊，等. ε-聚赖氨酸产生菌TUST-2的分离鉴定[J].微生物学报，2010,50(2):191-196.
[59]李树,陈旭升,廖莉娟,等. ε-聚赖氨酸产生菌的筛选方法改进[J].食品与生物技术学报，2010,29(2):282-287.
[60] Li S, Tang L, Chen XS, et al. Isolation and characterization of a novelε-poly-L-lysine producing strain: Streptomyces griseofuscus[J]. Journal of IndustrialMicrobiology and Biotechnology,2011,38:557-563.
[61] EI-Sersy NA, Abdelwahab AE, Abouelkhiir SS, et al. Antibacterial andanticancer activity of ε-poly-L-lysine (ε-PL) produced by a marine Bacillus subtilis sp[J]. Journal of Basic Microbiology,2012,52:1-10.
[62] Shima S, Oshima S, Sakai H. Biosynthesis of ε-poly-L-lysine by washedmycelium of Streptomyces albulus No346[J]. Nippon Nogeikagaku Kaishi,1983,57:221-226.
[63] Hiraki J, Hatakeyama M, Morita S, et al. Improved poly-L-lysine production ofan S-(2-aminoethyl)-L-cysteine resistance mutant of Streptomyces albulus[J]. SeibutsuKogaku,1998,76:487-493.
[64] Hamano Y, Nicchu I, Shimizu T, et al. ε-Poly-L-lysine producer, Streptomycesalbulus, has feedback-inhibition resistant aspartokinase[J]. Applied Microbiology andBiotechnology,2007,76:873-882.
[65] Hirohara H, Takehara M, Saimura M. Biosynthesis of poly(ε-L-lysine)s in twonewly isolated strains of Streptomyces sp.[J]. Applied Microbiology andBiotechnology,2006,73:321-331.
[66] Yamanaka K, Maruyama C, Takagi H, et al. ε-Poly-L-lysine dispersity iscontrolled by a highly unusual nonribosomal peptide synthetase. Nature ChemicalBiology,2008,4:766-772.
[67] Kobayashi K, Nishikawa M. Promotion of ε-poly-L-lysine by iron inKitasatospora kifunense[J]. World Journal of Microbiology and Biotechnology,2007,23:1033-1036.
[68] Wang GL, Jia SR, Wang T, et al. Effect of ferrous ion on ε-poly-L-lysinebiosynthesis by Streptomyces diastatochromogenes CGMCC3145[J]. CurrentMicrobiology,2011,62:1062-1067.
[69] Kawai T, Takaaki K, Hiraki J, et al. Biosynthesis of ε-poly-L-Lysine in a cell-freesystem of Streptomyces albulus[J]. Biochemical and Biophysical ResearchCommuniations,2003,311:635-640.
[70] Kito M, Takimoto R, Yoshida T, et al. Purification and characterization of anε-poly-L-lysine-degrading enzyme from an ε-poly-L-lysine-producing strain ofStreptomyces albulus[J]. Archives Microbiology,2002,178:325-330.
[71] Feng XH, Xu H, Xu XY, et al. Purification and some properties ofε-poly-L-lysine-degrading enzyme from Kitasatospora sp. CCTCC M205012[J].Process Biochemistry,2008,43:667-672.
[72] Kito M, Onji Y, Yoshida T, et al. Ocurrence of ε-poly-L-lysine-degradingenzyme in ε-poly-L-lysine-tolerant Shingobacterium multivorum OJ10: purificationand characterization[J]. FEMS Microbiology Letters,2002,207:147-151.
[73] Kito M, Takimoto R, Onji Y, et al. Purification and characterization of anε-poly-lysine-degrading enzyme from the ε-poly-L-lysine-tolerant Chryseobacteriumsp. OJ7[J]. Journal of Bioscience and Bioengineering,2003,96:92-94.
[74] Hamano Y, Yoshida T, Kito M, et al. Biological function of the pld gene productthat degrades ε-poly-L-lysine in Streptomyces albulus[J]. Applied Microbiology andBiotechnology,2006,72:173-181.
[75] Yamanaka K, Kito N, Imokawa Y, et al. Mechanism of ε-poly-L-lysineproduction and accumulation revealed by identification and analysis of anε-poly-L-lysine-degrading enzyme[J]. Applied and Environmental Microbiology,2010,76:5669-5675.
[76]李树，陈旭升，廖莉娟，等. ε-聚赖氨酸产生菌的筛选方法改进[J].食品与生物技术学报,2010,29(2):282-287.
[77]李荣杰.微生物诱变育种方法研究进展[J].河北农业科学，2009，13(10):73-76,78.
[78]贾红华，周华，韦萍.微波诱变育种研究及应用进展[J].工业微生物，2003，33(2):46-50.
[79]宫春波，刘鹭，谢丽琼，等.离子注入微生物诱变育种研究进展[J].生物技术，2003，13(2):47-49.
[80]张玲华，田兴山.微生物空间诱变育种的研究进展[J].核农学报，2004,18(4):294-294.
[81]田丰伟，程传荣，袁维涵，等.原生质体诱变选育ε-聚赖氨酸高产菌株[J].微生物学通报，2010,37(10)：1457-1461.
[82]张超，王正刚，段作营，等.大量紫外诱变选育ε-聚赖氨酸高产菌[J].生物加工过程，2007,5(3):64-68.
[83]张海涛，李燕，欧杰，等.诱变选育ε-聚赖氨酸菌产生菌突变株[J].食品科学，2007,28(09):398-401.
[84] Itzhaki FR. Colorimetric method for estimating polylysine and polyarginine[J].Analytical Biochemistry,1972,50:569-574.
[85] Kahar P, Iwata T, Hiraki J, et al. Enhancement of polylysine production byStreptomyces albulus strain410using pH control[J]. Journal of Bioscience andBioengineering,2001,91:190-194.
[86]骆健美，成永新，李培君，等.基于抑菌活性的ε-聚赖氨酸的微孔板生物检测法[J].微生物学通报，2011,38(7):976-981.
[87]刘双燕，贾士儒，王国良，等.荧光淬灭法测定ε-聚赖氨酸含量研究[J].现代食品科技，2010,26(11):1267-1270.
[88]程传荣，田丰伟，张灏，等.一种快速测定发酵液中ε-聚赖氨酸的方法[J].食品与发酵工业，2009,35(11):133-136.
[89]张超，张克峰，侯书国，等.利用响应面法优化ε-聚赖氨酸发酵培养基[J].微生物学通报，2011,38(5):641-646.
[90] Shih IL, Shen MH. Application of response surface methodology to optimizeproduction of poly-ε-lysine by Streptomyces albulus IFO14147[J]. Enzyme andMicrobial Technology,2006,39:15-21.
[91] Chen XS, Tang L, Li S, et al. Optimization of medium for enhancement ofε-poly-L-lysine production by Streptomyces sp. M-Z18with glycerol as carbonsource[J]. Bioresource Technology,2011,102:1727-1732.
[92] Bankar SB, Singhal RS. Optimization of ε-poly-L-lysine production byStreptomyces noursei NRRL5126[J]. Bioresource Technology,2010,101:8370-8375.
[93] EI-Naggar MY, Hassan MA, Said WY, et al. Effect of support materials onantibiotic MSW2000production by immobilized Streptomyces violatus[J]. Journal ofGeneral Applied Microbiology,2003,49:235-243.
[94] Srinivasulu B, Prakasham RS, Jetty A, et al. Neomycin production with free andimmobilized cells of Streptomyces marinensis in an airlift reactor[J]. ProcessBiochemistry,2002,38:593-598.
[95] Ogaki M, Sonomoto K, Nakajima H, et al. Continuous production ofoxytetracycline by immobilized growing Streptomyces rimosus cells[J]. AppliedMicrobiology and Biotechnology,1986,24:6-11.
[96] Devi S, Sridhar P. Production of cephamycin C in repeated batch operations fromimmobilized Streptomyces clavuligerus[J]. Process Biochemistry,2000,36:225-231.
[97] Hiraki J, Suzuki E. Process for producing ε-poly-L-lysine with immobilizedStreptomyces albulus[P]. US. Patent.1999, US5900363.
[98] Zhang Y, Feng XH, Xu H, et al. ε-Poly-L-lysine production by immobilized cellsof Kitasatospora sp. MY5-36in repeated fed-batch cultures[J]. BioresourceTechnology,2010,101:5523-5527.
[99] Teodoro JC, Baptista-Neto A, Cruz-Hernández IL, et al. Influence of feedingconditions on clavulanic acid production in fed-batch cultivation with mediumcontaining glycerol[J]. Applied Microbiology and Biotechnology,2006,72:450-455.
[100] Kim IC, Kim CH, Hong SI, et al. Fed-batch cultivation for the production ofclavulanic acid by an immobilized Streptomyces clavuligerus mutant[J]. WorldJournal of Microbiology and Biotechnology,2001,17:869-872.
[101] Lai LST, Pan CC, Tzeng BK. The influence of medium design on lovastatinproduction and pellet formation with a high-producing mutant of Aspergillus terreusin submerged cultures [J]. Process Biochemistry,2003,38:1317-1326.
[102] Kim YS, Lee JH, Kim NH, et al. Increase of lycopene production bysupplementing auxiliary carbon sources in metabolically engineered Escherichiacoli[J]. Applied Microbiology and Biotechnology,2011,90:489-497.
[103] Saint-amans S, Girbal L, Andrade J, et al. Regulation of carbon and electronflow in Clostridium butyricum VPI3266grown on glucose-glycerol mixtures[J].Journal of Bacteriology,183:1748-1754.
[104] Chen XS, Ren XD, Dong N, et al. Culture medium containing glucose andglycerol as a mixed carbon source improves ε-poly-L-lysine production byStreptomyces sp. M-Z18. Bioprocess Biosystems Engineering,2011,34:561-567
[105] Shih IL, Shen MH. Optimization of cell growth and poly(ε-lysine) production inbatch and fed-batch cultures by Streptomyces albulus IFO14147[J]. ProcessBiochemistry,2006,41:1644-1649.
[106] Nishikawa M, Ogawa K. Inhibition of epsilon-poly-L-lysine biosynthesis inStreptomycetaceae bacteria by short-chain polyols[J]. Applied and EnvironmentalMicrobiology,2006,72:2306-2312.
[107] Nishikawa M. Molecular mass control using polyanionic cyclodextrinderivatives for the epsilon-poly-L-lysine biosynthesis by Streptomyces[J]. Enzyme andMicrobial Technology,2009,45:295-298.
[108] Chen XS, Li S, Liao LJ, et al. Production of ε-poly-L-lysine using a noveltwo-stage pH control strategy by Streptomyces sp. M-Z18from glycerol[J].Bioprocess Biosystems Engineering,2011,34:561-567.
[109] Jia SR, Chen GB, Kahar P, et al. Effect of soybean oil on oxygen transfer in theproduction of tetracycline with an airlift bioreactor[J]. Journal of Bioscience andBioengineering,1999,87:825-827.
[110] Kahar P, Kobayashi K, Iwata T, et al. Production of ε-polylysine in an airliftbioreactor (ABR)[J]. Journal of Bioscience and Bioengineering,2002,93:274-280.
[111] Bankar SB, Singhal RS. Improved poly-ε-lysine biosynthesis usingStreptomyces noursei NRRL5126by controlling dissolved oxygen duringfermentation[J]. Journal of Microbiology and Biotechnology,2011,21:652-658.
[112]姜俊云，贾士儒，董惠钧，等.搅拌转速和pH对ε-聚赖氨酸发酵的影响[J].生物加工过程，2004,2(2):60-63.
[113] Ouyang J, Xu H, Li S, et al. Production of ε-poly-L-lysine by newly isolatedKitasatospora sp. PL6-3[J]. Biotechnology Journal,2006,1:1459-1463.
[114] Shirling EB, Gottlieb D. Methods for characterization of Streptomycesspecies[J]. International Journal of System Bacteriology,1966,16:313-340.
[115]邢芳芳，黄瑞林，张友明，等.改进Tricine-SDS-PAGE法分析重组牛乳铁蛋白肽[J].饲料工业，2007,28(9):10-13.
[116]王旭，何冰芳，李霜，等. Tricine-SDS-PAGE电泳分析小分子多肽[J].南京工业大学学报,2003,25(2):79-81.
[117]徐小华，陈天豹，李珑，等.一种改进的小分子多肽SDS-PAGE方法[J].福州大学学报(自然科学版)，2001,29(3):113-115.
[118]向弘，朱斌，徐昕荣，等.基质辅助激光解析电离-飞行时间质谱在高分子聚合物研究应用中的样品制备方法[J].广东化工，2009,36(196):85-86.
[119]徐昕荣，朱斌，马瑜璐.基质辅助激光解析电离飞行时间质谱快速测定水解胶原蛋白粉分子量[J].分析科学学报,2011,27(3):397-399.
[120]杨博，郭丽琼，郑冰昕，等. ε-聚赖氨酸产生菌的鉴定及产物特性研究[J].中国食品学报，2011,11(6):163-169.
[121]周俊，徐虹，王军，等.北里孢菌PL6-3产ε-聚赖氨酸的分离纯化和结构表征[J].化工学报，2006,57(8):1957-1961.
[122]顾觉奋主编.抗生素[M].上海：上海科学技术出版社,2001:13-20.
[123] Takagi H, Hoshino Y, Nakamori S, et al. Isolation and sequence analysis ofplasmid pNO33in the ε-poly-L-lysine-producing actinomycete Streptomyces albulusIFO14147[J]. Journal of Bioscience and Bioengineering,2000,89:94-96.
[124] Helander IM, Nurmiaho-Lassila EL, Ahvenainen R, et al. Chitosan disrupts thebarrier properties of the outer membrane of Gram-negative bacteria[J]. InternationalJournal of Food Microbiology,2001,71:235-244.
[125] Johnston MD, Hanlon GW, Denyer SP, et al. Membrane damage to bacteriacaused by single and combined biocides[J]. Journal of Applied Microbiology,2003,94:1015-1023.
[126] Hancock REW. Alterations in outer membrane permeability. Annual ReviewMicrobiology,1984,38:237-264.
[127] Kroll RG, Anagnostopoulos GD. Potassium leakage as a lethality index ofphenol and the effect of solute and water activity[J]. Journal of Applied Microbiology,1981,50:139-147.
[128] Hatzinger PB, Palmer P, Smith RL, et al. Applicability of tetrazolium salts forthe measurement of respiratory activity and viability of groundwater bacteria[J].Journal of Microbiology Methods,2003,52:47-58.
[129] Rodriguez GG, Phipps D, Ishiguro K, et al. Use of a fluorescent redox probe fordirect visualization of actively respiring bacteria[J]. Applied EnvironmentalMicrobiology,1992,58:1801-1808.
[130] Dufour P, Colon M. The tetrazolium reduction method for assessing theviability of individual bacterial cells in aquatic environments: improvements,performance and application[J]. Hydrobiologia,1992,232:211-218.
[131] Cundliffe E. How antibiotic-producing organisms avoid suicide[J]. AnnualReview. Microbiology,1989,43:207-233.
[132] Noda M, Kawahara Y, Ichikawa A, et al. Self-protection mechanism inD-cycloserine-producing Streptomyces lavendulae. Gene cloning, characterization,and kinetics of its alanine racemase and D-alanyl-D-alanine ligase, which are targetenzymes of D-cycloserine[J]. Journal of Biology Chemistry,2004,279:46143-46152.
[133] Sugiyama M, Kumagai T, Shionoya M, et al. Inactivation of bleomycin by anN-acetyltransferase in the bleomycin-producing strain Streptomyces verticillus[J].FEMS Microbiology Letters,1994,121:81-85.
[134] Zalacain M, Cundliffe E. Cloning of tlrD, a fourth resistance gene, from thetylosin producer, Streptomyces fradiae[J]. Gene,1991,97:137-142.
[135] Berney M, Hammes F, Bosshard F, et al. Assessment and interpretation ofbacterial viability by using the LIVE/DEAD BacLight kit in combination with flowcytometry[J]. Applied and Environmental Microbiology,2007,73:3283-3290.
[136] Boulos L, Prévost M, Barbeau B, et al. LIVE/DEAD BacLightTM: applicationof a new rapid staining method for direct enumeration of viable and total bacteria indrinking water[J]. Journal of Microbiology Methods,1999,37:77-86.
[137] Stocks SM. Mechanism and use of the commercially available viability stain,BacLight[J]. Cytometry A2004,61:189-195.
[138] Manteca A, Fernandez M, Sanchez J. Mycelium development in Streptomycesantibioticus ATCC11891occurs in an orderly pattern which determines multiphasegrowth curves[J]. BMC Microbiology,2005,5:51-60.
[139] Yagüe P, Manteca A, Simon A, et al. New method for monitoring programmedcell death and differentiation in submerged Streptomyces cultures[J]. Applied andEnvironmental Microbiology,2010,76:3401-3404.
[140] Diaper JP, Tither K, Edwards C. Rapid assessment of bacterial viability by flowcytometry[J]. Applied Microbiology and Biotechnology,1992,38:268-272.
[141] Smith JJ, McFeters GA. Mechanisms of INT(2-(4-iodophenyl)-3-(4-nitrophenyl)-5-phenyl tetrazolium chloride), and CTC(5-cyano-2,3-ditolyl tetrazolium chloride) reduction in Escherichia coli K-12[J].Journal of Microbiological Methods,1997,29:161-175.
[142] Miller GL. Use of dinitrosalicylic acid reagent for determination of reducingsugar[J]. Analytical Chemistry.1959,31:426-428.
[143] Bhupathiraju VK, Hernandez M, Landfear D, et al. Application of a tetrazoliumdyes as an indicator of viability in anaerobic bacteria[J]. Journal of MicrobiologicalMethods1999,37:231-243.
[144] Créach V, Baudoux AC, Bertru G, et al. Direct estimate of active bacteria: CTCuse and limitations[J]. Journal of Microbiological Methods,2003,52:19-28.
[145] Berney M, Hammes F, Bosshard F, et al. Assessment and interpretation ofbacterial viability by using the LIVE/DEAD BacLight Kit in combination with flowcytometry[J]. Applied and Environmental Microbiology,2007,73:3283-3290.
[146] Sebastine IM, Stocks SM, Cox P, et al. Characterisation of percentage viabilityof Streptomyces clavuligerus using image analysis[J]. Biotechnology Techniques,1999,13,419-423.
[147] Manteca A, Alvarez R, Salazar N, et al. Mycelium differentiation and antibioticproduction in submerged cultures of Streptomyces coelicolor[J]. Applied andEnvironmental Microbiology,2008,74:3877-3886.
[148] Pinto LS, Vieira LM, Pons MN, et al. Morphology and viability analysis ofStreptomyces clavuligerus in industrial cultivation systems[J]. Bioprocess BiosystemsEngineering,2004,26:177-184.
[149] Christiansen T, Michaelsen S, Wümpelmann M, et al. Production of savinaseand population viability of Bacillus clausii during high-cell-density fed-batchcultivations[J]. Biotechnology and Bioengineering,2003,83:344-352.
[150] Bouix M, Leveau JY. Rapid assessment of yeast viability and yeast vitalityduring alcoholic fermentation[J]. Journal of The Inistitute of Brewing,2001,107:217-225.
[151] Müller S, Hutter KJ, Bley T, et al. Dynamics of yeast cell states duringproliferation and non proliferation periods in a brewing reactor monitored bymultidimensional flow cytometry[J]. Bioprocess Engineering,1997,17:287-293.
[152] Bankar SB, Singhal RS. Metabolic precursors enhance the production ofpoly-ε-lysine by Streptomyces noursei NRRL5126[J]. Engineering in Life Sciences,2011,11:253-258.
[153] Kunioka M. Biosynthesis of poly(γ-glutamic acid) from L-glutamine, citric acidand ammonium sulfate in Bacillus subtilis IFO3335[J]. Applied Microbiology andBiotechnology,1995,44:501-506.
[154] Yoon SH, Do JH, Lee SY, et al. Production of poly-γ-glutamic acid by fed-batchculture of Bacillus licheniformis[J]. Biotechnology Letters,2000,22:585-588.
[155] Sasaki K, Tanaka T, Nishizawa Y, et al. Enhanced production of5-aminolevulinic acid by repeated addition of levulinic acid and supplement ofprecursors in photoheterotrophic culture of Rhodobacter sphaeroides[J]. Journal ofFermentation and Bioengineering,1991,71:403-406.
[156] Bajaj IB, Singhal RS. Enhanced production of poly(γ-glutamic acid) fromBacillus licheniformis NCIM2324by using metabolic precursors[J]. AppliedBiochemistry and Biotechnology,2009,159:133-141.
[157] Miller DL, Rodwell VW. Metabolism of basic amino acids in Pseudomonasputida. Catabolism of lysine by cyclic and acyclic intermediates[J]. Journal ofBiology Chemistry,1971,246:2758-2764.
[158] Fothergill JC, Guest JR. Catabolism of L-lysine by Pseudomonas aeruginosa[J].Journal of General Microbiology,1977,99:139-155.
[159] Stewart DJ. The decarboxylation of L-lysine by Pseudomonas aeruginosaisolates[J]. Journal of Applied Bacteriology,1970,33:501-504.
[160] Reitz MS, Rodwell VW. δ-Aminovaleramidase of Pseudomonas putida[J].Journal of Biology Chemistry,1970,245:3091-3096.
[161] Vandecasteele JP, Hermann M. Regulation of a catabolic pathway[J]. EuropeanJournal of Biochemistry,1972,31:80-85.
[162] Madduri K, Stuttard C, Vining LC. Lysine catabolism in Streptomyces spp. isprimarily through cadaverine: β-lactam producers also make α-aminoadipate[J].Journal of Bacteriology1989,171:299-302.
[163] Untrau S, Lebrihi A, Germain P, et al. Lysine catabolism in Streptomycesambofaciens producer of macrolide antibiotic, spiramycin[J]. Current Microbiology,1992,25:313-318.
[164] Kern BA, Hendlin D, Inamine E. L-Lysine epsilon-aminotransferase involved incephamycin C synthesis in Streptomyces lactamdurans[J]. Antimicrobial Agents andChemotherapy,1980,17:679-685.
[165] Tsueng G, Lam KS. Stabilization effect of resin on the production of potentproteasome inhibitor NPI-0052during submerged fermentation of Salinisporatropica[J]. Journal of Antibiotics,2007,60:469-472.
[166] Stark D, Von Stockar U. In situ product removal (ISPR) in whole cellbiotechnology during the last twenty years[J]. Advances in Biochemical EngineeringBiotechnology,2003,80:149-175.
[167] Kim CH, Kim SW, Hong SI. An integrated fermentation-separation process forthe production of red pigment by Serratia sp. KH-95[J]. Process Biochemistry,1999,35:485-490.
[168] Wong PL, Royce AJ, Lee-Parsons CWT. Improved ajmalicine production andrecovery from Catharanthus roseus suspensions with increased product removalrates[J]. Biochemical Engineering Journal,2004,21:253-258.
[169] Gastaldo L, Marinelli F, Acquarella C, et al. Improvement of the kirromycinfermentation by resin addition[J]. Journal of Industrial Microbiology,1996,16:305-308.
[170] Azuma S, Tsunekawa H, Okabe M, et al. Hyper-production of L-tryptophan viafermentation with crystallization[J]. Applied Microbiology and Biotechnology,1993,39:471-476.
[171] Ezeji TC, Qureshi N, Blaschek HP. Production of acetone, butanol and ethanolby Clostridium beijerinckii BA101and in situ recovery by gas stripping[J]. WorldJournal of Microbiology and Biotechnology,2003,19:595-603.
[172] Qureshi N, Hughes S, Maddox IS, et al. Energy-efficient recovery of butanolfrom model solutions and fermentation broth by adsorption[J]. Bioprocess BiosystemsEngineering,2005,27:215-222.
[173]胡红梅，蒋立科，林宇恒，等.乳酸菌肽自身免疫基因nisI的表达乳酸菌肽产量的影响[J].微生物学报,2010,50(10):1341-1346.
[174] Kim WS, Hall RJ, Dunn NW. Improving nisin production by increasing nisinimmunity/resistance genes in the producer organism Lactococcus lactis[J]. AppliedMicrobiology and Biotechnology,1998,50:429-433.
[175] Santos DT, Sarrouh BF, Rivaldi JD, et al. Use of sugarcane bagasse asbiomaterial for cell immobilization for xylitol production[J]. Journal of FoodEngineering,2008,86:542-548.
[176] Mukhopadhyay R, Chatterjee S, Chatterjee BP, et al. Production of gluconicacid from whey by free and immobilized Aspergillus niger[J]. Interational DairyJournal,2005,15:299-303.
[177] Yang SS, Yueh CY. Oxytetracycline production by immobilized Streptomycesrimosus[J]. Journal of Microbiology, Immunology and Infection,2001,34:235-242.
[178] Saudagar PS, Shaligram NS, Singhal RS. Immobilization of Streptomycesclavuligerus on loofah sponge for the production of clavulanic acid. BioresourceTechnology,2008,99:2250-2253.
[179] Evans PJ, Wang HY. Pigment production from immobilized Monascus sp.utilizing polymeric resin adsorption[J]. Applied and Environmental Microbiology,1984,47:1323-1326.
[180] Wu Z, Yang ST. Extractive fermentation for butyric acid production fromglucose by Clostridium tyrobutyricum[J]. Biotechnology and Bioengineering,2003,82:93-102.
[181] Friedl A, Qureshi N, Maddox IS. Continuous acetone-butanol-ethanol (ABE)fermentation using immobilized cells of Clostridium acetobutylicum in a packed bedreactor and integration with product removal by pervaporation[J]. Biotechnology andBioengineering,1991,38:518-527.
[182] Zeng Y, Ji XJ, Chang SM, et al. Improving arachidonic acid accumulation inMortierella alpina through B-group vitamin addition. Bioprocess BiosystemsEngineering,2011, DOI10.1007/s00449-011-0648-2.
[183] Xu GQ, Chu J, Zhuang YP, et al. Effects of vitamins on the lactic acidbiosynthesis of Lactobacillus paracasei NERCB0401[J]. Biochemical EngineeringJournal,2008,38:189-197.
[184] Nancib A, Nancib N, Meziane-Cherif D, et al. Joint effect of nitrogen sourcesand B vitamin supplementation of date juice on lactic acid production[J]. BioresourceTechnology,2005,96:63-67.
[185] Aeshlimann A, Von Stockar U. The effect of yeast extract supplementation onthe production of lactic acid from whey permeate by Lactobacillus helveticus[J].Applied Microbiology and Biotechnology,1990,32:398-402.
[186] Bizukojc M, Beata P, Stanislaw L. Supplementation of the cultivation mediawith B-group vitamins enhances lovastatin biosynthesis by Aspergillus terreus[J].Journal of Biotechnology,2007,127:258-268.
[187] Oh IJ, Kim DH, Oh EK, et al. Optimization and scale-up of succinic acidproduction by Mannheimia succiniciproducens LPK7[J]. Journal of Microbiology andBiotechnology,2009,19:167-17