氧化葡萄糖酸杆菌特异性氧化1-苯基-1，2-乙二醇及赤藓糖醇的研究
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摘要
氧化葡萄糖酸杆菌(Gluconobacter oxydans,简称G. oxydans)具有大量的膜结合脱氢酶,能够不完全氧化多种糖、醇类物质生产相应的醛、酮和酸,这种氧化大多具有区域选择性和立体选择性,而且氧化产物能够直接分泌到反应液中,因而,成功应用于多种产品的工业生产之中,如维生素C、(酮基)葡萄糖酸、二羟基丙酮等。随着G. oxydans基因组信息的公布,极大地推动了新酶的揭示以及已知酶功能扩展的研究工作,从而为G. oxydans的潜在应用开发奠定了基础。
本论文针对G. oxydans膜结合乙醇脱氢酶和甘油脱氢酶催化的两种多羟基醇氧化反应,即G. oxydans氧化拆分外消旋1-苯基-1,2-乙二醇(简称苯基乙二醇)和氧化赤藓糖醇生产赤藓酮糖两个反应为研究对象,对反应过程和反应过程中的关键参数进行分析,并探讨反应抑制因素和细胞催化活性的影响因素,提出相应的解决方案,建立了高效拆分苯基乙二醇的生产工艺,完成了赤藓酮糖合成的过程研究和优化,为这两种产品的产业化开发奠定了基础。
第一部分,G. oxydans立体选择性拆分外消旋1-苯基-1,2-乙二醇生产其(S)-构型对映体的研究。G. oxydans能区域选择性氧化1-苯基-1,2-乙二醇的α-羟基生成扁桃酸(即α-羟基苯乙酸),且对(R)、(S)-构型底物的反应亲和性存在显著的差异,因此可以使得(S)-构型底物在反应液中累积,从而达到拆分外消旋体生产(S)-苯基乙二醇的目的。
(1)确定了G. oxydans中催化苯基乙二醇氧化拆分反应的关键酶是以PQQ为辅酶的膜结合乙醇脱氢酶(ADH)和乙醛脱氢酶(ALDH)。其中,负责苯基乙二醇氧化的酶只有ADH,而ALDH仅参与后一步羟基酸的合成。
(2)通过测定G. oxydans (ADH)对(R)-和(S)-苯基乙二醇的表观动力学参数,显示出G. oxydans对(R)-构型底物的亲和力远大于(S)-构型底物,从而确定了使用G.oxydans作为生物催化剂,选择性氧化拆分外消旋体生产(S)-苯基乙二醇的可行性。
(3)对拆分反应条件进行了优化,确定了50g/L菌体最多可以将12g/L外消旋苯基乙二醇完全拆分,反应时间约为12h,(S)-苯基乙二醇得率40.8%,e.e.值达到96%以上。同时,明确了影响反应效率的因素主要是底物苯基乙二醇和氧化产物扁桃酸产生的抑制。其中底物苯基乙二醇对反应的影响相对较小,抑制浓度在30g/L以上；而5g/L的扁桃酸就会对反应产生明显的不可逆抑制(毒害作用),是影响反应效率的关键因素。
(4)针对扁桃酸抑制的问题,通过引入树脂原位吸附的方法,以降低反应液中扁桃酸的有效浓度。经过筛选,选择大孔型弱碱性阴离子交换树脂D301作为分离介质,并建立了树脂原位吸附的拆分反应体系,最终可以使用100g/L菌体将60g/L的外消旋苯基乙二醇完全拆分,反应时间20h,(S)-苯基乙二醇的得率39.5%,纯度达到96%e.e.以上,时空产量从0.41g L-1h-1增加到了1.18gL-1h-1。该结果优于目前文献报道微生物法生产(S)-苯基乙二醇的最高水平,为该产品的生产提供了一种可行的方法。
第二部分,G. oxydans选择性氧化赤藓糖醇生产赤藓酮糖的过程研究。基于以PQQ为辅酶的膜结合甘油脱氢酶特性,根据其与乙醇脱氢酶在表达上的内在联系,筛选出一株具有高甘油脱氢酶活性的G. oxydans菌株,用于选择性氧化赤藓糖醇生产赤藓酮糖,并在摇瓶和7L生物反应器中对氧化反应的过程进行了研究和优化。
(1)首先确定了催化赤藓糖醇生产赤藓酮糖的关键酶为以PQQ为辅酶的膜结合甘油脱氢酶(GDH)。基于GDH与ADH在G. oxydans中表达的关联性,对菌体生长环境进行调控,利用底物诱导驯化,获得了一株高甘油脱氢酶活性的菌株用于赤藓酮糖的生产。
(2)在摇瓶中初步优化了反应条件,并考察了赤藓糖醇和赤藓酮糖对反应的影响。底物赤藓糖醇对反应速率的抑制不明显,但是会对菌体细胞的菌体催化活性产生影响,抑制浓度约为50g/L；而产物赤藓酮糖对反应速率和菌体催化活性均有明显的抑制作用,且浓度越高,抑制作用越强。
(3)在7L生物反应器中,对赤藓糖醇氧化反应过程参数进行研究和优化。确定了转化条件为pH4.0,温度30℃,通气量达到最大为8L/min,搅拌转速为600rpm。20g/L菌体能够将150g/L赤藓糖醇在20h左右完全氧化,200g/L底物完全氧化则需40g/L菌体,反应时间18h,时空产率分别为6.65g L-1h-1和10.94g L-1h-1,单位菌体产量分别为7.31g/g cells和4.93g/g cells。
(4)针对赤藓糖醇对菌体催化活性的影响,为降低反应液中的赤藓糖醇浓度,采用了底物分批添加的策略。确定了底物添加方式为初始底物浓度为50g/L,2h后开始补加底物,速率为每小时加入20g/L。经过20h,20g/L菌体最多可将250g/L赤藓糖醇完全氧化,转化率达到100%,与单批次转化(相同菌体浓度)相比,其时空产率和单位菌体产量分别提高了78.6%和62.4%,达到了11.88gL-1h-1和11.88g/g cells。该结果显示出G. oxydans生产赤藓酮糖的快速和高效,具有一定的应用前景。
Gluconobacter oxydans (G. oxydans) is known for its regio-and stereoselective oxidation of a wide range of carbohydrates and alcohols to corresponding aldehydes, ketones or acids and the products can accumulate in the medium. And this microbiology has been used in a wide variety of biotechnological processes as the biocatalyst, such as the production of vitamin C,(keto-) gluconic acid, dihydroxyacetone (DHA) and so on. As the genome of G. oxydans621H was published in2005, the further investigations on the unknown or known enzymes in G. oxydans were developed, which was the base of the application development of G. oxydans.
In this dissertation, the oxidations of (R, S)-1-phenyl-1,2-ethanodiol and erythritol which were responsible by the membrane-bound alcohol dehydrogenase and membrane-bound glycerol dehydrogenase respectively were investigated. And the processes and their key factors were studied in detail.
In the first part, the resolution of racemic1-phenyl-1,2-ethanediol (PED) for the production of (S)-isomeride catalyzed by G. oxydans was performed. The resting cells of G. oxydans were able to catalyze the regio-and stereoselective concurrent oxidation of PED to the corresponding hydroxyl acid, mandelic acid. And due to the different reactive activities of cells to the two isomerides, optically pure (S)-PED was cumulated in the reaction resolution as the unreacted substrate.
(1) The membrane-bound alcohol dehydrogenase (ADH) and membrane-bound aldehyde dehydrogenase (ALDH) in G. oxydans were testified to be the key enzymes in the conversion of PED to mandelic acid. The oxidation of PED was only in the charge of the ADH, and the ALDH was beneficial for the production of mandelic acid but had no effect on the oxidation of PED.
(2) The kinetic parameters for the oxidation of (R)-and (S)-PED were obtained using Lineweaver-BurK method, respectively, which reflected the different activities of G. oxydans cells (ADH) on the two isomerides. And due to the differences, it was feasible to product (S)-PED from the raceme using G. oxydans cells.
(3) Through the optimization of reaction conditions,12g/L of (R, S)-PED was able to be separated completely by50g/L cells in12h, with40.8%of the productivity and over96%e.e. of purity. The substrate, PED, and oxidative product, mandelic acid, were testified to have inhibition to the reaction. The inhibited concentration of PED was over30g/L; and mandelic acid of only5g/L was able to create serious and irreversible inhibition (toxicity), which was the key inhibitor.
(3) In order to overcome the inhibition of mandelic acid, the anion exchange resin D301was selected and introduced as the adsorbent for in situ removal of inhibitor from the reaction system. This method allowed the concentration of substrate to be increased to60g/L, with39.5%of the productivity and over96%e.e. of purity for (S)-PED. Comparing with the conversion without resins, the final space-time yield increased by2-fold to1.18g L-1h-1from0.41g L-1h-1. This method was more effective for the production of (S)-PED than those from the reports.
In the second part, a high activity strain of G. oxydans DSM2003for the oxidation of erythritol was screened based on the membrane-bound glycerol dehydrogenase (GDH) and was used in the production of erythrulose. The process of the conversion was investigated and optimized.
(1) The membrane-bound glycerol dehydrogenase (GDH) of G. oxydans was testified to be in charge of the conversion of erythritol. And according to the relationship of GDH and ADH, a strain of G. oxydans DSM2003with high GDH activity was obtained through the regulation of the growth condition.
(2) The conversion conditions were optimized and the effects of erythritol and erythrulose were investigated in flasks. The erythritol didn't have effect on the reaction rate, but it would produce toxicity to the cells when the concentration was over50g/l. The erythrulose strongly inhibited on both of the reaction rate and the activities of the cells, and the higher the concentration of erythrulose was, the stronger the inhibition was.
(3) The process from erythritol to erythrulose was operated in a7L bioreactor and the reaction conditions were determined (pH4.0,30℃,8L/min of aeration and600rpm of agitation).150g/L of erythritol was oxidized completely in20h by20g/L of G. oxydans cells, and the space-time yield was6.65g L-1h-1and the yield per unit of cells was7.31g/g cells.40g/L of G. oxydans cells were required when the concentration of substrate was up to200g/L. The reaction time was18h and the space-time yield and the yield per unit of cells were10.96g L-1h-1and4.93g/g cells respectively.
(4) In order to reduce the effects of erythritol to G. oxydans cells, the substrate was added into the reaction solution in several times. The initial concentration of substrate was50g/L catalyzed by20g/L G. oxydans cells, and erythritol of20g/L was added per hour after2h. The maximal total concentration of erythritol was250g/L, which was able to be completely oxidized to erythrulose in20h. The space-time yield and the yield per unit of cells for the fed-batch conversion were11.88g L-1h-1and11.88g/g cells respectively, which were increased by78.6%and62.4%comparing with the conventional conversion catalyzed by the same concentration of G. oxydans cells。The method showed the good industrial application potential for the production of erythrulose.
本论文针对G. oxydans膜结合乙醇脱氢酶和甘油脱氢酶催化的两种多羟基醇氧化反应,即G. oxydans氧化拆分外消旋1-苯基-1,2-乙二醇(简称苯基乙二醇)和氧化赤藓糖醇生产赤藓酮糖两个反应为研究对象,对反应过程和反应过程中的关键参数进行分析,并探讨反应抑制因素和细胞催化活性的影响因素,提出相应的解决方案,建立了高效拆分苯基乙二醇的生产工艺,完成了赤藓酮糖合成的过程研究和优化,为这两种产品的产业化开发奠定了基础。
第一部分,G. oxydans立体选择性拆分外消旋1-苯基-1,2-乙二醇生产其(S)-构型对映体的研究。G. oxydans能区域选择性氧化1-苯基-1,2-乙二醇的α-羟基生成扁桃酸(即α-羟基苯乙酸),且对(R)、(S)-构型底物的反应亲和性存在显著的差异,因此可以使得(S)-构型底物在反应液中累积,从而达到拆分外消旋体生产(S)-苯基乙二醇的目的。
(1)确定了G. oxydans中催化苯基乙二醇氧化拆分反应的关键酶是以PQQ为辅酶的膜结合乙醇脱氢酶(ADH)和乙醛脱氢酶(ALDH)。其中,负责苯基乙二醇氧化的酶只有ADH,而ALDH仅参与后一步羟基酸的合成。
(2)通过测定G. oxydans (ADH)对(R)-和(S)-苯基乙二醇的表观动力学参数,显示出G. oxydans对(R)-构型底物的亲和力远大于(S)-构型底物,从而确定了使用G.oxydans作为生物催化剂,选择性氧化拆分外消旋体生产(S)-苯基乙二醇的可行性。
(3)对拆分反应条件进行了优化,确定了50g/L菌体最多可以将12g/L外消旋苯基乙二醇完全拆分,反应时间约为12h,(S)-苯基乙二醇得率40.8%,e.e.值达到96%以上。同时,明确了影响反应效率的因素主要是底物苯基乙二醇和氧化产物扁桃酸产生的抑制。其中底物苯基乙二醇对反应的影响相对较小,抑制浓度在30g/L以上；而5g/L的扁桃酸就会对反应产生明显的不可逆抑制(毒害作用),是影响反应效率的关键因素。
(4)针对扁桃酸抑制的问题,通过引入树脂原位吸附的方法,以降低反应液中扁桃酸的有效浓度。经过筛选,选择大孔型弱碱性阴离子交换树脂D301作为分离介质,并建立了树脂原位吸附的拆分反应体系,最终可以使用100g/L菌体将60g/L的外消旋苯基乙二醇完全拆分,反应时间20h,(S)-苯基乙二醇的得率39.5%,纯度达到96%e.e.以上,时空产量从0.41g L-1h-1增加到了1.18gL-1h-1。该结果优于目前文献报道微生物法生产(S)-苯基乙二醇的最高水平,为该产品的生产提供了一种可行的方法。
第二部分,G. oxydans选择性氧化赤藓糖醇生产赤藓酮糖的过程研究。基于以PQQ为辅酶的膜结合甘油脱氢酶特性,根据其与乙醇脱氢酶在表达上的内在联系,筛选出一株具有高甘油脱氢酶活性的G. oxydans菌株,用于选择性氧化赤藓糖醇生产赤藓酮糖,并在摇瓶和7L生物反应器中对氧化反应的过程进行了研究和优化。
(1)首先确定了催化赤藓糖醇生产赤藓酮糖的关键酶为以PQQ为辅酶的膜结合甘油脱氢酶(GDH)。基于GDH与ADH在G. oxydans中表达的关联性,对菌体生长环境进行调控,利用底物诱导驯化,获得了一株高甘油脱氢酶活性的菌株用于赤藓酮糖的生产。
(2)在摇瓶中初步优化了反应条件,并考察了赤藓糖醇和赤藓酮糖对反应的影响。底物赤藓糖醇对反应速率的抑制不明显,但是会对菌体细胞的菌体催化活性产生影响,抑制浓度约为50g/L；而产物赤藓酮糖对反应速率和菌体催化活性均有明显的抑制作用,且浓度越高,抑制作用越强。
(3)在7L生物反应器中,对赤藓糖醇氧化反应过程参数进行研究和优化。确定了转化条件为pH4.0,温度30℃,通气量达到最大为8L/min,搅拌转速为600rpm。20g/L菌体能够将150g/L赤藓糖醇在20h左右完全氧化,200g/L底物完全氧化则需40g/L菌体,反应时间18h,时空产率分别为6.65g L-1h-1和10.94g L-1h-1,单位菌体产量分别为7.31g/g cells和4.93g/g cells。
(4)针对赤藓糖醇对菌体催化活性的影响,为降低反应液中的赤藓糖醇浓度,采用了底物分批添加的策略。确定了底物添加方式为初始底物浓度为50g/L,2h后开始补加底物,速率为每小时加入20g/L。经过20h,20g/L菌体最多可将250g/L赤藓糖醇完全氧化,转化率达到100%,与单批次转化(相同菌体浓度)相比,其时空产率和单位菌体产量分别提高了78.6%和62.4%,达到了11.88gL-1h-1和11.88g/g cells。该结果显示出G. oxydans生产赤藓酮糖的快速和高效,具有一定的应用前景。
Gluconobacter oxydans (G. oxydans) is known for its regio-and stereoselective oxidation of a wide range of carbohydrates and alcohols to corresponding aldehydes, ketones or acids and the products can accumulate in the medium. And this microbiology has been used in a wide variety of biotechnological processes as the biocatalyst, such as the production of vitamin C,(keto-) gluconic acid, dihydroxyacetone (DHA) and so on. As the genome of G. oxydans621H was published in2005, the further investigations on the unknown or known enzymes in G. oxydans were developed, which was the base of the application development of G. oxydans.
In this dissertation, the oxidations of (R, S)-1-phenyl-1,2-ethanodiol and erythritol which were responsible by the membrane-bound alcohol dehydrogenase and membrane-bound glycerol dehydrogenase respectively were investigated. And the processes and their key factors were studied in detail.
In the first part, the resolution of racemic1-phenyl-1,2-ethanediol (PED) for the production of (S)-isomeride catalyzed by G. oxydans was performed. The resting cells of G. oxydans were able to catalyze the regio-and stereoselective concurrent oxidation of PED to the corresponding hydroxyl acid, mandelic acid. And due to the different reactive activities of cells to the two isomerides, optically pure (S)-PED was cumulated in the reaction resolution as the unreacted substrate.
(1) The membrane-bound alcohol dehydrogenase (ADH) and membrane-bound aldehyde dehydrogenase (ALDH) in G. oxydans were testified to be the key enzymes in the conversion of PED to mandelic acid. The oxidation of PED was only in the charge of the ADH, and the ALDH was beneficial for the production of mandelic acid but had no effect on the oxidation of PED.
(2) The kinetic parameters for the oxidation of (R)-and (S)-PED were obtained using Lineweaver-BurK method, respectively, which reflected the different activities of G. oxydans cells (ADH) on the two isomerides. And due to the differences, it was feasible to product (S)-PED from the raceme using G. oxydans cells.
(3) Through the optimization of reaction conditions,12g/L of (R, S)-PED was able to be separated completely by50g/L cells in12h, with40.8%of the productivity and over96%e.e. of purity. The substrate, PED, and oxidative product, mandelic acid, were testified to have inhibition to the reaction. The inhibited concentration of PED was over30g/L; and mandelic acid of only5g/L was able to create serious and irreversible inhibition (toxicity), which was the key inhibitor.
(3) In order to overcome the inhibition of mandelic acid, the anion exchange resin D301was selected and introduced as the adsorbent for in situ removal of inhibitor from the reaction system. This method allowed the concentration of substrate to be increased to60g/L, with39.5%of the productivity and over96%e.e. of purity for (S)-PED. Comparing with the conversion without resins, the final space-time yield increased by2-fold to1.18g L-1h-1from0.41g L-1h-1. This method was more effective for the production of (S)-PED than those from the reports.
In the second part, a high activity strain of G. oxydans DSM2003for the oxidation of erythritol was screened based on the membrane-bound glycerol dehydrogenase (GDH) and was used in the production of erythrulose. The process of the conversion was investigated and optimized.
(1) The membrane-bound glycerol dehydrogenase (GDH) of G. oxydans was testified to be in charge of the conversion of erythritol. And according to the relationship of GDH and ADH, a strain of G. oxydans DSM2003with high GDH activity was obtained through the regulation of the growth condition.
(2) The conversion conditions were optimized and the effects of erythritol and erythrulose were investigated in flasks. The erythritol didn't have effect on the reaction rate, but it would produce toxicity to the cells when the concentration was over50g/l. The erythrulose strongly inhibited on both of the reaction rate and the activities of the cells, and the higher the concentration of erythrulose was, the stronger the inhibition was.
(3) The process from erythritol to erythrulose was operated in a7L bioreactor and the reaction conditions were determined (pH4.0,30℃,8L/min of aeration and600rpm of agitation).150g/L of erythritol was oxidized completely in20h by20g/L of G. oxydans cells, and the space-time yield was6.65g L-1h-1and the yield per unit of cells was7.31g/g cells.40g/L of G. oxydans cells were required when the concentration of substrate was up to200g/L. The reaction time was18h and the space-time yield and the yield per unit of cells were10.96g L-1h-1and4.93g/g cells respectively.
(4) In order to reduce the effects of erythritol to G. oxydans cells, the substrate was added into the reaction solution in several times. The initial concentration of substrate was50g/L catalyzed by20g/L G. oxydans cells, and erythritol of20g/L was added per hour after2h. The maximal total concentration of erythritol was250g/L, which was able to be completely oxidized to erythrulose in20h. The space-time yield and the yield per unit of cells for the fed-batch conversion were11.88g L-1h-1and11.88g/g cells respectively, which were increased by78.6%and62.4%comparing with the conventional conversion catalyzed by the same concentration of G. oxydans cells。The method showed the good industrial application potential for the production of erythrulose.
引文
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