基因重组技术优化氧化葡萄糖酸杆菌催化制备二羟基丙酮的研究
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摘要
二羟基丙酮是一种简单的酮糖,是重要的医药、化学合成中间体及原料,在精细化工、食品工业和化妆品工业等多种行业发挥着重要的作用。目前,通过氧化葡萄糖酸杆菌对甘油的不完全氧化反应,二羟基丙酮的工业化生产已经得以实现。但是,氧化葡萄糖酸杆菌是一种专性嗜氧细菌,在生长代谢及催化甘油生成二羟基丙酮的反应中需要大量的氧气,溶氧成为影响反应速率的限制因素。此外,高浓度的底物及产物也会抑制细胞的催化活性,降低甘油的氧化速度。因此,为了提高二羟基丙酮的生产效率,本论文通过在氧化葡萄糖酸杆菌细胞内克隆表达透明颤菌血红蛋白基因和过量表达甘油脱氢酶这两条途径,构建了高产二羟基丙酮的氧化葡萄糖酸杆菌菌株,主要内容如下：
1.透明颤菌血红蛋白(VHb)在氧化葡萄糖酸杆菌细胞内的克隆表达
为了实现VHb的高效表达,重点考察了不同启动子对VHb表达的影响。首先在广宿主载体pBBR1MCS-5引入了编码VHb的基因vgb,然后在VHb基因上游分别插入了不同的启动子,如tufB、bla,tac及VHb基因的同源启动子。经过CO差光光谱分析表明,在氧化葡萄糖酸杆菌延长因子—TU蛋白基因启动子(tufB)的控制下,VHb的表达量最高,菌体培养24h后,每克湿菌体含19.0mol VHb。
2.透明颤菌血红蛋白的表达对氧化葡萄糖酸杆菌细胞生长及二羟基丙酮产量的影响
通过提高细胞的摄氧率,VHb可以促进氧化葡萄糖酸杆菌细胞的生长及提高二羟基丙酮的产量。这种影响在低供氧条件下更加显著：在5-L发酵罐中,当用山梨醇培养基和甘油培养基培养时,VHb表达菌株(VHb+)的最终菌体密度与对照菌株(VHb-)相比分别提高了19.27%和22.96%；在静息细胞催化反应中,VHb+菌株二羟基丙酮的产量较VHb-菌株提高了21.55%,而在发酵过程中,VHb的表达使二羟基丙酮的产量提高了35.39%。结果同时表明,VHb的表达并不能提高甘油脱氢酶的表达量,但可以提高细胞的摄氧率,提高细胞催化的最大反应速度,从而促进了细胞的生长,提高了二羟基丙酮的生产效率。
3.甘油脱氢酶在氧化葡萄糖酸杆菌细胞内过量表达对二羟丙酮产量的影响
甘油脱氢酶的过量表达可提高二羟丙酮的产量,尤其是以膜结合乙醇脱氢酶缺失菌株(M5AM)为宿主时效果更加显著。当在野生菌株过量表达时,甘油脱氢酶的酶活提高了26%,二羟基丙酮的产量提高了20%。然而,当在M5AM菌株细胞内过量表达后,甘油脱氢酶基因的转录水平比对照菌株(M5／pBBR)提高了129倍,酶活提高了74.57%。在5-L发酵罐中,当静息细胞催化在一个稳定的pH及充足氧气的反应条件下时,甘油脱氢酶过表达菌株M5AM／GDH二羟丙酮的比生产率由M5／pBBR菌株的1.05g/gCDW/h增加到2.39g/g CDW／h,提高了128%,20g/L的静息细胞催化完成100g/L甘油仅需8h。在批次反应中,M5AM／GDH反应4个批次,活性仅降低21.7%,可在34h内完成400g/L甘油的转化,二羟丙酮的产量累计达385.32g/L,平均产率为96.33%,平均比生产率为2.27g/g CDW／h。
增加底物的初始浓度后,M5AM／GDH菌株二羟基丙酮的比生产率随之下降。在甘油浓度为140g/L时,该菌株可在14h内完全消耗,二羟基丙酮的产率达95.58%,比生产率为1.89g/g CDW／h。当甘油的初始浓度提高到180g/L时,产物的不可逆抑制效应显现,二羟基丙酮的产率下降到87.4%,即使提高静息细胞的浓度至40g/L,产率仍然得不到提高。通过流式细胞仪检测发现,在甘油初始浓度为180g/L时,反应48h后,细胞的死亡率仅为12%,而此时的细胞在解除底物抑制后,甘油脱氢酶的活性仅剩初始活性的20%左右,说明二羟丙酮的不可逆抑制是造成细胞失活的主要原因。
4.透明颤菌血红蛋白和甘油脱氢酶在氧化葡萄糖酸杆菌细胞内的共同表达
通过载体构建,将甘油脱氢酶基因和VHb基因分别置于氧化葡萄糖酸杆菌组成型启动子(tufB)的下游,每个基因分别由其独立的启动子控制,达到同时表达两种蛋白的目的。其中,VHb的表达量为17.01nmol/g CWW,甘油脱氢酶活性为2.162.16U／mg蛋白,较对照菌株提高了15.51%。通过对发酵罐中溶氧浓度的检测发现,整个转化过程中,VHb和甘油脱氢酶共表达菌株M5／TVTG的摄氧量一直比M5／pBBR菌株高,与此同时,二羟丙酮的最终产量也提高了27.65%。上述结果表明,透明颤菌血红蛋白和甘油脱氢酶的共同表达,可同时促进氧化葡萄糖酸杆菌的生长及其催化甘油生成二羟基丙酮的效率,特别是在溶氧受限时,这种效果更加显著。
Dihydroxyacetone (DHA) is an important ketose sugar, which is extensively used in the cosmetic, chemical and pharmaceutical industries. Commercial synthesis of DHA has been realized via the incomplete oxidation of glycerol by G. oxydans, an obligate aerobic Gram-negative bacterium belonging to the family Acetobacteriaceae. In G. oxydans, the enzyme responsible for the oxidative reaction is a membrane-bound, PQQ-dependent glycerol dehydrogenase (GDH) which employs oxygen as the final electron acceptor without NADH involvement. So, the oxidation of glycerol to DHA is a high oxygen-consuming reaction and oxygen should be supplied enough for the production of DHA in a biocatalytic process. In addition, high concentration of substrate and product could also affect DHA production. In order to improve DHA production, Vitreoscilla Hemoglobin (VHb) was expressed to enhance the oxygen uptake of G. oxydans. Besides, the glycerol dehydrogenase was also homologously overexpressed in G. oxydans to facilitate the oxidation of glycerol to DHA.
In order to expression of VHb in G. oxydans, the gene vgb coding for VHb was inserted to the broad host range vector pBBR1MCS-5, and then the promoters of tufB, bla, and tac were inserted into the upstream of VHb gene respectively. When the VHb gene was controlled by the constitutive promoter of tufB, the VHb-expressing strain displayed the highest VHb expression level, reaching 19.0nmol/g cell wet weight determined by analysis of CO-difference spectra.
The expression of VHb improved the cell growth and DHA production in G. oxydans. Under low aeration conditions, the VHb+ strain displayed 19.27% and 22.96% more biomass compared to VHb- strain when cultured in sorbitol medium and glycerol medium in a 5-L fermentor. In a resting cell system, the DHA production was increased by 21.55%, from 49.65g/L to 60.35g/L, when 100g/L glycerol was supplied. In compared to the control strain, the VHb+ strain exhibited 35.39% more DHA production attributing to high oxygen uptake and more cell biomass in a fermentation process. Results also indicated that the expression of VHb could not increase the GDH expression level, and the enhancement of DHA production by VHb only resulted from the improvement of oxygen uptake rate. The Km and Vmax for glycerol of GDH were determined in whole cells of VHb+ and VHb- strains under both high and low aeration conditions. It was apparent that the presence of VHb increased the enzyme's Vmax by 39.92% to 62.46% and decreased the Km by 19.15% to 23.48%.
When the GDH gene was overexpressed in the wild strain G. oxydans M5, the GDH activity was increased by 26% and the DHA production was improved by 20% in shake flask test. Unexpectedly, the activity of GDH was increased by 74.57% when the GDH gene was overexpressed in M5AM strain, in which the gene coding for the membrane-bound alcohol dehydrogenase (ADH) was interrupted. Overproduction of GDH in M5AM strain led to a 2.28-fold increased DHA productivity of 2.39g/g CDW/h using a batch biotransformation process in a 5-L fermentor, yielding 96.74g/L DHA from 100g/L glycerol. When 140g/L glycerol was supplied, all the glycerol could be exhausted by the recombinant strain within 14h, and a final DHA concentration of 133.81g/L was accumulated. In repeated batch biotransformations, 385.32g/L DHA over a time period of 34h was achieved, with an average productivity of 2.27g/g CDW/h. However, when the initial glycerol concentration was increased to 180g/L, the DHA reached an approximately maximum concentration of about 152.55g/L after 18 h. Prolonged incubation for another 10h had little effect on DHA yield, so did increase in concentration of resting cells from 20g/L to 40g/L. High concentration of DHA could not result in cell lysis but probably lead to irreversible damage of GDH by interacting with the amine function localized on the enzymatic enzyme site. So, the glycerol at an initial concentration of 180g/L could not be oxidated completely and only a DHA yield of 87.4% was achieved after 18h bioconversion. In a word, this newly developed recombinant strain G. oxydans M5AM/GDH with high productivity and yield exhibits potential for the industrial production of DHA.
Both the expression of VHb and GDH gene could improve the production of DHA, so the two genes were co-expressed in G.oxydans M5, generating strain G.oxydans M5/TVTG. Analysis by CO-difference spectra showed that the expression level of VHb in M5/TVTG strain was 17.01nmol/g cell wet weight. And this recombinant strain displayed a GDH activity of 2.16U/g protein, 15.51% more than that of M5/pBBR strain. When biotransformation was performanced in a fermentor under low aeration conditions, the M5/TVTG strain exhibited a rapid oxidation of glycerol rate and 63.38g/L DHA was accumulated after 48h, 27.65% more than that of the M5/pBBR strain.
1.透明颤菌血红蛋白(VHb)在氧化葡萄糖酸杆菌细胞内的克隆表达
为了实现VHb的高效表达,重点考察了不同启动子对VHb表达的影响。首先在广宿主载体pBBR1MCS-5引入了编码VHb的基因vgb,然后在VHb基因上游分别插入了不同的启动子,如tufB、bla,tac及VHb基因的同源启动子。经过CO差光光谱分析表明,在氧化葡萄糖酸杆菌延长因子—TU蛋白基因启动子(tufB)的控制下,VHb的表达量最高,菌体培养24h后,每克湿菌体含19.0mol VHb。
2.透明颤菌血红蛋白的表达对氧化葡萄糖酸杆菌细胞生长及二羟基丙酮产量的影响
通过提高细胞的摄氧率,VHb可以促进氧化葡萄糖酸杆菌细胞的生长及提高二羟基丙酮的产量。这种影响在低供氧条件下更加显著：在5-L发酵罐中,当用山梨醇培养基和甘油培养基培养时,VHb表达菌株(VHb+)的最终菌体密度与对照菌株(VHb-)相比分别提高了19.27%和22.96%；在静息细胞催化反应中,VHb+菌株二羟基丙酮的产量较VHb-菌株提高了21.55%,而在发酵过程中,VHb的表达使二羟基丙酮的产量提高了35.39%。结果同时表明,VHb的表达并不能提高甘油脱氢酶的表达量,但可以提高细胞的摄氧率,提高细胞催化的最大反应速度,从而促进了细胞的生长,提高了二羟基丙酮的生产效率。
3.甘油脱氢酶在氧化葡萄糖酸杆菌细胞内过量表达对二羟丙酮产量的影响
甘油脱氢酶的过量表达可提高二羟丙酮的产量,尤其是以膜结合乙醇脱氢酶缺失菌株(M5AM)为宿主时效果更加显著。当在野生菌株过量表达时,甘油脱氢酶的酶活提高了26%,二羟基丙酮的产量提高了20%。然而,当在M5AM菌株细胞内过量表达后,甘油脱氢酶基因的转录水平比对照菌株(M5／pBBR)提高了129倍,酶活提高了74.57%。在5-L发酵罐中,当静息细胞催化在一个稳定的pH及充足氧气的反应条件下时,甘油脱氢酶过表达菌株M5AM／GDH二羟丙酮的比生产率由M5／pBBR菌株的1.05g/gCDW/h增加到2.39g/g CDW／h,提高了128%,20g/L的静息细胞催化完成100g/L甘油仅需8h。在批次反应中,M5AM／GDH反应4个批次,活性仅降低21.7%,可在34h内完成400g/L甘油的转化,二羟丙酮的产量累计达385.32g/L,平均产率为96.33%,平均比生产率为2.27g/g CDW／h。
增加底物的初始浓度后,M5AM／GDH菌株二羟基丙酮的比生产率随之下降。在甘油浓度为140g/L时,该菌株可在14h内完全消耗,二羟基丙酮的产率达95.58%,比生产率为1.89g/g CDW／h。当甘油的初始浓度提高到180g/L时,产物的不可逆抑制效应显现,二羟基丙酮的产率下降到87.4%,即使提高静息细胞的浓度至40g/L,产率仍然得不到提高。通过流式细胞仪检测发现,在甘油初始浓度为180g/L时,反应48h后,细胞的死亡率仅为12%,而此时的细胞在解除底物抑制后,甘油脱氢酶的活性仅剩初始活性的20%左右,说明二羟丙酮的不可逆抑制是造成细胞失活的主要原因。
4.透明颤菌血红蛋白和甘油脱氢酶在氧化葡萄糖酸杆菌细胞内的共同表达
通过载体构建,将甘油脱氢酶基因和VHb基因分别置于氧化葡萄糖酸杆菌组成型启动子(tufB)的下游,每个基因分别由其独立的启动子控制,达到同时表达两种蛋白的目的。其中,VHb的表达量为17.01nmol/g CWW,甘油脱氢酶活性为2.162.16U／mg蛋白,较对照菌株提高了15.51%。通过对发酵罐中溶氧浓度的检测发现,整个转化过程中,VHb和甘油脱氢酶共表达菌株M5／TVTG的摄氧量一直比M5／pBBR菌株高,与此同时,二羟丙酮的最终产量也提高了27.65%。上述结果表明,透明颤菌血红蛋白和甘油脱氢酶的共同表达,可同时促进氧化葡萄糖酸杆菌的生长及其催化甘油生成二羟基丙酮的效率,特别是在溶氧受限时,这种效果更加显著。
Dihydroxyacetone (DHA) is an important ketose sugar, which is extensively used in the cosmetic, chemical and pharmaceutical industries. Commercial synthesis of DHA has been realized via the incomplete oxidation of glycerol by G. oxydans, an obligate aerobic Gram-negative bacterium belonging to the family Acetobacteriaceae. In G. oxydans, the enzyme responsible for the oxidative reaction is a membrane-bound, PQQ-dependent glycerol dehydrogenase (GDH) which employs oxygen as the final electron acceptor without NADH involvement. So, the oxidation of glycerol to DHA is a high oxygen-consuming reaction and oxygen should be supplied enough for the production of DHA in a biocatalytic process. In addition, high concentration of substrate and product could also affect DHA production. In order to improve DHA production, Vitreoscilla Hemoglobin (VHb) was expressed to enhance the oxygen uptake of G. oxydans. Besides, the glycerol dehydrogenase was also homologously overexpressed in G. oxydans to facilitate the oxidation of glycerol to DHA.
In order to expression of VHb in G. oxydans, the gene vgb coding for VHb was inserted to the broad host range vector pBBR1MCS-5, and then the promoters of tufB, bla, and tac were inserted into the upstream of VHb gene respectively. When the VHb gene was controlled by the constitutive promoter of tufB, the VHb-expressing strain displayed the highest VHb expression level, reaching 19.0nmol/g cell wet weight determined by analysis of CO-difference spectra.
The expression of VHb improved the cell growth and DHA production in G. oxydans. Under low aeration conditions, the VHb+ strain displayed 19.27% and 22.96% more biomass compared to VHb- strain when cultured in sorbitol medium and glycerol medium in a 5-L fermentor. In a resting cell system, the DHA production was increased by 21.55%, from 49.65g/L to 60.35g/L, when 100g/L glycerol was supplied. In compared to the control strain, the VHb+ strain exhibited 35.39% more DHA production attributing to high oxygen uptake and more cell biomass in a fermentation process. Results also indicated that the expression of VHb could not increase the GDH expression level, and the enhancement of DHA production by VHb only resulted from the improvement of oxygen uptake rate. The Km and Vmax for glycerol of GDH were determined in whole cells of VHb+ and VHb- strains under both high and low aeration conditions. It was apparent that the presence of VHb increased the enzyme's Vmax by 39.92% to 62.46% and decreased the Km by 19.15% to 23.48%.
When the GDH gene was overexpressed in the wild strain G. oxydans M5, the GDH activity was increased by 26% and the DHA production was improved by 20% in shake flask test. Unexpectedly, the activity of GDH was increased by 74.57% when the GDH gene was overexpressed in M5AM strain, in which the gene coding for the membrane-bound alcohol dehydrogenase (ADH) was interrupted. Overproduction of GDH in M5AM strain led to a 2.28-fold increased DHA productivity of 2.39g/g CDW/h using a batch biotransformation process in a 5-L fermentor, yielding 96.74g/L DHA from 100g/L glycerol. When 140g/L glycerol was supplied, all the glycerol could be exhausted by the recombinant strain within 14h, and a final DHA concentration of 133.81g/L was accumulated. In repeated batch biotransformations, 385.32g/L DHA over a time period of 34h was achieved, with an average productivity of 2.27g/g CDW/h. However, when the initial glycerol concentration was increased to 180g/L, the DHA reached an approximately maximum concentration of about 152.55g/L after 18 h. Prolonged incubation for another 10h had little effect on DHA yield, so did increase in concentration of resting cells from 20g/L to 40g/L. High concentration of DHA could not result in cell lysis but probably lead to irreversible damage of GDH by interacting with the amine function localized on the enzymatic enzyme site. So, the glycerol at an initial concentration of 180g/L could not be oxidated completely and only a DHA yield of 87.4% was achieved after 18h bioconversion. In a word, this newly developed recombinant strain G. oxydans M5AM/GDH with high productivity and yield exhibits potential for the industrial production of DHA.
Both the expression of VHb and GDH gene could improve the production of DHA, so the two genes were co-expressed in G.oxydans M5, generating strain G.oxydans M5/TVTG. Analysis by CO-difference spectra showed that the expression level of VHb in M5/TVTG strain was 17.01nmol/g cell wet weight. And this recombinant strain displayed a GDH activity of 2.16U/g protein, 15.51% more than that of M5/pBBR strain. When biotransformation was performanced in a fermentor under low aeration conditions, the M5/TVTG strain exhibited a rapid oxidation of glycerol rate and 63.38g/L DHA was accumulated after 48h, 27.65% more than that of the M5/pBBR strain.
引文
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