氧化葡萄糖酸杆菌高密度培养及生物催化合成羟基酸的研究
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摘要
羟基酸可作为许多生物起源化合物的双功能构建模块,是重要的医药、农药和精细化工产品的中间体。开展生物催化醇类化合物制备羟基酸的研究具有重要的理论价值和现实意义。
氧化葡萄糖酸杆菌(Gluconobacter oxydans)具有大量的膜结合脱氢酶,能够不完全氧化多种糖、醇化合物生成相应的醛、酮和酸。本论文以两种羟基酸(羟基乙酸和β-羟基异丁酸)的生物合成为研究对象,详细探讨了氧化葡萄糖酸杆菌的培养、全细胞催化过程以及产物的分离等方面内容。
第一,以氧化葡萄糖酸杆菌DSM 2003为出发菌株,对它的高密度培养进行了较为系统的研究,目的是为了获得大量的细胞催化剂和高效的催化效率。
(1)首先采用单因素法和均匀设计法对氧化葡萄糖酸杆菌的培养基组分进行优化,确定发酵培养基的最佳配方：山梨醇73.0g/l,酵母粉18.4g/l,硫酸铵1.5g/l,磷酸二氢钾1.52g/l,七水硫酸镁0.47g/l,并初步确定了氧化葡萄糖酸杆菌DSM 2003菌株培养的最适培养条件。在最适条件下,菌体密度为9.6g/l。
(2)在摇瓶实验的基础上,进行3.7L发酵罐放大培养,菌体密度达到44.3g/l,比摇瓶的培养结果提高了361%。采取合适的补料策略,菌体的密度进一步提高到54.2g/l(干重14.1g/l),高于目前文献报道的最好结果13.5g/l(干重),同时细胞的相对催化活性也提高了40%。高密度、高活性细胞的获得,为羟基酸的生物法合成奠定了基础。
第二,以氧化葡萄糖酸杆菌全细胞催化乙二醇合成羟基乙酸为模式反应,揭示催化反应的关键酶,详细研究生物催化合成羟基酸的过程。
(1)通过基因敲除和互补以及全细胞催化实验,鉴定了氧化葡萄糖酸杆菌中催化乙二醇的关键酶——膜结合的乙醇脱氢酶(GOX1067-1068)。
(2)确定了氧化葡萄糖酸杆菌在摇瓶中转化乙二醇的最优反应条件,并在摇瓶实验的基础上在3.7L生物反应器中进行转化过程的放大,通过流加底物,提高溶氧水平和在线调节pH等优化手段,经过50h的反应,羟基乙酸的浓度达到74.5g/l,转化率达到87.1%。产物抑制效应是限制反应产率的关键问题。
(3)针对乙二醇反应过程中存在的产物抑制问题,引入原位分离技术,进行乙二醇的催化过程研究。
①选择D315树脂作为原位分离的介质。为了截留细胞,选用聚乙烯醇-海藻酸钠对细胞进行固定化。经过72h的原位分离转化,羟基乙酸的浓度达到90.2g/l,转化率为80.3%。
②鉴于固定化细胞催化活性较低、在剪切力下容易破碎的问题,引入中空纤维膜模块,实现游离细胞的循环利用。经过50h的原位分离转化,羟基乙酸浓度达到93.2g/l,转化率为81%。相比于常规的分批转化结果,采用膜反应器原位分离技术后,羟基乙酸的最终浓度从74.5g/l提高到了93.2g/l,转化效率也从1.5g/(1·h)提高到了1.9g/(1·h)。开展氧化葡萄糖酸杆菌催化乙二醇合成羟基乙酸的研究,对于氧化葡萄糖酸杆菌的开发应用和羟基乙酸的生物法制备都具有十分重要的意义。
(4)根据催化体系的特点及转化液的组成,详细地给出了羟基乙酸分离提纯的流程。经过活性炭进行脱色、D315阴离子树脂和D113阳离子树脂纯化、浓缩结晶等步骤,过程总收率85%,羟基乙酸晶体的纯度为97.3%。
第三,对氧化葡萄糖酸杆菌立体选择催化2-甲基-1,3-丙二醇生成(R)-β-羟基异丁酸进行研究。
(1)首先对2-甲基-1,3-丙二醇的转化产物进行了分离纯化和鉴定,产物是(R)-β-羟基异丁酸,副产物为2-甲基丙烯醛和2-甲基丙烯酸。通过基因敲除、互补和静息细胞催化实验,确定了膜结合的乙醇脱氢酶是催化2-甲基-1,3-丙二醇生成(R)-β-羟基异丁酸反应的关键酶。
(2)确定了氧化葡萄糖酸杆菌在摇瓶中催化2-甲基-1,3-丙二醇生成(R)-β-羟基异丁酸的最优反应条件,并在摇瓶实验的基础上在3.7L生物反应器中进行放大,经过24h的反应,(R)-β-羟基异丁酸的积累浓度达到50.2g/l,转化率和光学纯度分别达到90.5%和93.2%。这为生物法合成(R)-β-羟基异丁酸提供了新的选择,具有进一步开发前景。
Hydroxy acids are important dual functional building blocks and fine intermediates, which are conventionally used as materials of pharmaceuticals, agrochemicals, etc. Therefore, the studies on the preparation of hydroxy acids from diols by biocatalysis are very important both for the knowledge on biocatalytic mechanism and its application.
Gluconobacter oxydans is known for its incomplete oxidation of a wide range of carbohydrates and alcohols in a process that is referred to as oxidative fermentation. The corresponding oxidative products are secreted almost completely into the medium. In this dissertation, two hydroxyl acids were selected as the target product of bioconversion. The culture conditions of G.oxydans DSM 2003, bioconversion process by the resting cells and purification of the product were studied in detail.
In the first section, high cell density culture of Gluconobacter oxydans DSM 2003 was studied.
(1) Single factor analysis and uniform design were used to optimize the medium components. The optimum medium compositions were as follows:sorbitol 73.0g/l, yeast extract 18.4g/l, (NH4)2SO4 1.5g/l, KH2PO4 1.52g/l, MgSO4·7H2O 0.47g/l. Under the optimal conditions, cell density was 9.6g/l in shaking flasks.
(2) To enhance G.oxydans DSM 2003 cell growth to higher cell density, the process of fermentation was improved in 3.7L bioreactor based on the optimized parameters in shaking flasks. Cell density achieved was 44.3g/l, which was increased by 361% compared with that in shaking flasks. The final cell density was 54.2g/l (DCW,14.1g/l) from the improved fed-batch culture in 3.7L bioreactor. To the best of our knowledge, this was the highest cell density until now. Furthermore, the activity the resting cells was also improved by 40%. The cells of the high density and the high activity laid the foundation of biosynthesis of hydroxyl acids.
In the second section, bioconversion of ethylene glycol to glycolic acid by Gluconobacter oxydans DSM 2003 was studied.
(1) The mutant strain defective in alcohol dehydrogenase (ADH, GOX1067-1068) and the complementary strain were constructed and the results of bioconversion of ethylene glycol using the resting cells showed that the ADH was the key enzyme responsible for biooxidation of ethylene glycol to glycolic acid in G. oxydans DSM 2003.
(2) G.oxydans DSM 2003 was used to synthesize glycolic acid through microbial oxidation of ethylene glycol. To enhance glycolic acid production, the process of bioconversion was improved in 3.7L bioreactor based on the optimized parameters in shaking flasks. The ethylene glycol was controlled accurately by maintaining corresponding feeding rate. The pH was well controlled automatically by computer. Dissolve oxygen (DO) was controlled by increasing agitation speed, airflow and bioreactor pressure to keep it over 30% air saturation. Under the optimized reaction conditions,74.5g/l glycolic acid was obtained with a molar conversion yield of 87.1% after a 50-h reaction. The inhibition of glycolic acid was a key limitation for the bioconversion.
(3) To resolve the problem of product inhibition and improve glycolic acid yield, a bioconversion strategy using ion-exchange resin D315 was investigated.
①In order to entrap the cells, PVA-sodium alginate was used as carrier for the immobilization of the cells of Gluconobacter oxydans. D315 resin was chosen to adsorb glycolic acid in situ during the bioconversion. Under the optimized reaction conditions, 90.2g/l glycolic acid was obtained with a molar conversion yield of 80.3% after a 72-h reaction.
②A adsorptive bioconversion for glycolic acid production from ethylene glycol using resting cells of Gluconobacter oxydans in a hollow fiber membrane bioreaction system was developed by using D315 resin as the adsorbent for selective removal of glycolic acid from the reaction mixture. This approach allowed the yield of glycolic acid to be increased to 93.2g/l, compared to 74.5g/l obtained from a conventional fed-batch mode after a 50-h reaction. Microbial bioconversion of ethylene glycol by G.oxydans DSM 2003 was very important for the application development of G.oxydans DSM 2003 and biosynthesis of hydroxyl acids.
(4) According to the reaction mixture of glycolic acid, the process of separation and purification was present in detail. After decolorization by active carbon, purification by D315 and D113 resins, the crystallization was carried out at 4℃, the crystalloid purity of glycolic acid was 97.3%, and the total yield was 85%.
In the third section, study on microbial asymmetric oxidation of 2-methyl-1, 3-propanediol by Gluconobacter oxydans was investigated.
(1) Firstly, purification and identification of the reaction products was carried out. Two byproducts were identified to be 2-methyl propenal and methacrylic acid, respectively. Secondly, the alcohol dehydrogenase was demonstrated to serve as the key enzyme for the oxidation reaction of 2-methyl-1,3-propanediol toβ-hydroxyisobutyric acid by gene disruption and complementation.
(2) We optimized the reaction conditions for (R)-β-hydroxyisobutyric acid production from 2-methyl-1,3-propandiol using G.oxydans DSM 2003. A yield 50.2g/l of (R)-β-hydroxyisobutyric acid was obtained with a molar conversion rate of 90.5% and 93.2% enantiomeric excess within 24 h in a 2-1 batch reaction in a 3.7L fermentor. Microbial asymmetric oxidation of 2-methyl-1,3-propanediol by G.oxydans DSM 2003 provides a new biological methods to synthesis to (R)-β-hydroxyisobutyric acid, an important building block.
氧化葡萄糖酸杆菌(Gluconobacter oxydans)具有大量的膜结合脱氢酶,能够不完全氧化多种糖、醇化合物生成相应的醛、酮和酸。本论文以两种羟基酸(羟基乙酸和β-羟基异丁酸)的生物合成为研究对象,详细探讨了氧化葡萄糖酸杆菌的培养、全细胞催化过程以及产物的分离等方面内容。
第一,以氧化葡萄糖酸杆菌DSM 2003为出发菌株,对它的高密度培养进行了较为系统的研究,目的是为了获得大量的细胞催化剂和高效的催化效率。
(1)首先采用单因素法和均匀设计法对氧化葡萄糖酸杆菌的培养基组分进行优化,确定发酵培养基的最佳配方：山梨醇73.0g/l,酵母粉18.4g/l,硫酸铵1.5g/l,磷酸二氢钾1.52g/l,七水硫酸镁0.47g/l,并初步确定了氧化葡萄糖酸杆菌DSM 2003菌株培养的最适培养条件。在最适条件下,菌体密度为9.6g/l。
(2)在摇瓶实验的基础上,进行3.7L发酵罐放大培养,菌体密度达到44.3g/l,比摇瓶的培养结果提高了361%。采取合适的补料策略,菌体的密度进一步提高到54.2g/l(干重14.1g/l),高于目前文献报道的最好结果13.5g/l(干重),同时细胞的相对催化活性也提高了40%。高密度、高活性细胞的获得,为羟基酸的生物法合成奠定了基础。
第二,以氧化葡萄糖酸杆菌全细胞催化乙二醇合成羟基乙酸为模式反应,揭示催化反应的关键酶,详细研究生物催化合成羟基酸的过程。
(1)通过基因敲除和互补以及全细胞催化实验,鉴定了氧化葡萄糖酸杆菌中催化乙二醇的关键酶——膜结合的乙醇脱氢酶(GOX1067-1068)。
(2)确定了氧化葡萄糖酸杆菌在摇瓶中转化乙二醇的最优反应条件,并在摇瓶实验的基础上在3.7L生物反应器中进行转化过程的放大,通过流加底物,提高溶氧水平和在线调节pH等优化手段,经过50h的反应,羟基乙酸的浓度达到74.5g/l,转化率达到87.1%。产物抑制效应是限制反应产率的关键问题。
(3)针对乙二醇反应过程中存在的产物抑制问题,引入原位分离技术,进行乙二醇的催化过程研究。
①选择D315树脂作为原位分离的介质。为了截留细胞,选用聚乙烯醇-海藻酸钠对细胞进行固定化。经过72h的原位分离转化,羟基乙酸的浓度达到90.2g/l,转化率为80.3%。
②鉴于固定化细胞催化活性较低、在剪切力下容易破碎的问题,引入中空纤维膜模块,实现游离细胞的循环利用。经过50h的原位分离转化,羟基乙酸浓度达到93.2g/l,转化率为81%。相比于常规的分批转化结果,采用膜反应器原位分离技术后,羟基乙酸的最终浓度从74.5g/l提高到了93.2g/l,转化效率也从1.5g/(1·h)提高到了1.9g/(1·h)。开展氧化葡萄糖酸杆菌催化乙二醇合成羟基乙酸的研究,对于氧化葡萄糖酸杆菌的开发应用和羟基乙酸的生物法制备都具有十分重要的意义。
(4)根据催化体系的特点及转化液的组成,详细地给出了羟基乙酸分离提纯的流程。经过活性炭进行脱色、D315阴离子树脂和D113阳离子树脂纯化、浓缩结晶等步骤,过程总收率85%,羟基乙酸晶体的纯度为97.3%。
第三,对氧化葡萄糖酸杆菌立体选择催化2-甲基-1,3-丙二醇生成(R)-β-羟基异丁酸进行研究。
(1)首先对2-甲基-1,3-丙二醇的转化产物进行了分离纯化和鉴定,产物是(R)-β-羟基异丁酸,副产物为2-甲基丙烯醛和2-甲基丙烯酸。通过基因敲除、互补和静息细胞催化实验,确定了膜结合的乙醇脱氢酶是催化2-甲基-1,3-丙二醇生成(R)-β-羟基异丁酸反应的关键酶。
(2)确定了氧化葡萄糖酸杆菌在摇瓶中催化2-甲基-1,3-丙二醇生成(R)-β-羟基异丁酸的最优反应条件,并在摇瓶实验的基础上在3.7L生物反应器中进行放大,经过24h的反应,(R)-β-羟基异丁酸的积累浓度达到50.2g/l,转化率和光学纯度分别达到90.5%和93.2%。这为生物法合成(R)-β-羟基异丁酸提供了新的选择,具有进一步开发前景。
Hydroxy acids are important dual functional building blocks and fine intermediates, which are conventionally used as materials of pharmaceuticals, agrochemicals, etc. Therefore, the studies on the preparation of hydroxy acids from diols by biocatalysis are very important both for the knowledge on biocatalytic mechanism and its application.
Gluconobacter oxydans is known for its incomplete oxidation of a wide range of carbohydrates and alcohols in a process that is referred to as oxidative fermentation. The corresponding oxidative products are secreted almost completely into the medium. In this dissertation, two hydroxyl acids were selected as the target product of bioconversion. The culture conditions of G.oxydans DSM 2003, bioconversion process by the resting cells and purification of the product were studied in detail.
In the first section, high cell density culture of Gluconobacter oxydans DSM 2003 was studied.
(1) Single factor analysis and uniform design were used to optimize the medium components. The optimum medium compositions were as follows:sorbitol 73.0g/l, yeast extract 18.4g/l, (NH4)2SO4 1.5g/l, KH2PO4 1.52g/l, MgSO4·7H2O 0.47g/l. Under the optimal conditions, cell density was 9.6g/l in shaking flasks.
(2) To enhance G.oxydans DSM 2003 cell growth to higher cell density, the process of fermentation was improved in 3.7L bioreactor based on the optimized parameters in shaking flasks. Cell density achieved was 44.3g/l, which was increased by 361% compared with that in shaking flasks. The final cell density was 54.2g/l (DCW,14.1g/l) from the improved fed-batch culture in 3.7L bioreactor. To the best of our knowledge, this was the highest cell density until now. Furthermore, the activity the resting cells was also improved by 40%. The cells of the high density and the high activity laid the foundation of biosynthesis of hydroxyl acids.
In the second section, bioconversion of ethylene glycol to glycolic acid by Gluconobacter oxydans DSM 2003 was studied.
(1) The mutant strain defective in alcohol dehydrogenase (ADH, GOX1067-1068) and the complementary strain were constructed and the results of bioconversion of ethylene glycol using the resting cells showed that the ADH was the key enzyme responsible for biooxidation of ethylene glycol to glycolic acid in G. oxydans DSM 2003.
(2) G.oxydans DSM 2003 was used to synthesize glycolic acid through microbial oxidation of ethylene glycol. To enhance glycolic acid production, the process of bioconversion was improved in 3.7L bioreactor based on the optimized parameters in shaking flasks. The ethylene glycol was controlled accurately by maintaining corresponding feeding rate. The pH was well controlled automatically by computer. Dissolve oxygen (DO) was controlled by increasing agitation speed, airflow and bioreactor pressure to keep it over 30% air saturation. Under the optimized reaction conditions,74.5g/l glycolic acid was obtained with a molar conversion yield of 87.1% after a 50-h reaction. The inhibition of glycolic acid was a key limitation for the bioconversion.
(3) To resolve the problem of product inhibition and improve glycolic acid yield, a bioconversion strategy using ion-exchange resin D315 was investigated.
①In order to entrap the cells, PVA-sodium alginate was used as carrier for the immobilization of the cells of Gluconobacter oxydans. D315 resin was chosen to adsorb glycolic acid in situ during the bioconversion. Under the optimized reaction conditions, 90.2g/l glycolic acid was obtained with a molar conversion yield of 80.3% after a 72-h reaction.
②A adsorptive bioconversion for glycolic acid production from ethylene glycol using resting cells of Gluconobacter oxydans in a hollow fiber membrane bioreaction system was developed by using D315 resin as the adsorbent for selective removal of glycolic acid from the reaction mixture. This approach allowed the yield of glycolic acid to be increased to 93.2g/l, compared to 74.5g/l obtained from a conventional fed-batch mode after a 50-h reaction. Microbial bioconversion of ethylene glycol by G.oxydans DSM 2003 was very important for the application development of G.oxydans DSM 2003 and biosynthesis of hydroxyl acids.
(4) According to the reaction mixture of glycolic acid, the process of separation and purification was present in detail. After decolorization by active carbon, purification by D315 and D113 resins, the crystallization was carried out at 4℃, the crystalloid purity of glycolic acid was 97.3%, and the total yield was 85%.
In the third section, study on microbial asymmetric oxidation of 2-methyl-1, 3-propanediol by Gluconobacter oxydans was investigated.
(1) Firstly, purification and identification of the reaction products was carried out. Two byproducts were identified to be 2-methyl propenal and methacrylic acid, respectively. Secondly, the alcohol dehydrogenase was demonstrated to serve as the key enzyme for the oxidation reaction of 2-methyl-1,3-propanediol toβ-hydroxyisobutyric acid by gene disruption and complementation.
(2) We optimized the reaction conditions for (R)-β-hydroxyisobutyric acid production from 2-methyl-1,3-propandiol using G.oxydans DSM 2003. A yield 50.2g/l of (R)-β-hydroxyisobutyric acid was obtained with a molar conversion rate of 90.5% and 93.2% enantiomeric excess within 24 h in a 2-1 batch reaction in a 3.7L fermentor. Microbial asymmetric oxidation of 2-methyl-1,3-propanediol by G.oxydans DSM 2003 provides a new biological methods to synthesis to (R)-β-hydroxyisobutyric acid, an important building block.
引文
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