产乳糖酶酵母菌株的遗传改良和乳糖酶的发酵生产
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摘要
马克斯克鲁维酵母菌（Kluyveromyces marxianus）具有代谢底物广、耐热性好及比生长速率快等多种优良特性，并且能合成大量的乳糖酶、菊粉酶、β-葡萄糖苷酶和其它酶，因而引起国内外学者的广泛关注。与其它种类的微生物相比，该酵母菌是一类在食品工业中普遍采用的微生物，用作酶源非常合适。
微生物中普遍存在葡萄糖阻遏现象，当有葡萄糖存在时，许多酶的合成和基因表达都会受到抑制。参与葡萄糖阻遏作用的主要为Snf1复合体和Mig1蛋白，当培养基中葡萄糖浓度较高时，Snf1复合体去磷酸化，Snf1复合体失去活性，这时Migl由于不能被磷酸化，进入细胞核中与受葡萄糖阻遏基因的启动子结合，使基因表达受到抑制，说明Mig1在菌株的酶合成和调控中起重要的作用。如果将编码Mig1的MIG1基因敲除，相关基因的阻遏效应解除。因而本研究通过基因敲除法阻断K. marxianus km菌株MIG1基因，然后研究该基因的敲除对该菌株酶的合成和相关基因的表达产生的影响。首先利用编码潮霉素的HPT基因的ORF替换km-15菌株的MIG1基因的ORF，在含有潮霉素的YPD平板上筛选获得了敲除菌株km-15，它能在含有2-脱氧-D-葡萄糖的乳糖培养基平板上生长，而野生型菌株km则都不能，表明敲除菌株葡萄糖阻遏作用解除。与野生型菌株km相比，敲除菌株km-15的乳糖酶、菊粉酶和β-葡萄糖苷酶的产量均有很大提高，同时编码这些酶基因的表达量也有极大提高。这表明，K. marxianus km中的Mig1确实能阻遏某些基因的表达，对一些酶的合成具有调控作用。
对敲除菌株km-15产乳糖酶培养基进行了优化，确定了最佳培养基成分为（w/v）：乳清粉10.0%、酵母粉1.5%、蛋白胨1.0%和MnCl21.0mM。在28°C、pH7.0条件下180rpm振荡培养48h，km-15菌株乳糖酶产量为111.7U/mL。经过2-L发酵罐发酵，该菌株乳糖酶产量提高到121.7U/mL。同时，确定了酶法水解乳糖的适宜条件，即乳糖浓度9.0%（w/v）、乳糖酶使用量为440U/g乳糖、40°C、pH7.0和水解时间2.5h，在这种条件下乳糖水解率为99.2%。在同样条件下，12.0%（w/v）的乳清粉经过该酶水解3.5h后，乳清粉中乳糖水解率为98.7%。调节乳糖酶使用量为260U/g乳糖添加到5.0mL牛奶中，水解3.0h后，牛奶中乳糖水解率为99.3%。将上述水解液进行薄层层析，结果显示水解产物只有单糖，即葡萄糖和半乳糖，其中的乳糖完全水解，表明该乳糖酶在食品工业中具有潜在的应用价值。
就上面所说的那样，该酵母菌还产菊粉酶。对敲除菌株km-15产菊粉酶培养基进行了优化，确定了最佳培养基成分为（w/v）：菊粉8.0%、酵母粉3.0%，在28°C、pH4.5的条件下180rpm振荡培养42h，km-15菌株菊粉酶的活力为69.0U/mL。分别以菊粉和菊芋汁作为碳源，经过2-L发酵罐发酵，发酵48h和60h后，菊粉酶活性分别为79.9U/mL和73.3U/mL。然后，确定了酶法水解菊粉的适宜条件，即菊粉浓度6.0%（w/v）、菊粉酶使用量为400U/g菊粉、50°C、pH4.5、水解时间3.0h，菊粉水解率为96.2%。将其水解产物进行薄层层析分析，水解终产物以单糖为主，仅有少许寡糖，表明km-15菌株所产菊粉酶为外切菊粉酶。
本实验室自南极海洋沉积物中分离出1株耐冷酵母Guehomyces pullulans17-1菌株在15°C可同时产胞外和与细胞结合的乳糖酶。故采用NTG对G.pullulans17-1菌株进行诱变，结合X-gal显蓝斑和发酵培养测定的选育方法，获得乳糖酶活力达24.8U/mL且遗传稳定的突变菌株NTG-133，产量比野生型菌株（13.9U/mL）提高近一倍。对突变菌株NTG-133产乳糖酶培养基进行了优化，确定了最佳培养基成分为（w/v）：乳清粉4.0%、蛋白胨1.0%、酵母粉0.5%，于15°C、pH4.5条件下，170rpm振荡培养132h，乳糖酶活达38.0U/mL。采用发酵罐发酵产酶，乳糖酶活提高到48.1U/mL。然后，确定了酶法水解乳糖的适宜条件，即乳糖浓度9.0%（w/v）、乳糖酶的使用量为550U/g乳糖、40°C、pH4.0、水解时间6.0h，乳糖水解率为91.8%。在最适水解条件下，12.0%（w/v）的乳清粉，水解7.5h后，乳清粉中乳糖水解率为88.3%。将上述水解液进行薄层层析分析，结果显示水解产物主要是单糖，即葡萄糖和半乳糖，但没有水解完全，仍有残留乳糖存在。
As Kluyveromyces marxianus has the capacity to assimilate variable substrates;an extremely rapid growth rate, short generation time, thermotolerance, and a highsecretory capacity, it has been widely used in biotechnology. A lot of advantagesmake K. marxianus more suitable to produce enzymes in food industry compared toother microorganisms.
Many enzymes synthesis and gene expression in microrganisms are repressedwhen high concentration of gluose exists in the medium, and this is called glucoserepression which is a common regulation phenomenon found in microorganisms. Twomain proteins involved in glucose repression are Snf1and Mig1. When the glucoseconcentration in the medium is very low or there is no glucose in the growth medium,the Snf1complex is phosphorylated by another unknown kinase in yeast cells. In thiscase, the Snf1complex is active and can catalyze the phosphorylation of Mig1. Thephosphorylated Mig1fails in binding to the promoters of the genes repressed byglucose and is translocated to cytoplasm, leading to the active transcription of thegenes. Therefore, the Mig1protein is a central component for glucose repression inyeasts. The transcriptional repressor was found to play an important role in glucoserepression. In this study, the MIG1gene in Kluyveromyces marxianus KM wasdisrupted by integrating the HPT (hygromycin B phosphotransferase) gene into ORF(Open Reading Frame) of the MIG1gene. The disruptant (mig1) km-15obtainedcould grow in the media containing hygromycin and2-deoxy-D-glucose, respectively.β-galactosidase, inulinase and β-glucosidase production by the disruptant andexpression of their genes in the disruptant km-15were significantly enhanced. Thisconfirms that Mig1, the transcriptional repressor, indeed regulates expression of thegenes and production of the enzymes in K. marxianus km.
Then, β-galactosidase production by the mig1mutant of K. marxianus km wasoptimized and the optimal medium was whey powder10.0%(w/v), polypeptone1.0% (w/v), yeast extract1.5%(w/v), MnCl21.0mM. Under the optimal conditions, theβ-galactosidase activity of111.7U/mL was reached within48h at flask level whilethe β-galactosidase activity of121.0U/ml was achieved within60h during2-Lfermentation.99.2%of lactose in9.0%(w/v) of lactose solution was hydrolyzedwithin2.5h when the added β-galactosidase activity was440U/g of lactose whereas98.7%of lactose in12.0%of whey powder suspension was degraded within3.5hwhen the added β-galactosidase activity was440U/g of the whey powder.99.3%oflactose in milk was hydrolyzed within3.0h when the added β-galactosidase activitywas260U/g of lactose. This suggests that the β-galactosidase produced could veryefficiently hydrolyze lactose and whey lactose. The hydrolysates obatimed wereanalyzed by TLC. The results showed that only monosaccharides such as glucose andgalactose existed in the hydrolysates, indicating the lactose was almost completelyhydrolyzed and the lactase had potential applications in food industry.
At the same time, inulinase production by K. marxianus km-15was optimizedand the optimal medium was inulin8.0%(w/v), yeast extract3.0%(w/v). Under theoptimal conditions, the inulinase activity of69.0U/mL was reached within42h atflask level while the inulinase activity of79.9U/ml was achieved within60h during2-L fermentation. Over96.2%of inulin (6.0%, w/v) was hydrolyzed in the presenceof the inulinase activity of400U/g of inulin within3.0h. The hydrolysates were alsoanalyzed by TLC. The result showed that main monosaccharides with minoroligosaccharides existed in the final hydrolysates, demontrating the inulinaseproduced by K. marxianus km-15was an exo-inulinase.
The psychrotolerant yeast Guehomyces pullulans17-1isolated from seasediment in Antarctica can produce a large amount of cell-bound and extracellularβ-galactosidase, and the yeast strain grew best and produced high level ofβ-galactosidase at15°C. In order to isolate β-galactosidase overproducers of G.pullulans17-1, its cells were mutated by using nitrosoguanidine (NTG). One mutant(NTG-133) with enhanced β-galactosidase production was obtained. Afteroptimization of the medium and cultivation conditions, the mutant could produce38.0U/ml of total β-galactosidase activity within132h at the flask level while the mutant could produce48.1U/ml of total β-galactosidase activity within144h in2-Lfermentor. Over91.8%of lactose solution (9.0%, w/v) was hydrolyzed in thepresence of the β-galactosidase activity of550U/g of lactose within6.0h while over88.3%of lactose in the whey powder was hydrolyzed in the presence ofβ-galactosidase activity of550U/g of lactose within7.5h. The hydrolysates wereanalyzed by TLC. The results showed that main monosaccharides such as glucose andgalactose existed in the hydrolysates.
微生物中普遍存在葡萄糖阻遏现象，当有葡萄糖存在时，许多酶的合成和基因表达都会受到抑制。参与葡萄糖阻遏作用的主要为Snf1复合体和Mig1蛋白，当培养基中葡萄糖浓度较高时，Snf1复合体去磷酸化，Snf1复合体失去活性，这时Migl由于不能被磷酸化，进入细胞核中与受葡萄糖阻遏基因的启动子结合，使基因表达受到抑制，说明Mig1在菌株的酶合成和调控中起重要的作用。如果将编码Mig1的MIG1基因敲除，相关基因的阻遏效应解除。因而本研究通过基因敲除法阻断K. marxianus km菌株MIG1基因，然后研究该基因的敲除对该菌株酶的合成和相关基因的表达产生的影响。首先利用编码潮霉素的HPT基因的ORF替换km-15菌株的MIG1基因的ORF，在含有潮霉素的YPD平板上筛选获得了敲除菌株km-15，它能在含有2-脱氧-D-葡萄糖的乳糖培养基平板上生长，而野生型菌株km则都不能，表明敲除菌株葡萄糖阻遏作用解除。与野生型菌株km相比，敲除菌株km-15的乳糖酶、菊粉酶和β-葡萄糖苷酶的产量均有很大提高，同时编码这些酶基因的表达量也有极大提高。这表明，K. marxianus km中的Mig1确实能阻遏某些基因的表达，对一些酶的合成具有调控作用。
对敲除菌株km-15产乳糖酶培养基进行了优化，确定了最佳培养基成分为（w/v）：乳清粉10.0%、酵母粉1.5%、蛋白胨1.0%和MnCl21.0mM。在28°C、pH7.0条件下180rpm振荡培养48h，km-15菌株乳糖酶产量为111.7U/mL。经过2-L发酵罐发酵，该菌株乳糖酶产量提高到121.7U/mL。同时，确定了酶法水解乳糖的适宜条件，即乳糖浓度9.0%（w/v）、乳糖酶使用量为440U/g乳糖、40°C、pH7.0和水解时间2.5h，在这种条件下乳糖水解率为99.2%。在同样条件下，12.0%（w/v）的乳清粉经过该酶水解3.5h后，乳清粉中乳糖水解率为98.7%。调节乳糖酶使用量为260U/g乳糖添加到5.0mL牛奶中，水解3.0h后，牛奶中乳糖水解率为99.3%。将上述水解液进行薄层层析，结果显示水解产物只有单糖，即葡萄糖和半乳糖，其中的乳糖完全水解，表明该乳糖酶在食品工业中具有潜在的应用价值。
就上面所说的那样，该酵母菌还产菊粉酶。对敲除菌株km-15产菊粉酶培养基进行了优化，确定了最佳培养基成分为（w/v）：菊粉8.0%、酵母粉3.0%，在28°C、pH4.5的条件下180rpm振荡培养42h，km-15菌株菊粉酶的活力为69.0U/mL。分别以菊粉和菊芋汁作为碳源，经过2-L发酵罐发酵，发酵48h和60h后，菊粉酶活性分别为79.9U/mL和73.3U/mL。然后，确定了酶法水解菊粉的适宜条件，即菊粉浓度6.0%（w/v）、菊粉酶使用量为400U/g菊粉、50°C、pH4.5、水解时间3.0h，菊粉水解率为96.2%。将其水解产物进行薄层层析分析，水解终产物以单糖为主，仅有少许寡糖，表明km-15菌株所产菊粉酶为外切菊粉酶。
本实验室自南极海洋沉积物中分离出1株耐冷酵母Guehomyces pullulans17-1菌株在15°C可同时产胞外和与细胞结合的乳糖酶。故采用NTG对G.pullulans17-1菌株进行诱变，结合X-gal显蓝斑和发酵培养测定的选育方法，获得乳糖酶活力达24.8U/mL且遗传稳定的突变菌株NTG-133，产量比野生型菌株（13.9U/mL）提高近一倍。对突变菌株NTG-133产乳糖酶培养基进行了优化，确定了最佳培养基成分为（w/v）：乳清粉4.0%、蛋白胨1.0%、酵母粉0.5%，于15°C、pH4.5条件下，170rpm振荡培养132h，乳糖酶活达38.0U/mL。采用发酵罐发酵产酶，乳糖酶活提高到48.1U/mL。然后，确定了酶法水解乳糖的适宜条件，即乳糖浓度9.0%（w/v）、乳糖酶的使用量为550U/g乳糖、40°C、pH4.0、水解时间6.0h，乳糖水解率为91.8%。在最适水解条件下，12.0%（w/v）的乳清粉，水解7.5h后，乳清粉中乳糖水解率为88.3%。将上述水解液进行薄层层析分析，结果显示水解产物主要是单糖，即葡萄糖和半乳糖，但没有水解完全，仍有残留乳糖存在。
As Kluyveromyces marxianus has the capacity to assimilate variable substrates;an extremely rapid growth rate, short generation time, thermotolerance, and a highsecretory capacity, it has been widely used in biotechnology. A lot of advantagesmake K. marxianus more suitable to produce enzymes in food industry compared toother microorganisms.
Many enzymes synthesis and gene expression in microrganisms are repressedwhen high concentration of gluose exists in the medium, and this is called glucoserepression which is a common regulation phenomenon found in microorganisms. Twomain proteins involved in glucose repression are Snf1and Mig1. When the glucoseconcentration in the medium is very low or there is no glucose in the growth medium,the Snf1complex is phosphorylated by another unknown kinase in yeast cells. In thiscase, the Snf1complex is active and can catalyze the phosphorylation of Mig1. Thephosphorylated Mig1fails in binding to the promoters of the genes repressed byglucose and is translocated to cytoplasm, leading to the active transcription of thegenes. Therefore, the Mig1protein is a central component for glucose repression inyeasts. The transcriptional repressor was found to play an important role in glucoserepression. In this study, the MIG1gene in Kluyveromyces marxianus KM wasdisrupted by integrating the HPT (hygromycin B phosphotransferase) gene into ORF(Open Reading Frame) of the MIG1gene. The disruptant (mig1) km-15obtainedcould grow in the media containing hygromycin and2-deoxy-D-glucose, respectively.β-galactosidase, inulinase and β-glucosidase production by the disruptant andexpression of their genes in the disruptant km-15were significantly enhanced. Thisconfirms that Mig1, the transcriptional repressor, indeed regulates expression of thegenes and production of the enzymes in K. marxianus km.
Then, β-galactosidase production by the mig1mutant of K. marxianus km wasoptimized and the optimal medium was whey powder10.0%(w/v), polypeptone1.0% (w/v), yeast extract1.5%(w/v), MnCl21.0mM. Under the optimal conditions, theβ-galactosidase activity of111.7U/mL was reached within48h at flask level whilethe β-galactosidase activity of121.0U/ml was achieved within60h during2-Lfermentation.99.2%of lactose in9.0%(w/v) of lactose solution was hydrolyzedwithin2.5h when the added β-galactosidase activity was440U/g of lactose whereas98.7%of lactose in12.0%of whey powder suspension was degraded within3.5hwhen the added β-galactosidase activity was440U/g of the whey powder.99.3%oflactose in milk was hydrolyzed within3.0h when the added β-galactosidase activitywas260U/g of lactose. This suggests that the β-galactosidase produced could veryefficiently hydrolyze lactose and whey lactose. The hydrolysates obatimed wereanalyzed by TLC. The results showed that only monosaccharides such as glucose andgalactose existed in the hydrolysates, indicating the lactose was almost completelyhydrolyzed and the lactase had potential applications in food industry.
At the same time, inulinase production by K. marxianus km-15was optimizedand the optimal medium was inulin8.0%(w/v), yeast extract3.0%(w/v). Under theoptimal conditions, the inulinase activity of69.0U/mL was reached within42h atflask level while the inulinase activity of79.9U/ml was achieved within60h during2-L fermentation. Over96.2%of inulin (6.0%, w/v) was hydrolyzed in the presenceof the inulinase activity of400U/g of inulin within3.0h. The hydrolysates were alsoanalyzed by TLC. The result showed that main monosaccharides with minoroligosaccharides existed in the final hydrolysates, demontrating the inulinaseproduced by K. marxianus km-15was an exo-inulinase.
The psychrotolerant yeast Guehomyces pullulans17-1isolated from seasediment in Antarctica can produce a large amount of cell-bound and extracellularβ-galactosidase, and the yeast strain grew best and produced high level ofβ-galactosidase at15°C. In order to isolate β-galactosidase overproducers of G.pullulans17-1, its cells were mutated by using nitrosoguanidine (NTG). One mutant(NTG-133) with enhanced β-galactosidase production was obtained. Afteroptimization of the medium and cultivation conditions, the mutant could produce38.0U/ml of total β-galactosidase activity within132h at the flask level while the mutant could produce48.1U/ml of total β-galactosidase activity within144h in2-Lfermentor. Over91.8%of lactose solution (9.0%, w/v) was hydrolyzed in thepresence of the β-galactosidase activity of550U/g of lactose within6.0h while over88.3%of lactose in the whey powder was hydrolyzed in the presence ofβ-galactosidase activity of550U/g of lactose within7.5h. The hydrolysates wereanalyzed by TLC. The results showed that main monosaccharides such as glucose andgalactose existed in the hydrolysates.
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