催化抗体制备及其用于选择性水解和不对称还原反应的研究
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摘要
催化抗体,也称抗体酶,是一类具有催化活性的免疫球蛋白。它兼具抗体的高度选择性和酶的高效催化性。催化抗体的研究和开发预示着生物催化剂可以通过人工设计与制备,由此开辟了一个崭新的模拟酶的研究方向,也成为生物催化和生物催化剂的一个新的研究领域,无论是在理论探索还是实践应用方面都具有极其广阔的前景,尤其在医学、生物学、制药学等学科中将产生重要的影响。催化抗体是多学科研究的交汇点,涉及了化学、生物学、生物技术、有机生物和药物研究等领域。催化抗体的优化设计和制备以及催化抗体的酶学性质和反应规律等是在发展催化抗体技术中的几个关键问题,需要深入探究。本文的主要目的就是要运用分子设计和制备手段来制得特定的催化抗体,为制备手性药物和手性药物中间体服务,重点考虑在非水介质中的应用研究。本文完成的主要工作如下:
催化布洛芬甲酯选择性水解的催化抗体设计和制备。通过对布洛芬甲酯水解的机理分析,根据过渡态理论设计和合成了四面体含磷和含硫半抗原作为半抗原,并与牛血清蛋白(BSA)偶联制备成免疫源,经免疫和克隆成功筛选出具有催化加速选择性水解生成S-布洛芬的特异性催化抗体,其k_(cat)/k_(uncat)达到了1.6×10~4。通过对所筛选的催化抗体的酶学性质和反应性的考察,得到了催化抗体的最适pH和温度范围,分别为7.0～8.0和30～40℃。在对其热稳定性的考察中发现,催化抗体对热很敏感,超过55℃其催化活性基本消失。通过对催化抗体催化布洛芬甲酯的选择性反应动力学分析,建立了动力学方程。结果显示,尽管催化抗体与酶在形成的中间态不一样,但催化反应同样符合Michaelis-Menten的动力学规律,并拟合得到了动力学参数K_m为28.31μmol·l~(-1),k_(cat)为1.01 s~(-1)。
W/O型微乳液体系中催化抗体催化布洛芬甲酯选择性水解:探索了催化抗体在W/O型微乳液体系中的酶学性质,结果表明,催化抗体在W/O型微乳中保持着催化能力。影响催化抗体催化的反应初速度的最佳w_o(体系中水和琥珀酸二辛酯磺酸钠(AOT)的摩尔比)为21,较适合的pH和温度为8.0和30～40℃。在分析了水不溶性的底物在微乳胶束体系内的物质分配和表面活性剂影响的基础上,对催化抗体作为催化剂在W/O型微乳液介质中的反应的动力学进行了探索研究,从理论上得到了在胶束体系中V_(max)和k_(cat)~(app)不变,而(?)较水相反应的K_m有所增加。实验结果较好地验证了这个结论。在本研究的微乳体系中,表面活性剂对催化抗体的活性抑制为竞争性抑制,其K_i为1.5×10~(-3)mol·l~(-1)。
共溶剂体系中催化抗体的催化消旋布洛芬甲酯的选择性水解反应:首次把由催化抗体催化消旋布洛芬甲酯的选择性水解反应用到共溶剂体系中。基于产物的转化率和对映选择性,考察了9种与水共溶的溶剂,建立了以N,N-二甲基甲酰胺为添加的共溶剂,加量为6%(v/v)和缓冲液组成的共溶剂体系。利用建立的共溶剂体系中溶剂疏水作用和底物及产物的良好分散作用,促进了反应的进程,在保持良好的对映选择性(ee>99%)基础上,有效地提高了转化率,使之达到了41.7%。通过考察催化抗体在共溶剂体系中动力学参数,说明了单相共溶剂体系对催化抗体的催化转化率的提高有着积极的作用。
脂包衣的催化抗体在单相共溶剂体系中催化布洛芬甲酯的选择性水解:以催化活性为指标,得到了N,N-二甲基甲酰胺20%(v/v)和磷酸缓冲溶液组成的单相共溶剂反应体系。考察了用脂包衣催化抗体和脂包衣脂肪酶催化选择性水解布洛芬甲酯的实验。得到了最佳反应温度和pH值的范围分别是脂包衣催化抗体反应条件35～40℃和7.5～8.5,脂包衣脂肪酶的最适反应条件为:pH值为7.5,温度为40℃。在最适的反应条件下,用脂包衣的脂肪酶催化选择性水解拆分得到了S-布洛芬的最大转化率可达46.3%,对映选择率达241。脂包衣催化抗体的最大转化率可达44.5%,对映选择率>500。同时考察了脂包衣催化抗体和脂包衣脂肪酶的催化选择性水解的动力学,结果符合米氏动力学方程。其中V_(max)为0.56mmol·min~(-1)·g~(-1),K_(cat)为5.7min~(-1),比在水相和6%DMF加量的单相共溶剂体系催化水平明显有所提高。在脂包衣脂肪酶(250 mg/ml),DMF 20%(v/v),40℃,pH=7.5条件下,脂包衣脂肪酶催化布洛芬甲酯的选择性水解符合米氏方程。结果表明,脂包衣脂肪酶的K_m只有没有包衣的天然酶的K_m的一半,V_(max)是未包衣的酶的1.4倍左右。脂包衣催化抗体在单相共溶剂体系中和在缓冲液中的失活动力学符合一级失活动力学模型,其失活反应方程为:(?),在缓冲液中的失活反应方程为:(?)。
催化抗体催化3-氯苯丙酮还原制备3-氯-苯丙醇:在分析了3-氯-苯丙酮不对称还原反应机理的基础上,根据半抗原设计的诱导和转换设计的原理,设计和合成了N-氧化物作为反应过渡态类似物作为半抗原,免疫并克隆化后筛选分离得到了一株能立体选择性催化3-氯-苯丙酮还原生成(S)-3-氯-苯丙醇的单克隆抗体。催化反应得到的ee值和转化率分别为96.2%和83.2%。通过对催化抗体催化3-氯-苯丙酮的不对称还原动力学过程的研究,得到其过程符合有序序列BiBi机制,经多步回归和计算得到了其速度方程:动力学方程与实验值较为符合。
总之,本文围绕着催化选择性水解和不对称羰基还原的反应规律设计和制备了特异性催化抗体,考察了催化抗体在水介质和一些非水介质中的催化的酶学性质和反应性,并探索了各自的催化机理和动力学性质,实现了从催化抗体的设计与制备到反应性能考察的完整过程,为今后进一步深入研究催化抗体及其相关催化反应和作用机理奠定了一定的基础。
Catalytic antibody, abzyme, is an immunoglobulin that provided with catalytic activities ofcatalyzing a chemical reaction similarly to enzymes and highly selectivity similar to antibody. It is anewly developed research area derived from chemistry and biology. The development of catalyticantibody indicates that the preparation of man-made enzyme with highly effective multiple functionscatalyssis by rational design is possible. These work gave rise to a new area of investigation ofmimic enzyme and new domain of catalyst. It is great value both in theoretical and practical sciencesuch as medical science and chemistry and biology and pharmaceutics and so on. How to design andprepare catalytic antibodies and the enzymological properties and catalysis properties of the catalyticantibodies applied in non-aqueous medium are one of important things for catalytic antibodiesapplication. In this research, the special catalytic antibodies which were application in resolution ofchirle drug, ibuprofen, and selective reduction to prepare chirle pharmacuetical intermediate,(S)-3-chloro-1-phenyl- propanol, were generated from synthetic haptens that designed for thesereactions. Some reaction systems and media were investigated in detail, and emphasis was given tomicroemulsion, cosolvent systems. This study mainly includes the following contents:
Firstly, based on the hydrolysis reaction mechanism, the two sulphate haptens and twophosphate haptens were designed and synthetized. These haptens was similar as TSA in structureand electric properties. In the space, they all has the tetrahedron structure. A catalytic antibody whichaccelerates the rate of enantioselective hydrolysis of ibuprofen methyl ester was successfully elicitedagainst an immunogen which was these haptens attached to bovine serum albumin (BSA). The rateconstant enhancement factor k_(cat)/k_(uncat) is about 1.6×10~4. As a result, the catalytic antibody canacceleratory catalysis S-ibuprofen methyl ester but R-ibuprofen methyl ester. The most active is atabout pH 7.0～8.0 and temperature 30～40℃. In the result of thermostable test, the catalyticantibody is very sensitive in hot. The catalytic activity almost lost at 55℃. The reaction kineticsequation was established according to the selective hydrolysis of ibuprofen methyl ester catalysed bythe catalytic antibody. The results shows that the kinetics conform to the Michaelis-Menten kineticequation. The values of k_(cat) and K_m obtained from the empirical data by the least squares method fitting analysis were 1.01 s~(-1) and 28.31μmol·l~(-1), respectively.
Secondly, catalytic antibody catalyzed enantioselective hydrolysis of ibuprofen ester in W/Omicroemulsion was studied. The experiments reveal that the catalytic antibodies retains theircatalytic function after their entrapment in AOT/isooctane microemulsion. The enantioselctivity wastotal for S-enantioer of ibuprofen in this work. Optimal antibody activity was observed at a w_o valueof 21. Temperature effect, pH profile was determined. The optima temperature and pH are 30～40℃and 8.0 respectively. Kinetic analysis of the catalytic antibody catalyzed reaction was found to bepossible in this system. Kinetic studies showed that the hydrolysis in microemulsion systemfollowed Michaelis-Menten kinetics. Base on the analysis of partition of insoluble substrate indifferent phases in microemulsion, the results deduced theoretically reveal that parameters V_(max) andk_(cat)~(app) aqueous but K_m was increased. The experimental results were confirmed thisconclusion well. The catalytic active influence of surfactant in this system is the competitiveinhibition, the K_i is 1.5×10~(-3) mol·l~(-1).
Thirdly, the catalytic activity of the catalytic antibody in the water-miscible organic-solventsystem composed of a buffer solution and N, N-dimethylformamide (DMF) was studied. With 6%DMF in the buffer solution (containing catalytic antibody 0.25μmol, 0.2 M phosphate buffer, pH 8)at 37℃for 10 h, a good conversion (41.7%) and high enantiomeric excess (>99%) could bereached. The kinetic analysis of the catalytic antibody-catalyzed reaction showed that the hydrolysisin the water-miscible organic-solvent system with DMF in buffer solution followed theMichaelis-Menten kinetics.
Fourthly, the catalytic activity of enantioselective hydrolysis of ibuprofen methyl ester bycatalytic antibodies and the Candida cylindrucea lipase coated with didodecylN-D-glucono-L-glutamate in the water-miscible organic-solvent system composed of buffersolution and DMF was studied. The main variables affecting the resolution reaction by thelipid-coated catalytic antibody and lipid-coated lipase were optimized, including organic solvent,temperature, pH and so on. The optimal pH and temperature for lipid-coated catalytic antibodieswere 7.5～8.5 and 35～40℃. Under this condition, the total conversion rate and the enantiomericratio could reach 44.5% and >500, respectively. The optimal pH and temperature for lipase-coated lipid were 7.5 and 40℃. Under this conditions, the total conversion rate and the enantiomeric ratiocould reach 46.3% and 241 respectively. The kinetic results showed that the hydrolysis in thewater-miscible organic-solvent system followed Michaelis-Menten kinetics. The catalytic rateconstant (k_(cat)) and V_(max) of the lipid-coated catalytic antibodies were 5.7 min~(-1) and 0.56mmol·min~(-1)·g~(-1). The Micheaelis contant (K_m) of the lipid-coated lipase was only half that of thenative lipase while the maximum velocity (V_(max)) was 1.4 times higher. The deactivationkinetics of lipid-coated catalytic antibodies in the water-miscible organic-solvent system and inaqueous phase were studied. Two deactivation kinetics deduced and fitted by experimental datawere consistent with first kinetic model. The deactivation kinetic equation were(?) ( in the water-miscible organic-solvent system) and(?) (in aqueous phase).
Fifthly, based on analysis of the asymmetric reduction mechanism of3-chloropropiophenone to (S)-3-Chloro-1-phenylpropanol, the N-oxide hapten as TSA wasdesigned and synthesized. A catalytic antibody was successfully elicited against an immunogenwhich was this hapten attached to bovine serum albumin (BSA). A high enantiomeric excess(96.2%) and conversion (83.2%) of (S)-3-chloro-1-phenylpropanol can be achieved byasymmetric reduction of 3-chloropropiophenone using the catalytic antibodies.The catalytickinetics was investigated. The result indicated that the reaction is consistent withreaction-in-sequence mechanism. The kinetic model was:
The model simulating curves were in good agreement with the experimental data.
In a word, the preparation, characterization and application of catalytic antibodies werecarried out in this thesis. Some important information was obtained and the differentmechanism in microemulsion and the water-miscible organic-solvent system etc. was discussed,which would certainly be useful for the application of catalytic antibodies.
催化布洛芬甲酯选择性水解的催化抗体设计和制备。通过对布洛芬甲酯水解的机理分析,根据过渡态理论设计和合成了四面体含磷和含硫半抗原作为半抗原,并与牛血清蛋白(BSA)偶联制备成免疫源,经免疫和克隆成功筛选出具有催化加速选择性水解生成S-布洛芬的特异性催化抗体,其k_(cat)/k_(uncat)达到了1.6×10~4。通过对所筛选的催化抗体的酶学性质和反应性的考察,得到了催化抗体的最适pH和温度范围,分别为7.0～8.0和30～40℃。在对其热稳定性的考察中发现,催化抗体对热很敏感,超过55℃其催化活性基本消失。通过对催化抗体催化布洛芬甲酯的选择性反应动力学分析,建立了动力学方程。结果显示,尽管催化抗体与酶在形成的中间态不一样,但催化反应同样符合Michaelis-Menten的动力学规律,并拟合得到了动力学参数K_m为28.31μmol·l~(-1),k_(cat)为1.01 s~(-1)。
W/O型微乳液体系中催化抗体催化布洛芬甲酯选择性水解:探索了催化抗体在W/O型微乳液体系中的酶学性质,结果表明,催化抗体在W/O型微乳中保持着催化能力。影响催化抗体催化的反应初速度的最佳w_o(体系中水和琥珀酸二辛酯磺酸钠(AOT)的摩尔比)为21,较适合的pH和温度为8.0和30～40℃。在分析了水不溶性的底物在微乳胶束体系内的物质分配和表面活性剂影响的基础上,对催化抗体作为催化剂在W/O型微乳液介质中的反应的动力学进行了探索研究,从理论上得到了在胶束体系中V_(max)和k_(cat)~(app)不变,而(?)较水相反应的K_m有所增加。实验结果较好地验证了这个结论。在本研究的微乳体系中,表面活性剂对催化抗体的活性抑制为竞争性抑制,其K_i为1.5×10~(-3)mol·l~(-1)。
共溶剂体系中催化抗体的催化消旋布洛芬甲酯的选择性水解反应:首次把由催化抗体催化消旋布洛芬甲酯的选择性水解反应用到共溶剂体系中。基于产物的转化率和对映选择性,考察了9种与水共溶的溶剂,建立了以N,N-二甲基甲酰胺为添加的共溶剂,加量为6%(v/v)和缓冲液组成的共溶剂体系。利用建立的共溶剂体系中溶剂疏水作用和底物及产物的良好分散作用,促进了反应的进程,在保持良好的对映选择性(ee>99%)基础上,有效地提高了转化率,使之达到了41.7%。通过考察催化抗体在共溶剂体系中动力学参数,说明了单相共溶剂体系对催化抗体的催化转化率的提高有着积极的作用。
脂包衣的催化抗体在单相共溶剂体系中催化布洛芬甲酯的选择性水解:以催化活性为指标,得到了N,N-二甲基甲酰胺20%(v/v)和磷酸缓冲溶液组成的单相共溶剂反应体系。考察了用脂包衣催化抗体和脂包衣脂肪酶催化选择性水解布洛芬甲酯的实验。得到了最佳反应温度和pH值的范围分别是脂包衣催化抗体反应条件35～40℃和7.5～8.5,脂包衣脂肪酶的最适反应条件为:pH值为7.5,温度为40℃。在最适的反应条件下,用脂包衣的脂肪酶催化选择性水解拆分得到了S-布洛芬的最大转化率可达46.3%,对映选择率达241。脂包衣催化抗体的最大转化率可达44.5%,对映选择率>500。同时考察了脂包衣催化抗体和脂包衣脂肪酶的催化选择性水解的动力学,结果符合米氏动力学方程。其中V_(max)为0.56mmol·min~(-1)·g~(-1),K_(cat)为5.7min~(-1),比在水相和6%DMF加量的单相共溶剂体系催化水平明显有所提高。在脂包衣脂肪酶(250 mg/ml),DMF 20%(v/v),40℃,pH=7.5条件下,脂包衣脂肪酶催化布洛芬甲酯的选择性水解符合米氏方程。结果表明,脂包衣脂肪酶的K_m只有没有包衣的天然酶的K_m的一半,V_(max)是未包衣的酶的1.4倍左右。脂包衣催化抗体在单相共溶剂体系中和在缓冲液中的失活动力学符合一级失活动力学模型,其失活反应方程为:(?),在缓冲液中的失活反应方程为:(?)。
催化抗体催化3-氯苯丙酮还原制备3-氯-苯丙醇:在分析了3-氯-苯丙酮不对称还原反应机理的基础上,根据半抗原设计的诱导和转换设计的原理,设计和合成了N-氧化物作为反应过渡态类似物作为半抗原,免疫并克隆化后筛选分离得到了一株能立体选择性催化3-氯-苯丙酮还原生成(S)-3-氯-苯丙醇的单克隆抗体。催化反应得到的ee值和转化率分别为96.2%和83.2%。通过对催化抗体催化3-氯-苯丙酮的不对称还原动力学过程的研究,得到其过程符合有序序列BiBi机制,经多步回归和计算得到了其速度方程:动力学方程与实验值较为符合。
总之,本文围绕着催化选择性水解和不对称羰基还原的反应规律设计和制备了特异性催化抗体,考察了催化抗体在水介质和一些非水介质中的催化的酶学性质和反应性,并探索了各自的催化机理和动力学性质,实现了从催化抗体的设计与制备到反应性能考察的完整过程,为今后进一步深入研究催化抗体及其相关催化反应和作用机理奠定了一定的基础。
Catalytic antibody, abzyme, is an immunoglobulin that provided with catalytic activities ofcatalyzing a chemical reaction similarly to enzymes and highly selectivity similar to antibody. It is anewly developed research area derived from chemistry and biology. The development of catalyticantibody indicates that the preparation of man-made enzyme with highly effective multiple functionscatalyssis by rational design is possible. These work gave rise to a new area of investigation ofmimic enzyme and new domain of catalyst. It is great value both in theoretical and practical sciencesuch as medical science and chemistry and biology and pharmaceutics and so on. How to design andprepare catalytic antibodies and the enzymological properties and catalysis properties of the catalyticantibodies applied in non-aqueous medium are one of important things for catalytic antibodiesapplication. In this research, the special catalytic antibodies which were application in resolution ofchirle drug, ibuprofen, and selective reduction to prepare chirle pharmacuetical intermediate,(S)-3-chloro-1-phenyl- propanol, were generated from synthetic haptens that designed for thesereactions. Some reaction systems and media were investigated in detail, and emphasis was given tomicroemulsion, cosolvent systems. This study mainly includes the following contents:
Firstly, based on the hydrolysis reaction mechanism, the two sulphate haptens and twophosphate haptens were designed and synthetized. These haptens was similar as TSA in structureand electric properties. In the space, they all has the tetrahedron structure. A catalytic antibody whichaccelerates the rate of enantioselective hydrolysis of ibuprofen methyl ester was successfully elicitedagainst an immunogen which was these haptens attached to bovine serum albumin (BSA). The rateconstant enhancement factor k_(cat)/k_(uncat) is about 1.6×10~4. As a result, the catalytic antibody canacceleratory catalysis S-ibuprofen methyl ester but R-ibuprofen methyl ester. The most active is atabout pH 7.0～8.0 and temperature 30～40℃. In the result of thermostable test, the catalyticantibody is very sensitive in hot. The catalytic activity almost lost at 55℃. The reaction kineticsequation was established according to the selective hydrolysis of ibuprofen methyl ester catalysed bythe catalytic antibody. The results shows that the kinetics conform to the Michaelis-Menten kineticequation. The values of k_(cat) and K_m obtained from the empirical data by the least squares method fitting analysis were 1.01 s~(-1) and 28.31μmol·l~(-1), respectively.
Secondly, catalytic antibody catalyzed enantioselective hydrolysis of ibuprofen ester in W/Omicroemulsion was studied. The experiments reveal that the catalytic antibodies retains theircatalytic function after their entrapment in AOT/isooctane microemulsion. The enantioselctivity wastotal for S-enantioer of ibuprofen in this work. Optimal antibody activity was observed at a w_o valueof 21. Temperature effect, pH profile was determined. The optima temperature and pH are 30～40℃and 8.0 respectively. Kinetic analysis of the catalytic antibody catalyzed reaction was found to bepossible in this system. Kinetic studies showed that the hydrolysis in microemulsion systemfollowed Michaelis-Menten kinetics. Base on the analysis of partition of insoluble substrate indifferent phases in microemulsion, the results deduced theoretically reveal that parameters V_(max) andk_(cat)~(app) aqueous but K_m was increased. The experimental results were confirmed thisconclusion well. The catalytic active influence of surfactant in this system is the competitiveinhibition, the K_i is 1.5×10~(-3) mol·l~(-1).
Thirdly, the catalytic activity of the catalytic antibody in the water-miscible organic-solventsystem composed of a buffer solution and N, N-dimethylformamide (DMF) was studied. With 6%DMF in the buffer solution (containing catalytic antibody 0.25μmol, 0.2 M phosphate buffer, pH 8)at 37℃for 10 h, a good conversion (41.7%) and high enantiomeric excess (>99%) could bereached. The kinetic analysis of the catalytic antibody-catalyzed reaction showed that the hydrolysisin the water-miscible organic-solvent system with DMF in buffer solution followed theMichaelis-Menten kinetics.
Fourthly, the catalytic activity of enantioselective hydrolysis of ibuprofen methyl ester bycatalytic antibodies and the Candida cylindrucea lipase coated with didodecylN-D-glucono-L-glutamate in the water-miscible organic-solvent system composed of buffersolution and DMF was studied. The main variables affecting the resolution reaction by thelipid-coated catalytic antibody and lipid-coated lipase were optimized, including organic solvent,temperature, pH and so on. The optimal pH and temperature for lipid-coated catalytic antibodieswere 7.5～8.5 and 35～40℃. Under this condition, the total conversion rate and the enantiomericratio could reach 44.5% and >500, respectively. The optimal pH and temperature for lipase-coated lipid were 7.5 and 40℃. Under this conditions, the total conversion rate and the enantiomeric ratiocould reach 46.3% and 241 respectively. The kinetic results showed that the hydrolysis in thewater-miscible organic-solvent system followed Michaelis-Menten kinetics. The catalytic rateconstant (k_(cat)) and V_(max) of the lipid-coated catalytic antibodies were 5.7 min~(-1) and 0.56mmol·min~(-1)·g~(-1). The Micheaelis contant (K_m) of the lipid-coated lipase was only half that of thenative lipase while the maximum velocity (V_(max)) was 1.4 times higher. The deactivationkinetics of lipid-coated catalytic antibodies in the water-miscible organic-solvent system and inaqueous phase were studied. Two deactivation kinetics deduced and fitted by experimental datawere consistent with first kinetic model. The deactivation kinetic equation were(?) ( in the water-miscible organic-solvent system) and(?) (in aqueous phase).
Fifthly, based on analysis of the asymmetric reduction mechanism of3-chloropropiophenone to (S)-3-Chloro-1-phenylpropanol, the N-oxide hapten as TSA wasdesigned and synthesized. A catalytic antibody was successfully elicited against an immunogenwhich was this hapten attached to bovine serum albumin (BSA). A high enantiomeric excess(96.2%) and conversion (83.2%) of (S)-3-chloro-1-phenylpropanol can be achieved byasymmetric reduction of 3-chloropropiophenone using the catalytic antibodies.The catalytickinetics was investigated. The result indicated that the reaction is consistent withreaction-in-sequence mechanism. The kinetic model was:
The model simulating curves were in good agreement with the experimental data.
In a word, the preparation, characterization and application of catalytic antibodies werecarried out in this thesis. Some important information was obtained and the differentmechanism in microemulsion and the water-miscible organic-solvent system etc. was discussed,which would certainly be useful for the application of catalytic antibodies.
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