发酵与分离耦合高强度生产L-乳酸的研究
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摘要
L-乳酸是一种重要的有机酸,广泛应用于食品、医药和化工领域,作为合成可生物降解、环境友好新材料—聚乳酸(PLA)的主要原料,L-乳酸应用前景极其光明。目前存在着原料成本较高、发酵周期较长产率较低、发酵过程能耗和三废排放量较大等问题,导致L-乳酸生产成本居高不下,成为制约L-乳酸产业发展的瓶颈。为解决上述问题,本研究采用廉价的盾叶薯蓣为原料,实行分段控制培养条件和细胞回流高强度发酵,大幅提高L-乳酸产量和生产率,同时清洁联产副产物薯蓣皂苷元,增加原料附加值,力争多途径降低L-乳酸发酵生产成本。
(1)从自然界筛选出一株高光学纯度L-乳酸产生菌Lactobacillus rhamnosusHG09,以该菌株为出发菌株,先进行紫外线联合诱变剂的复合诱变,再进行5轮递推式原生质体融合(Genome shuffling),最终筛选出1株遗传性能稳定的正向突变株L.rhamnosus HG09F5-27,在含160g/L的盾叶薯蓣淀粉酶解糖和0.35mol/L薯蓣皂苷的培养基中,L-乳酸产量达到141.33±4.11g/L,生产率达到1.76±0.04g/L/h,分别是出发菌株的4.09和4.40倍,为高强度发酵奠定了菌种基础。
(2)为不与人争粮,筛选出非粮原料——盾叶薯蓣淀粉为L-乳酸发酵生产碳源,以替代较为昂贵的玉米淀粉碳源,从农副产品中筛选出廉价高效的麸皮水解液替代玉米浆等作为氮源,选择罗田甜柿汁替代极为昂贵的酵母粉提供生长因子,并采用析因实验和响应面法优化培养基,获得最大L-乳酸产量144.28±2.71g/L,其对应的麸皮水解液和甜柿汁用量分别为比优化前节约了0.75%和16.00%。
(3)建立了以盾叶薯蓣淀粉酶解糖液为底物的L.rhamnosus HG09F5-27的单批发酵动力学模型方程,发现L-乳酸产量、糖酸转化率和最大比生长速率(μmax)随培养基初糖浓度的升高而降低；研究了几种常用中和剂解除发酵产物抑制的效果,发现Ca(OH)2调节pH能力较为理想；确立了不同发酵阶段pH、温度和通风等培养条件的分段控制策略,L-乳酸产量和生产率分别达到151.27±3.15g/L和2.70±0.06g/L/h,分别比恒定条件发酵提高5.57%和32.35%。
(4)采用100 L规模的外循环式膜生物反应器,实现细胞回流式半连续发酵生产L-乳酸；发现脉冲补料能有效解除底物抑制,生产率比不补料提高了32.07%；在细胞循环发酵中,第N轮发酵末期活细胞数目愈多,第N+1轮发酵L-乳酸产量和生产率就越大；采用脉冲补料及细胞回流发酵,随着发酵轮次的增加生物量缓慢上升,L-乳酸产量、生产率及糖酸转化率先升后降,第8轮L-乳酸产量达到157.26±3.06g/L,比单批发酵提高了12.89%,生产率达到8.73±0.17g/L/h,是单批发酵的4.11倍,大大降低了能耗；
(5)为获得L-乳酸发酵副产物——薯蓣皂苷元,采用蒸汽爆破及多种酶水解联合预处理盾叶薯蓣原料,使90%以上的薯蓣皂苷分配到糖液中；随后进行发酵与分离耦合的L-乳酸生产,采用纳滤浓缩发酵液,富集薯蓣皂苷,使薯蓣皂苷元的得率达到2.21±0.13g/100g,比传统酸水解法提高了6.76%,而废水和废渣排放量减少了95%以上,实现了盾叶薯蓣皂苷元生产的源头治理污染。
本研究的创新点包括：通过传统物理化学复合诱变结合原生质体融合技术,选育出一株耐L-乳酸盐和薯蓣皂苷的正向突变菌株,L-乳酸光学纯度大于98%,产量和生产率分别是出发菌株的4.09和4.40倍；筛选出一种可用于L-乳酸发酵的新非粮原料——盾叶薯蓣,使L-乳酸生产原料成本间接降低至玉米原料的1/2；采用脉冲补料和细胞回流发酵技术,使L-乳酸发酵生产半连续进行12轮次,与单批发酵相比,L-乳酸产量提高12.89%,生产率提高3倍；采用二级发酵与多级膜分离耦合技术,使L-乳酸生产废水和废渣排放量分别只有传统钙盐法的1/5和1/4,同时实现了L-乳酸的副产品——薯蓣皂苷元的清洁生产,其得率比传统酸水解法提高了6.76%,硫酸用量、废水和废渣排放减少95%以上,实现了节能减排的目标。
本研究提供的发酵与膜分离耦合系统和技术,有可能同样适用于以其它杆状、球状细菌或酵母菌等微生物为生产菌的发酵生产,筛选出的盾叶薯蓣原料有可能同样适用于琥珀酸和乙醇等产品的发酵生产。本研究为利用一种非粮原料联产多个产品提供了方法学借鉴。
L-lactic acid is an important organic acid. It is widely used in the field of food, medicine and chemical engineering. The most promising application of L-lactic acid is to be an important starting material for the synthesis of poly (lactic acid) which is a new biodegradable and environmental friendly material. At present, there are many issues such as high cost of material, low yield and long period of batch fermentation, and large amount of energy consumption and pollution in process, which hinder its development. In order to overcome these disadvantages, inexpensive yam tuber was used as the main raw material for the fermentation. The sectional control of culture conditions and cell recycle fermentation were applied to increase the yield and productivity of L-lactic acid and obtain the by-product diosgenin cleanly. The major goal was to reduce the production cost.
(1) Strain Lactobacillus rhamnosus HG09, producing L-lactic acid with high optical purity, was isolated from nature. Then an excellent positive forward mutant L.rhamnosus HG09F5-27 was obtained trough cooperation mutagenesis of ultraviolet and mutagens and subsequent five times of recursive protoplast fusions (Genome shuffling). When the fermentation was carried out in the medium containing 160g/L of yam starch hydrolysis sugar and 0.35mol/L of dioscin, the yield and productivity of L-lactic acid reached 141.33±4.11g/L and 1.76±0.04g/L/h, which were 4.09 times and 4.40 times those of the wild strain, respectively.
(2) In order to save grain for human, a new no-grain material, yam tuber was screened out and used as the carbon source of L-lactic acid production to replace the more expensive corn. The wheat bran hydrolyzate, obtained from low-cost agricultural byproducts, was used as the nitrogen source. The expensive yeast extract was replaced by cheap persimmon juice to provide growth factors. Factorial experiment and response surface methods were adapted to optimize the medium. As a result, the maximum L-lactic acid concentration reached 144.28±2.71g/L, with the corresponding dosages of bran hydrolyzate and persimmon juice reduced by 0.750 and 16.00%, compared with those before optimization, respectively.
(3) Kinetic model equations of batch fermentation using yam starch hydrolysis sugar as the substrate for L.rhamnosus HG09F5-27 were established. It was found that L-lactic acid yield, conservation rate andμmax firstly increased and then decreased with the increase of initial glucose concentration. Ca(OH)2 was found to be the most excellent neutralizer for pH adjustment to relieve the product inhibition during the fermentation. The culture conditions such as pH, temperature and dissolved oxygen were controlled step by step, and the appropriate subsection controlling strategy was established. The yield and productivity of L-lactic acid production reached 150.11±3.47g/L and 2.67±0.10g/L/h, which were 4.77% and 30.88% higher than those of constant controlling condition fermentations, respectively.
(4) 100 L of external membrane bioreactor was utilized to realize the semi-continuous fermentation of L-lactic acid with cell recycles. It was found that substrate inhibition could be effectively relieved by feeding medium fermentations and the productivity of L-lactic acid production was 32.07% higher than that of non-feeding medium fermentation. In the cell recycle fermentation, the more the living cells at the end of Nth round of fermentation, the higher the productivity and the shorter the fermentation period in the (N+1)th round. When the cell recycle fermentation coupled with feeding substrate was carried out, the yield, conservation rate and productivity of L-lactic acid production arose first and decreased later. In the 8th round of L-lactic acid fermentation, the yield was 157.26±3.06g/L, which increased 12.89% compared with that of batch fermentation; the productivity reached 8.73±0.17g/L/h, which were 4.11 times of that of batch fermentation.
(5) In order to obtain diosgenin, the by-product of L-lactic acid production, the pretreatment of yam tuber by steam explosion and enzymatic hydrolysis was performed, resulting that more than 90% of dioscin was dissolved in the yam sugar solution. And then the cell recycle fermentation coupled with separation was carried out. The fermentation broth was concentrated by nanofiltration equipment to enrich the dioscin. As a result, diosgenin yield reached to 2.21±0.13g/100g, which was 6.76% higher than that of traditional acid hydrolysis method (2.07±0.10g/100g), while the waste water and residue were reduced more than 95%. Thus, a clean process for diosgenin production was established.
The main novelties of our work were as follows:(i) a L-lactate and dioscin resistant positive mutant strain was isolated by traditional physiochemical mutagens and genome shuffling methods. The optical purity of L-lactic acid from the mutant strain was more than 98%, and the yield and productivity were 4.09 times and 4.40 times of those of the wild strain, respectively; (ii) yam tuber, a new no-grain material, was screened out for L-lactic acid production. The material cost of L-lactic acid production was reduced by half compared with that of the corn material; (iii) pulse-feeding medium and cell recycle fermentations were applied to enhance L-lactic acid production. As a result, the yield of L-lactic acid increased by 12.89% and the productivity increased 3-fold in the 12-batch of semi-continuous fermentations, compared with those of the batch fermentation; (iv) the two-grade fermentations coupled with membrane separation were used to produce L-lactic acid and its by-product, diosgenin. Meanwhile, the waste water and residue of L-lactic acid production were only one-fifth and one quarter of those of traditional calcium salt methods, respectively, and the dosage of H2SO4, discharge of waste water and the residue was reduced by 95% than those of the traditional acid-hydrolysis methods, indicating that the goals to decrease the energy consumption and pollution were achieved.
The systems and methods of fermentation coupled with membrane separation might also be suitable for the fermentations using other bacteria and yeast as the producing strains. The yam tuber material might also be suitable for the production of other products such as succinic acid and ethanol. This investigation has provided a reference for the production of several products from one starting no-grain material.
(1)从自然界筛选出一株高光学纯度L-乳酸产生菌Lactobacillus rhamnosusHG09,以该菌株为出发菌株,先进行紫外线联合诱变剂的复合诱变,再进行5轮递推式原生质体融合(Genome shuffling),最终筛选出1株遗传性能稳定的正向突变株L.rhamnosus HG09F5-27,在含160g/L的盾叶薯蓣淀粉酶解糖和0.35mol/L薯蓣皂苷的培养基中,L-乳酸产量达到141.33±4.11g/L,生产率达到1.76±0.04g/L/h,分别是出发菌株的4.09和4.40倍,为高强度发酵奠定了菌种基础。
(2)为不与人争粮,筛选出非粮原料——盾叶薯蓣淀粉为L-乳酸发酵生产碳源,以替代较为昂贵的玉米淀粉碳源,从农副产品中筛选出廉价高效的麸皮水解液替代玉米浆等作为氮源,选择罗田甜柿汁替代极为昂贵的酵母粉提供生长因子,并采用析因实验和响应面法优化培养基,获得最大L-乳酸产量144.28±2.71g/L,其对应的麸皮水解液和甜柿汁用量分别为比优化前节约了0.75%和16.00%。
(3)建立了以盾叶薯蓣淀粉酶解糖液为底物的L.rhamnosus HG09F5-27的单批发酵动力学模型方程,发现L-乳酸产量、糖酸转化率和最大比生长速率(μmax)随培养基初糖浓度的升高而降低；研究了几种常用中和剂解除发酵产物抑制的效果,发现Ca(OH)2调节pH能力较为理想；确立了不同发酵阶段pH、温度和通风等培养条件的分段控制策略,L-乳酸产量和生产率分别达到151.27±3.15g/L和2.70±0.06g/L/h,分别比恒定条件发酵提高5.57%和32.35%。
(4)采用100 L规模的外循环式膜生物反应器,实现细胞回流式半连续发酵生产L-乳酸；发现脉冲补料能有效解除底物抑制,生产率比不补料提高了32.07%；在细胞循环发酵中,第N轮发酵末期活细胞数目愈多,第N+1轮发酵L-乳酸产量和生产率就越大；采用脉冲补料及细胞回流发酵,随着发酵轮次的增加生物量缓慢上升,L-乳酸产量、生产率及糖酸转化率先升后降,第8轮L-乳酸产量达到157.26±3.06g/L,比单批发酵提高了12.89%,生产率达到8.73±0.17g/L/h,是单批发酵的4.11倍,大大降低了能耗；
(5)为获得L-乳酸发酵副产物——薯蓣皂苷元,采用蒸汽爆破及多种酶水解联合预处理盾叶薯蓣原料,使90%以上的薯蓣皂苷分配到糖液中；随后进行发酵与分离耦合的L-乳酸生产,采用纳滤浓缩发酵液,富集薯蓣皂苷,使薯蓣皂苷元的得率达到2.21±0.13g/100g,比传统酸水解法提高了6.76%,而废水和废渣排放量减少了95%以上,实现了盾叶薯蓣皂苷元生产的源头治理污染。
本研究的创新点包括：通过传统物理化学复合诱变结合原生质体融合技术,选育出一株耐L-乳酸盐和薯蓣皂苷的正向突变菌株,L-乳酸光学纯度大于98%,产量和生产率分别是出发菌株的4.09和4.40倍；筛选出一种可用于L-乳酸发酵的新非粮原料——盾叶薯蓣,使L-乳酸生产原料成本间接降低至玉米原料的1/2；采用脉冲补料和细胞回流发酵技术,使L-乳酸发酵生产半连续进行12轮次,与单批发酵相比,L-乳酸产量提高12.89%,生产率提高3倍；采用二级发酵与多级膜分离耦合技术,使L-乳酸生产废水和废渣排放量分别只有传统钙盐法的1/5和1/4,同时实现了L-乳酸的副产品——薯蓣皂苷元的清洁生产,其得率比传统酸水解法提高了6.76%,硫酸用量、废水和废渣排放减少95%以上,实现了节能减排的目标。
本研究提供的发酵与膜分离耦合系统和技术,有可能同样适用于以其它杆状、球状细菌或酵母菌等微生物为生产菌的发酵生产,筛选出的盾叶薯蓣原料有可能同样适用于琥珀酸和乙醇等产品的发酵生产。本研究为利用一种非粮原料联产多个产品提供了方法学借鉴。
L-lactic acid is an important organic acid. It is widely used in the field of food, medicine and chemical engineering. The most promising application of L-lactic acid is to be an important starting material for the synthesis of poly (lactic acid) which is a new biodegradable and environmental friendly material. At present, there are many issues such as high cost of material, low yield and long period of batch fermentation, and large amount of energy consumption and pollution in process, which hinder its development. In order to overcome these disadvantages, inexpensive yam tuber was used as the main raw material for the fermentation. The sectional control of culture conditions and cell recycle fermentation were applied to increase the yield and productivity of L-lactic acid and obtain the by-product diosgenin cleanly. The major goal was to reduce the production cost.
(1) Strain Lactobacillus rhamnosus HG09, producing L-lactic acid with high optical purity, was isolated from nature. Then an excellent positive forward mutant L.rhamnosus HG09F5-27 was obtained trough cooperation mutagenesis of ultraviolet and mutagens and subsequent five times of recursive protoplast fusions (Genome shuffling). When the fermentation was carried out in the medium containing 160g/L of yam starch hydrolysis sugar and 0.35mol/L of dioscin, the yield and productivity of L-lactic acid reached 141.33±4.11g/L and 1.76±0.04g/L/h, which were 4.09 times and 4.40 times those of the wild strain, respectively.
(2) In order to save grain for human, a new no-grain material, yam tuber was screened out and used as the carbon source of L-lactic acid production to replace the more expensive corn. The wheat bran hydrolyzate, obtained from low-cost agricultural byproducts, was used as the nitrogen source. The expensive yeast extract was replaced by cheap persimmon juice to provide growth factors. Factorial experiment and response surface methods were adapted to optimize the medium. As a result, the maximum L-lactic acid concentration reached 144.28±2.71g/L, with the corresponding dosages of bran hydrolyzate and persimmon juice reduced by 0.750 and 16.00%, compared with those before optimization, respectively.
(3) Kinetic model equations of batch fermentation using yam starch hydrolysis sugar as the substrate for L.rhamnosus HG09F5-27 were established. It was found that L-lactic acid yield, conservation rate andμmax firstly increased and then decreased with the increase of initial glucose concentration. Ca(OH)2 was found to be the most excellent neutralizer for pH adjustment to relieve the product inhibition during the fermentation. The culture conditions such as pH, temperature and dissolved oxygen were controlled step by step, and the appropriate subsection controlling strategy was established. The yield and productivity of L-lactic acid production reached 150.11±3.47g/L and 2.67±0.10g/L/h, which were 4.77% and 30.88% higher than those of constant controlling condition fermentations, respectively.
(4) 100 L of external membrane bioreactor was utilized to realize the semi-continuous fermentation of L-lactic acid with cell recycles. It was found that substrate inhibition could be effectively relieved by feeding medium fermentations and the productivity of L-lactic acid production was 32.07% higher than that of non-feeding medium fermentation. In the cell recycle fermentation, the more the living cells at the end of Nth round of fermentation, the higher the productivity and the shorter the fermentation period in the (N+1)th round. When the cell recycle fermentation coupled with feeding substrate was carried out, the yield, conservation rate and productivity of L-lactic acid production arose first and decreased later. In the 8th round of L-lactic acid fermentation, the yield was 157.26±3.06g/L, which increased 12.89% compared with that of batch fermentation; the productivity reached 8.73±0.17g/L/h, which were 4.11 times of that of batch fermentation.
(5) In order to obtain diosgenin, the by-product of L-lactic acid production, the pretreatment of yam tuber by steam explosion and enzymatic hydrolysis was performed, resulting that more than 90% of dioscin was dissolved in the yam sugar solution. And then the cell recycle fermentation coupled with separation was carried out. The fermentation broth was concentrated by nanofiltration equipment to enrich the dioscin. As a result, diosgenin yield reached to 2.21±0.13g/100g, which was 6.76% higher than that of traditional acid hydrolysis method (2.07±0.10g/100g), while the waste water and residue were reduced more than 95%. Thus, a clean process for diosgenin production was established.
The main novelties of our work were as follows:(i) a L-lactate and dioscin resistant positive mutant strain was isolated by traditional physiochemical mutagens and genome shuffling methods. The optical purity of L-lactic acid from the mutant strain was more than 98%, and the yield and productivity were 4.09 times and 4.40 times of those of the wild strain, respectively; (ii) yam tuber, a new no-grain material, was screened out for L-lactic acid production. The material cost of L-lactic acid production was reduced by half compared with that of the corn material; (iii) pulse-feeding medium and cell recycle fermentations were applied to enhance L-lactic acid production. As a result, the yield of L-lactic acid increased by 12.89% and the productivity increased 3-fold in the 12-batch of semi-continuous fermentations, compared with those of the batch fermentation; (iv) the two-grade fermentations coupled with membrane separation were used to produce L-lactic acid and its by-product, diosgenin. Meanwhile, the waste water and residue of L-lactic acid production were only one-fifth and one quarter of those of traditional calcium salt methods, respectively, and the dosage of H2SO4, discharge of waste water and the residue was reduced by 95% than those of the traditional acid-hydrolysis methods, indicating that the goals to decrease the energy consumption and pollution were achieved.
The systems and methods of fermentation coupled with membrane separation might also be suitable for the fermentations using other bacteria and yeast as the producing strains. The yam tuber material might also be suitable for the production of other products such as succinic acid and ethanol. This investigation has provided a reference for the production of several products from one starting no-grain material.
引文
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