离子液体介质双酶串联L-肉碱及其酰化物制备技术研究
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摘要
L-肉碱和酰基-L-肉碱广泛应用于食品、功能食品、化妆品及药品等领域。巴豆甜菜碱在肉碱脱水酶催化下合成L-肉碱是国内生物催化法生产L-肉碱所采用的方法。但该方法存在前体转化率低和产物分离纯化过程中底物巴豆甜菜碱不能回收利用的问题。国内酰基-L-肉碱种类较少,其脂肪酶催化合成中乙腈作为反应介质产品得率较低、酶活损失严重。针对以上问题,本论文提出以离子液体为介质的双酶串联催化工艺。
建立了巴豆甜菜碱水合反应体系中的肉碱脱水酶和L-肉碱酯化体系中的酰基-L-肉碱的检测方法。采用紫外法测定的以巴豆甜菜碱消耗量表示的肉碱脱水酶活力经拟合方程校正后与DTNB法测定的以L-肉碱生成量表示的肉碱脱水酶活力两组数据之间无显著差异。拟合方程为:y=7.286-5.45/ [1+e(x-8.746)/ 2318],x为紫外法测定的L-肉碱脱水酶酶活力,y为DTNB法测定的L-肉碱脱水酶酶活力,该方法检测限为1.87 U。采用比色法测定酰基-L-肉碱,两相显色体系的酰基-L-肉碱含量在20-130μmol范围内同显色反应吸光度成线性关系(R2 > 0.99)。加标回收率为99.53-103.33%,相对标准偏差低于4.30%,检测限为1.85μmol,该方法不受L-肉碱的干扰。
对肉碱脱水酶催化巴豆甜菜碱合成L-肉碱的反应条件进行了优化。适宜的反应条件为:温度40℃,pH7.0,巴豆甜菜碱浓度2.0%,酶添加量2.0 g/100 ml(湿重),富马酸添加量0.2%,反应时间5-8 h。Mg~(2+)降低肉碱脱水酶活力,Zn~(2+)、K~+、Cu~(2+)、Li~+、Ba~(2+)、Fe~(2+)均能提高酶活力,其中以Fe~(2+)对酶活力的提高最为明显。
对脂肪酶催化的L-肉碱酰化反应条件进行了优化。异戊酰-L-肉碱、辛酰-L-肉碱和棕榈酰-L-肉碱在[Bmim]PF_6离子液体中的酶催化酯合成,体系L-肉碱含量均为0.4 mmol,[Bmim]PF_6均为2.0 ml,均以Novozyme 435(10000 PLU/g)作为催化剂,初始水分活度均为0.22,反应温度依次为60、60和65℃,脂肪酸和L-肉碱摩尔比为4:1、5:1和5:1,脂肪酶用量为50、40和40 mg,转速为150、200和200 r/min,反应时间为60、48和48 h。以上条件下三种酰基-L-肉碱的产品得率分别达到59.61%、90.79%和98.03%。异戊酰-L-肉碱合成反应的活化能(163.08 KJ/mol)高于辛酰-L-肉碱(130.74 KJ/mol)和棕榈酰-L-肉碱(127.16 KJ/mol)。同乙腈相比较,[Bmim]PF_6离子液体作为介质具有产品得率高、酶操作稳定性好、绿色环保等特点。上述三种酰基-L-肉碱的以脂肪酸烯酯作为酰基供体的酯交换合成,适宜的反应条件为:体系L-肉碱含量均为0.4 mmol,[Bmim]PF_6均为2.0 ml,均以Novozyme 435作为催化剂,初始水分活度均为0.22,反应温度均为60℃,脂肪酸烯酯和L-肉碱摩尔比依次为6:1、3:1和3:1,脂肪酶用量为40、30和30 mg,转速为120、150和150 r/min,反应时间为48、32和32 h。以上条件下三种酰基-L-肉碱的产品得率分别达到73.61%、96.76%和98.82%。
提出了L-肉碱及其酰化物制备的双酶串联工艺:采用[Bmim]PF_6离子液体作为巴豆甜菜碱水合反应和L-肉碱酰化反应的介质,巴豆甜菜碱在肉碱脱水酶催化下转化为L-肉碱,L-肉碱又在脂肪酶催化下转化为酰基-L-肉碱,酰基-L-肉碱由叔戊醇萃取。酰基-L-肉碱可以作为终产品,也可以水解得到L-肉碱。通过5次间歇萃取,总L-肉碱摩尔产率达到87.20%。真空旋转蒸发器是目前最适宜作为双酶串联反应的反应器。双酶串联工艺提高了底物转化率、解决了产物分离和纯化的关键技术、生产出酰基-L-肉碱产品。
对酰基-L-肉碱从离子液体中分离提取的关键技术进行了研究。丙酮能使三种酰基-L-肉碱从[Bmim]PF_6离子液体中沉淀分离,需要的丙酮/[Bmim]PF_6体积比为6-7:1,沉淀时间通常需要10-14 h,产品得率90%以上,冷冻离心有助于沉淀完全并缩短沉淀时间。异戊酰-L-肉碱和辛酰-L-肉碱较适宜的萃取剂是水,二者在水—离子液体中的分配系数分别为1.35和1.16;棕榈酰-L-肉碱较适宜的萃取剂为叔戊醇,分配系数达到5.31;萃取时间均控制在15-30 min;降低温度对萃取有利;萃取操作时极易发生乳化现象,采用1000 r/min、1 min离心可消除乳化。
L-carnitine and acyl-L-carnitine are widely useful in pharmaceutical, cosmetic, and food industries at present. L-carnitine can be biosynthesized through the hydration of crotonobetaine under the action of carnitine dehydratase. However, the conversion is relatively low, and crotonobetaine can not be recoveried in the process of L-carnitine extraction and separation. Acetonitrile is by far the best reaction medium for the enzymatic synthesis of acyl-L-carnitine, but the product yield is low and the lipase activity loss is serious in acetonitrile. In adition, compared to the foreign countries, there are only a few varieties of acyl-L-carnitine in china. In order to solve these problems, the synthesis of L-carnitine and its acylate catalyzed in series by two enzymes in ionic liquid medium was studied in the paper.
The methods for determination of carnitine dehydratase and acyl-L-carnitine were established. The activity of carnitine dehydratase can be defined as the total mmols of crotonobetaine consumed per hour, or that of L-carnitine produced per hour. The former could be determined by UV. But the value (x) must be modified through curve fit by the latter, which could be accurately determined by DTNB (y). The curve fit formula was y=7.286-5.45/[1+e(x-8.746)/ 2318]. The detection limit was 1.87 U. Acyl-L-carnitine could be measured by colorimetry method. Color reaction was performed in organic solution-salt solution biphasic system. The organic solution was 1, 2-dichloroethane-isoamyl alcohol mixture (V/V=96:4) added bromophenol blue (per 100 ml added 0.05 g). The salt solution was 55% K2HPO4 aqueous solution added Na2CO3 (per 100 ml added 14 g). There was a linear relationship (R2>0.99) between OD value and acyl-L-carnitine content which range was 20-130μmol in the biphasic system. To analyze the system of L-arnitine esterification, the recovery was 99.53-103.33%, the RSD was below 4.30%, and the detection limit was 1.85μmol. The method was not disturbed by L-carnitine.
The conditions for the bioconversion of L-carnitine from crotonobetaine were optimized. The optimal reaction conditions were: 40°C of reaction temperature, pH7.0, 2.0% crotonobetaine, 2.0 g/100ml carnitine dehydratase (wet weight), 0.2% fumarate, 5-8 h of reaction time. The medal ion including Zn~(2+), K~+, Cu~(2+), Li~+, Ba~(2+) and Fe~(2+) could increase the activity of carnitine dehydratase, and all of these, Fe~(2+) was the most effective to improve the enzymatic activity. Mg~(2+) could decrease the enzymatic activity.
The conditions of lipase-catalyzed acyl-L-carnitine synthesis in ionic liquid were optimized. The optimal reaction conditions were: for isovaleryl-L-carnitine, 0.4 mmol L-carnitine, 2.0 ml [Bmim]PF_6, 50 mg Novozyme 435 (10 000 PLU/g), 0.22 a_W, 200 mg molecular sieves, 4:1 molar ratio of fatty acid and L-carnitine, 60 oC, 150 r/min and 60 h; for octanoyl-L-carnitine and palmitoyl-L-carnitine, 0.4 mmol L-carnitine, 2.0 ml [Bmim]PF_6, 40 mg Novozyme 435, 0.22 aW, 250 mg molecular sieves, 5:1 molar ratio of fatty acid and L-carnitine, 60 oC (octanoyl-L-carnitine) and 65 oC (palmitoyl-L-carnitine), 200 r/min, 48 h. Their overall yields could reach 59.14%, 90.79% and 98.03%, respectively. The activation energy of isovaleryl-L-carnitine (163.08 KJ/mol) was higher than that of octanoyl-L-carnitine (130.74 KJ/mol) and palmitoyl-L-carnitine (127.16 KJ/mol). The higher yield and operational stability were obtained in [Bmim]PF_6 than in acetonitrile. The optimal conditions for acyl-L-carnitine synthesis by transesterification were: for isovaleryl-L-carnitine, 0.4 mmol L-carnitine, 2.0 ml [Bmim]PF_6, 40 mg Novozyme 435, 0.22 aW, 6:1 molar ratio of Allylisovalerate and L-carnitine, 60oC, 120 r/min and 48 h; for octanoyl-L-carnitine and palmitoyl-L-carnitine, 0.4 mmol L-carnitine, 2.0 ml [Bmim]PF_6, 30 mg Novozyme 435, 0.22 aW, 3:1 molar ratio of fatty acid vinyl ester and L-carnitine, 60 oC, 150 r/min, 32 h. Their overall yields could reach 73.61%, 96.76% and 98.82%, respectively.
The route“synthesis of L-carnitine and its acylate catalyzed in series by two enzymes”was established. Using [Bmim]PF_6 ionic liquid as the reaction medium, L-carnitine was biosynthesized through the hydration of crotonobetaine under the action of carnitine dehydratase, which was transformed into palmitoyl-L-carnitine by lipase. Palmitoyl-L-carnitine was extracted with 2-methyl-2-butano. With the removal of L-carnitine, the biotransformation of crotonobetaine into L-carnitine was continued in the reversible hydration reaction. The molar yield of total L-carnitine could attain 87.2% after the five times intermittent extraction. Vacuum-rotary evaporator was a suitable reactor to realize the strategy. Through the route, the conversion was improved, the key technology of L-carnitine separation and extraction was solved, and acyl-L-carnitine was synthesized in the meantime.
The key technology of acyl-L-carnitine separation and extraction was studied. Acetone could precipitate the three acyl-L-carnitine from [Bmim]PF_6 ionic liquid, with 6-7:1 volume ritio of acetone and [Bmim]PF_6, and their precipitation rates could reach 90%. The centrifugation after refrigeration could lead to the complete precipitation and decrease the time of precipitation. Water could extract isovaleryl-L-carnitine and octanoyl-L-carnitine from [Bmim]PF_6. Their partition ratio between water and the ionic liquid were 1.35 and 1.16, respectively. Palmitoyl-L-carnitine could be extracted from the ionic liquid by 2-Methyl-2-butano, and partition ratio between 2-Methyl-2-butano and the ionic liquid was 5.31. The extraction time was 15-30 min. The decrease of temperature was favourable to the extraction. Emulsification easily occurred during the extraction, which could be eradicated by centrifugation at 1000 r/min for 10 min.
建立了巴豆甜菜碱水合反应体系中的肉碱脱水酶和L-肉碱酯化体系中的酰基-L-肉碱的检测方法。采用紫外法测定的以巴豆甜菜碱消耗量表示的肉碱脱水酶活力经拟合方程校正后与DTNB法测定的以L-肉碱生成量表示的肉碱脱水酶活力两组数据之间无显著差异。拟合方程为:y=7.286-5.45/ [1+e(x-8.746)/ 2318],x为紫外法测定的L-肉碱脱水酶酶活力,y为DTNB法测定的L-肉碱脱水酶酶活力,该方法检测限为1.87 U。采用比色法测定酰基-L-肉碱,两相显色体系的酰基-L-肉碱含量在20-130μmol范围内同显色反应吸光度成线性关系(R2 > 0.99)。加标回收率为99.53-103.33%,相对标准偏差低于4.30%,检测限为1.85μmol,该方法不受L-肉碱的干扰。
对肉碱脱水酶催化巴豆甜菜碱合成L-肉碱的反应条件进行了优化。适宜的反应条件为:温度40℃,pH7.0,巴豆甜菜碱浓度2.0%,酶添加量2.0 g/100 ml(湿重),富马酸添加量0.2%,反应时间5-8 h。Mg~(2+)降低肉碱脱水酶活力,Zn~(2+)、K~+、Cu~(2+)、Li~+、Ba~(2+)、Fe~(2+)均能提高酶活力,其中以Fe~(2+)对酶活力的提高最为明显。
对脂肪酶催化的L-肉碱酰化反应条件进行了优化。异戊酰-L-肉碱、辛酰-L-肉碱和棕榈酰-L-肉碱在[Bmim]PF_6离子液体中的酶催化酯合成,体系L-肉碱含量均为0.4 mmol,[Bmim]PF_6均为2.0 ml,均以Novozyme 435(10000 PLU/g)作为催化剂,初始水分活度均为0.22,反应温度依次为60、60和65℃,脂肪酸和L-肉碱摩尔比为4:1、5:1和5:1,脂肪酶用量为50、40和40 mg,转速为150、200和200 r/min,反应时间为60、48和48 h。以上条件下三种酰基-L-肉碱的产品得率分别达到59.61%、90.79%和98.03%。异戊酰-L-肉碱合成反应的活化能(163.08 KJ/mol)高于辛酰-L-肉碱(130.74 KJ/mol)和棕榈酰-L-肉碱(127.16 KJ/mol)。同乙腈相比较,[Bmim]PF_6离子液体作为介质具有产品得率高、酶操作稳定性好、绿色环保等特点。上述三种酰基-L-肉碱的以脂肪酸烯酯作为酰基供体的酯交换合成,适宜的反应条件为:体系L-肉碱含量均为0.4 mmol,[Bmim]PF_6均为2.0 ml,均以Novozyme 435作为催化剂,初始水分活度均为0.22,反应温度均为60℃,脂肪酸烯酯和L-肉碱摩尔比依次为6:1、3:1和3:1,脂肪酶用量为40、30和30 mg,转速为120、150和150 r/min,反应时间为48、32和32 h。以上条件下三种酰基-L-肉碱的产品得率分别达到73.61%、96.76%和98.82%。
提出了L-肉碱及其酰化物制备的双酶串联工艺:采用[Bmim]PF_6离子液体作为巴豆甜菜碱水合反应和L-肉碱酰化反应的介质,巴豆甜菜碱在肉碱脱水酶催化下转化为L-肉碱,L-肉碱又在脂肪酶催化下转化为酰基-L-肉碱,酰基-L-肉碱由叔戊醇萃取。酰基-L-肉碱可以作为终产品,也可以水解得到L-肉碱。通过5次间歇萃取,总L-肉碱摩尔产率达到87.20%。真空旋转蒸发器是目前最适宜作为双酶串联反应的反应器。双酶串联工艺提高了底物转化率、解决了产物分离和纯化的关键技术、生产出酰基-L-肉碱产品。
对酰基-L-肉碱从离子液体中分离提取的关键技术进行了研究。丙酮能使三种酰基-L-肉碱从[Bmim]PF_6离子液体中沉淀分离,需要的丙酮/[Bmim]PF_6体积比为6-7:1,沉淀时间通常需要10-14 h,产品得率90%以上,冷冻离心有助于沉淀完全并缩短沉淀时间。异戊酰-L-肉碱和辛酰-L-肉碱较适宜的萃取剂是水,二者在水—离子液体中的分配系数分别为1.35和1.16;棕榈酰-L-肉碱较适宜的萃取剂为叔戊醇,分配系数达到5.31;萃取时间均控制在15-30 min;降低温度对萃取有利;萃取操作时极易发生乳化现象,采用1000 r/min、1 min离心可消除乳化。
L-carnitine and acyl-L-carnitine are widely useful in pharmaceutical, cosmetic, and food industries at present. L-carnitine can be biosynthesized through the hydration of crotonobetaine under the action of carnitine dehydratase. However, the conversion is relatively low, and crotonobetaine can not be recoveried in the process of L-carnitine extraction and separation. Acetonitrile is by far the best reaction medium for the enzymatic synthesis of acyl-L-carnitine, but the product yield is low and the lipase activity loss is serious in acetonitrile. In adition, compared to the foreign countries, there are only a few varieties of acyl-L-carnitine in china. In order to solve these problems, the synthesis of L-carnitine and its acylate catalyzed in series by two enzymes in ionic liquid medium was studied in the paper.
The methods for determination of carnitine dehydratase and acyl-L-carnitine were established. The activity of carnitine dehydratase can be defined as the total mmols of crotonobetaine consumed per hour, or that of L-carnitine produced per hour. The former could be determined by UV. But the value (x) must be modified through curve fit by the latter, which could be accurately determined by DTNB (y). The curve fit formula was y=7.286-5.45/[1+e(x-8.746)/ 2318]. The detection limit was 1.87 U. Acyl-L-carnitine could be measured by colorimetry method. Color reaction was performed in organic solution-salt solution biphasic system. The organic solution was 1, 2-dichloroethane-isoamyl alcohol mixture (V/V=96:4) added bromophenol blue (per 100 ml added 0.05 g). The salt solution was 55% K2HPO4 aqueous solution added Na2CO3 (per 100 ml added 14 g). There was a linear relationship (R2>0.99) between OD value and acyl-L-carnitine content which range was 20-130μmol in the biphasic system. To analyze the system of L-arnitine esterification, the recovery was 99.53-103.33%, the RSD was below 4.30%, and the detection limit was 1.85μmol. The method was not disturbed by L-carnitine.
The conditions for the bioconversion of L-carnitine from crotonobetaine were optimized. The optimal reaction conditions were: 40°C of reaction temperature, pH7.0, 2.0% crotonobetaine, 2.0 g/100ml carnitine dehydratase (wet weight), 0.2% fumarate, 5-8 h of reaction time. The medal ion including Zn~(2+), K~+, Cu~(2+), Li~+, Ba~(2+) and Fe~(2+) could increase the activity of carnitine dehydratase, and all of these, Fe~(2+) was the most effective to improve the enzymatic activity. Mg~(2+) could decrease the enzymatic activity.
The conditions of lipase-catalyzed acyl-L-carnitine synthesis in ionic liquid were optimized. The optimal reaction conditions were: for isovaleryl-L-carnitine, 0.4 mmol L-carnitine, 2.0 ml [Bmim]PF_6, 50 mg Novozyme 435 (10 000 PLU/g), 0.22 a_W, 200 mg molecular sieves, 4:1 molar ratio of fatty acid and L-carnitine, 60 oC, 150 r/min and 60 h; for octanoyl-L-carnitine and palmitoyl-L-carnitine, 0.4 mmol L-carnitine, 2.0 ml [Bmim]PF_6, 40 mg Novozyme 435, 0.22 aW, 250 mg molecular sieves, 5:1 molar ratio of fatty acid and L-carnitine, 60 oC (octanoyl-L-carnitine) and 65 oC (palmitoyl-L-carnitine), 200 r/min, 48 h. Their overall yields could reach 59.14%, 90.79% and 98.03%, respectively. The activation energy of isovaleryl-L-carnitine (163.08 KJ/mol) was higher than that of octanoyl-L-carnitine (130.74 KJ/mol) and palmitoyl-L-carnitine (127.16 KJ/mol). The higher yield and operational stability were obtained in [Bmim]PF_6 than in acetonitrile. The optimal conditions for acyl-L-carnitine synthesis by transesterification were: for isovaleryl-L-carnitine, 0.4 mmol L-carnitine, 2.0 ml [Bmim]PF_6, 40 mg Novozyme 435, 0.22 aW, 6:1 molar ratio of Allylisovalerate and L-carnitine, 60oC, 120 r/min and 48 h; for octanoyl-L-carnitine and palmitoyl-L-carnitine, 0.4 mmol L-carnitine, 2.0 ml [Bmim]PF_6, 30 mg Novozyme 435, 0.22 aW, 3:1 molar ratio of fatty acid vinyl ester and L-carnitine, 60 oC, 150 r/min, 32 h. Their overall yields could reach 73.61%, 96.76% and 98.82%, respectively.
The route“synthesis of L-carnitine and its acylate catalyzed in series by two enzymes”was established. Using [Bmim]PF_6 ionic liquid as the reaction medium, L-carnitine was biosynthesized through the hydration of crotonobetaine under the action of carnitine dehydratase, which was transformed into palmitoyl-L-carnitine by lipase. Palmitoyl-L-carnitine was extracted with 2-methyl-2-butano. With the removal of L-carnitine, the biotransformation of crotonobetaine into L-carnitine was continued in the reversible hydration reaction. The molar yield of total L-carnitine could attain 87.2% after the five times intermittent extraction. Vacuum-rotary evaporator was a suitable reactor to realize the strategy. Through the route, the conversion was improved, the key technology of L-carnitine separation and extraction was solved, and acyl-L-carnitine was synthesized in the meantime.
The key technology of acyl-L-carnitine separation and extraction was studied. Acetone could precipitate the three acyl-L-carnitine from [Bmim]PF_6 ionic liquid, with 6-7:1 volume ritio of acetone and [Bmim]PF_6, and their precipitation rates could reach 90%. The centrifugation after refrigeration could lead to the complete precipitation and decrease the time of precipitation. Water could extract isovaleryl-L-carnitine and octanoyl-L-carnitine from [Bmim]PF_6. Their partition ratio between water and the ionic liquid were 1.35 and 1.16, respectively. Palmitoyl-L-carnitine could be extracted from the ionic liquid by 2-Methyl-2-butano, and partition ratio between 2-Methyl-2-butano and the ionic liquid was 5.31. The extraction time was 15-30 min. The decrease of temperature was favourable to the extraction. Emulsification easily occurred during the extraction, which could be eradicated by centrifugation at 1000 r/min for 10 min.
引文
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