生物催化合成α-氨基酸和手性胺医药中间体研究
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摘要
生物催化是高效的温和催化体系,具有优良的化学选择性、区域选择性和立体选择性。尤其近年来,基因组学、蛋白质组学等生物技术的飞速发展,大大推动了生物催化的基础和应用研究。目前,利用生物体系(如各种细胞和酶)作为催化剂催化合成手性化合物己成为有机合成化学的研究热点以及生物有机化学和生物技术研究的新生长点。本论文采用生物催化方法制备一些重要生理活性的手性化合物,以谷氨酰转移酶、天冬氨酸转氨酶、亮氨酸脱氢酶和甲酸脱氢酶为研究对象,结合酶的特性,在天然底物研究的基础上,选择一些非正常底物进行酶催化研究,并通过这些研究揭示酶-底物的催化机制。本论文为高效高选择性合成这些手性化合物提供了新方法,并为它们的进一步研究奠定了基础。
为了能够使γ-谷氨酰转移酶催化合成重要的γ-谷氨酰化合物,对酶催化机制进行了研究。制备了十个γ-谷氨酰苯胺类似物,以它们为γ-谷氨酰基供体,乙胺为Y-谷氨酰基受体,经酶催化合成茶氨酸,通过HPLC测定茶氨酸生成量来评价酶活性。以L-γ-谷氨酰对硝基苯胺为底物,对酶转化条件如pH、温度、底物摩尔比等进行优化。在最优转化条件下,分别酶催化十个γ-谷氨酰苯胺类似物形成茶氨酸,测定这些酶转化反应动力学常数,并转换成Hammett方程,结合Hammett曲线表明,γ-谷氨酰转移酶限速酰化反应步骤的反应速度能被吸电子或供电子取代基取代的Y-谷氨酰苯胺类似物加速,此步酰化反应受到动力学酸催化,通过autodock计算模拟,Asp-433羧基或者Tyr-444酚羟基可能是此酸质子来源,此酸质子的进一步确定还需通过实施定点突变。
采用γ-谷氨酰转移酶催化合成β-N-(γ-L(+)-谷氨酰)苯肼以及β-N-(γ-L(+)-谷氨酰)对羧基苯肼。合成谷氨酰苯肼最佳反应条件为：配制pH9的转化液,底物浓度为60mM L-谷氨酰胺,300mM苯肼,加入40Uγ,-谷氨酰转移酶/ml,37℃反应6h,底物转化率高达93%；蘑菇氨酸的合成前体,谷氨酰对羧基苯肼最佳反应条件为：50mM L-谷氨酰胺,500mM对羧基苯肼,40U γ-谷氨酰转移酶/ml,pH8、37℃反应24h,产物转化率达90%。虽然苯肼曾被报道为泪腺过氧化酶的自杀性抑制剂,但是苯肼只有在高于300mM浓度时才会可逆性抑制谷氨酰转移酶,而对羧基苯肼即使在1000mM也不会出现抑制现象。这种新的谷氨酰转移酶催化合成方法将有助于合成蘑菇氨酸等重要的谷氨酰化合物,并进一步促进它们的深入研究。
光学纯手性胺是一类有重要价值的医药及精细化工中间体,对手性胺类化合物的不对称合成进行更深层次研究具有较大的经济效益和应用价值。目前手性胺的主要制备方法有化学合成、化学及酶法拆分以及酶催化合成,其中酶催化合成更具有优势。本论文以天冬氨酸转氨酶、联用亮氨酸脱氢酶和甲酸脱氢酶催化合成手性胺及氨基酸。为了更好地了解这些酶的特性,化学合成了8个α-酮酸,天冬氨酸转氨酶对苯丙酮酸钠和邻甲氧基苯丙酮酸钠的转化率较高,邻羟基苯丙酮酸钠和对二甲氨基苯丙酮酸钠的活性则较差；而对于烷基取代α-酮酸,5-甲基-2-酮基已酸钠和4-甲基-2-酮基戊酸钠的转化活性比另外两个烷基取代酮酸好,其最高转化率约为苯丙酮酸钠的60%。另外,本论文还采用天冬氨酸转氨酶催化间羟基苯乙酮合成卡巴拉汀的手性胺中间体3-(1-氨基乙基)苯酚,但天冬氨酸转氨酶催化合成此化合物的能力有限,在加入10%DMSO情况下,其最高转化率不超过40%。
联用亮氨酸脱氢酶和甲酸脱氢酶可制备手性胺化合物。本论文构建了亮氨酸脱氢酶和甲酸脱氢酶大肠杆菌基因工程菌,将这两种酶联合运用,以上述α-酮酸为底物,考察了反应条件pH、温度、辅酶NAD用量对酶活性影响,在pH9、30℃、1mM NAD的优化条件下,烷基取代α-酮酸反应良好,24h的转化率均在90%左右。除苯丙酮酸钠外,亮氨酸脱氢酶和甲酸脱氢酶对苯环取代α-酮酸的催化活性都很低。
本论文立足于酶催化合成手性化合物,结合基因工程手段重组表达生物酶,为手性化合物的合成拓宽了思路,具有重要的理论意义和应用潜力。
Biocatalysis, thus applying enzymes for organic synthetic transformations, has become a common applied 'green technology' for selected asymmetric transformations as well as the excellent stereo-, regio-and chemoselectivity of the biocatalysts exceeding many other methodologies. Furthermore, during the last decade the advancements in genomics and protein engineering allow to design enzymes which fulfil the requirements for industrial scale. Focusing on the past years, enzymatic transformations have been paid more attention, whereby it can easily be noted from the examples published recently. In this study, some significant chiral compounds were synthesized with Escherichia coli y-glutamyltranspeptidase, Escherichia coli aspartate aminotransferase, Bacillus sphaericus leucine dehydrogenase and candida boidinii formate dehydrogenase, these enzymes were used to catalyze the natural and unnatural substrates to further investigate the catalytic mechanism and promote biocatalysis of some chiral compounds.
In order to investigate the catalytic mechanism of Escherichia coli γ-glutamyltranspeptidase, ten para-and meta-substituted y-glutamyl anilides were chemically prepared and employed as substrates to synthesize L-theanine to assay the activity of y-glutamyltranspeptidase. The reaction was optimized for γ-glutamyl-p-nitroanilide. Key factors such as substrate specificity, pH, temperature, and substrate mole ratio were all investigated. Kinetic studies of the acyl transfer reaction were described and Hammett plot was constructed. This study indicated that the rate-limiting acylation reaction of γ-glutamyltranspeptidase can apparently be accelerated by either electron-withdrawing or electron-donating substituents of y-glutamyl anilides. The reaction could be catalyzed by the general acid and carboxy of Asp-433or phenolic hydroxyl Tyr-444may be the acid by autodock simulation for all prepared y-glutamyl anilides.
A new method for the synthesis of β-N-(γ-L(+)-glutamyl)phenylhydrazine is presented. This compound was prepared from L-glutamine and phenylhydrazine through the transpeptidation reaction of Escherichia coli y-glutamyltranspeptidase, while phenylhydrazine had been reported as a typical inhibitor of the enzyme. The optimum reaction conditions for the production of β-N-(γ-L(+)-glutamyl) phenylhydrazine were60mM L-glutamine,300mM phenylhydrazine,40U y-glutamyltranspeptidase/ml, and pH9in approx.800ml. After6h at37℃, the product was obtained with a conversion rate of93%(mol/mol). y-Glutamyltranspeptidase was reversibly inhibited only when phenylhydrazine concentration was above300mM.
A new method for the synthesis of β-N-(γ-L(+)-glutamyl)-4-carboxyphenylhydrazine, a precursor of agaritine, is presented. This compound was prepared from L-glutamine and4-hydrazinobenzoic acid through the transpeptidation reaction catalyzed by the Escherichia coli y-glutamyltransferase. The optimum reaction conditions for the production of β-N-(γ-L(+)-glutamyl)-4-carboxyphenylhydrazine were50mM L-glutamine,500mM4-hydrazinobenzoic acid and40U γ-glutamyltransferase/mL at pH8and37℃for24h. The product was obtained with a conversion rate of90%(mol/mol). γ-Glutamyltransferase activity was not inhibited by4-hydrazinobenzoic acid at concentrations up to1000mM. This simple and efficient method would facilitate the synthesis of glutamyl phenylhydrazine analogues, including agaritine.
Enantiomerically pure chiral amines are highly valuable functionalized molecules with a wide range of applications including intermediates for the synthesis of pharmaceutical and agrochemical active ingredients, resolving agents for the separation of enantiomers via diastereomeric salt formation, and ligands for asymmetric synthesis using either transition metal catalysis or organocatalysis. Compared with chemical synthesis and kinetic resolution, the option of preparing chiral amines using biocatalytic approaches is now viewed as attractive as a result of recent developments in biocatalyst availability, methods for improving biocatalyst stability, and the inherent high selectivity and catalytic activity that can be obtained through enzyme catalysis. Eight α-keto acids were synthesized to investigate the characteristics of these enzymes including aspartate aminotransferase, leucine dehydrogenase. For aspartate aminotransferase, the conversion rates of phenylpyruvate and o-methoxyphenylpyruvate substrates were higher than o-hydroxyphenylpyruvate and p-dimethylamino phenylpyruvate. And4-methyl-2-oxovaleric acid and5-methyl-2-oxohexanoic acid were catalyzed well using aspartate aminotransferase when compared with the two other alkyl a-keto acids among which the highest conversion ratio was about sixty percent of the phenylpyruvate. In addition,3-hydroxyacetophenone was considered as the substrate of aspartate aminotransferase to prepare the intermediate of rivastigmine, however, it was unfortunate that the enzyme activity of3-hydroxyacetophenone was less than those a-keto acids which the conversion rate was not higher than40%even in the present of10%DMSO.
Leucine dehydrogenase was successfully applied for the synthesis of L-leucine and L-tertiary leucine. The necessary NADH regeneration was performed with formate dehydrogenase with formate as the ultimate hydrogen source. It has been demonstrated that in-situ coenzyme regeneration is in principle economically feasible. In this study, a structural gene (leudh) encoding leucine dehydrogenase from B. sphaericus IFO3525was cloned into Escherichia coli cells and sequenced. And a formate dehydrogenase gene from candida boidinii was cloned, sequenced and over-expressed in E. coli. The available a-keto acids described above were tested as substrates in the coupled reaction system of leucine dehydrogenase and formate dehydrogenase. Key factors such as pH, temperature, and NAD usage were all investigated. The alkyl a-keto acids all reacted well at pH9、30℃、1mM NAD after24h, of which the conversion rates were all approximately90%. However, the phenyl a-keto acids did not proceed smoothly except for phenylpyruvate.
The number of examples of drugs and drug intermediates prepared by biocatalytic approaches has significantly increased over the past years, so that this study only got a start in biocatalysis and implied a further development of suitable enzymes for asymmetric organic synthesis in the future.
为了能够使γ-谷氨酰转移酶催化合成重要的γ-谷氨酰化合物,对酶催化机制进行了研究。制备了十个γ-谷氨酰苯胺类似物,以它们为γ-谷氨酰基供体,乙胺为Y-谷氨酰基受体,经酶催化合成茶氨酸,通过HPLC测定茶氨酸生成量来评价酶活性。以L-γ-谷氨酰对硝基苯胺为底物,对酶转化条件如pH、温度、底物摩尔比等进行优化。在最优转化条件下,分别酶催化十个γ-谷氨酰苯胺类似物形成茶氨酸,测定这些酶转化反应动力学常数,并转换成Hammett方程,结合Hammett曲线表明,γ-谷氨酰转移酶限速酰化反应步骤的反应速度能被吸电子或供电子取代基取代的Y-谷氨酰苯胺类似物加速,此步酰化反应受到动力学酸催化,通过autodock计算模拟,Asp-433羧基或者Tyr-444酚羟基可能是此酸质子来源,此酸质子的进一步确定还需通过实施定点突变。
采用γ-谷氨酰转移酶催化合成β-N-(γ-L(+)-谷氨酰)苯肼以及β-N-(γ-L(+)-谷氨酰)对羧基苯肼。合成谷氨酰苯肼最佳反应条件为：配制pH9的转化液,底物浓度为60mM L-谷氨酰胺,300mM苯肼,加入40Uγ,-谷氨酰转移酶/ml,37℃反应6h,底物转化率高达93%；蘑菇氨酸的合成前体,谷氨酰对羧基苯肼最佳反应条件为：50mM L-谷氨酰胺,500mM对羧基苯肼,40U γ-谷氨酰转移酶/ml,pH8、37℃反应24h,产物转化率达90%。虽然苯肼曾被报道为泪腺过氧化酶的自杀性抑制剂,但是苯肼只有在高于300mM浓度时才会可逆性抑制谷氨酰转移酶,而对羧基苯肼即使在1000mM也不会出现抑制现象。这种新的谷氨酰转移酶催化合成方法将有助于合成蘑菇氨酸等重要的谷氨酰化合物,并进一步促进它们的深入研究。
光学纯手性胺是一类有重要价值的医药及精细化工中间体,对手性胺类化合物的不对称合成进行更深层次研究具有较大的经济效益和应用价值。目前手性胺的主要制备方法有化学合成、化学及酶法拆分以及酶催化合成,其中酶催化合成更具有优势。本论文以天冬氨酸转氨酶、联用亮氨酸脱氢酶和甲酸脱氢酶催化合成手性胺及氨基酸。为了更好地了解这些酶的特性,化学合成了8个α-酮酸,天冬氨酸转氨酶对苯丙酮酸钠和邻甲氧基苯丙酮酸钠的转化率较高,邻羟基苯丙酮酸钠和对二甲氨基苯丙酮酸钠的活性则较差；而对于烷基取代α-酮酸,5-甲基-2-酮基已酸钠和4-甲基-2-酮基戊酸钠的转化活性比另外两个烷基取代酮酸好,其最高转化率约为苯丙酮酸钠的60%。另外,本论文还采用天冬氨酸转氨酶催化间羟基苯乙酮合成卡巴拉汀的手性胺中间体3-(1-氨基乙基)苯酚,但天冬氨酸转氨酶催化合成此化合物的能力有限,在加入10%DMSO情况下,其最高转化率不超过40%。
联用亮氨酸脱氢酶和甲酸脱氢酶可制备手性胺化合物。本论文构建了亮氨酸脱氢酶和甲酸脱氢酶大肠杆菌基因工程菌,将这两种酶联合运用,以上述α-酮酸为底物,考察了反应条件pH、温度、辅酶NAD用量对酶活性影响,在pH9、30℃、1mM NAD的优化条件下,烷基取代α-酮酸反应良好,24h的转化率均在90%左右。除苯丙酮酸钠外,亮氨酸脱氢酶和甲酸脱氢酶对苯环取代α-酮酸的催化活性都很低。
本论文立足于酶催化合成手性化合物,结合基因工程手段重组表达生物酶,为手性化合物的合成拓宽了思路,具有重要的理论意义和应用潜力。
Biocatalysis, thus applying enzymes for organic synthetic transformations, has become a common applied 'green technology' for selected asymmetric transformations as well as the excellent stereo-, regio-and chemoselectivity of the biocatalysts exceeding many other methodologies. Furthermore, during the last decade the advancements in genomics and protein engineering allow to design enzymes which fulfil the requirements for industrial scale. Focusing on the past years, enzymatic transformations have been paid more attention, whereby it can easily be noted from the examples published recently. In this study, some significant chiral compounds were synthesized with Escherichia coli y-glutamyltranspeptidase, Escherichia coli aspartate aminotransferase, Bacillus sphaericus leucine dehydrogenase and candida boidinii formate dehydrogenase, these enzymes were used to catalyze the natural and unnatural substrates to further investigate the catalytic mechanism and promote biocatalysis of some chiral compounds.
In order to investigate the catalytic mechanism of Escherichia coli γ-glutamyltranspeptidase, ten para-and meta-substituted y-glutamyl anilides were chemically prepared and employed as substrates to synthesize L-theanine to assay the activity of y-glutamyltranspeptidase. The reaction was optimized for γ-glutamyl-p-nitroanilide. Key factors such as substrate specificity, pH, temperature, and substrate mole ratio were all investigated. Kinetic studies of the acyl transfer reaction were described and Hammett plot was constructed. This study indicated that the rate-limiting acylation reaction of γ-glutamyltranspeptidase can apparently be accelerated by either electron-withdrawing or electron-donating substituents of y-glutamyl anilides. The reaction could be catalyzed by the general acid and carboxy of Asp-433or phenolic hydroxyl Tyr-444may be the acid by autodock simulation for all prepared y-glutamyl anilides.
A new method for the synthesis of β-N-(γ-L(+)-glutamyl)phenylhydrazine is presented. This compound was prepared from L-glutamine and phenylhydrazine through the transpeptidation reaction of Escherichia coli y-glutamyltranspeptidase, while phenylhydrazine had been reported as a typical inhibitor of the enzyme. The optimum reaction conditions for the production of β-N-(γ-L(+)-glutamyl) phenylhydrazine were60mM L-glutamine,300mM phenylhydrazine,40U y-glutamyltranspeptidase/ml, and pH9in approx.800ml. After6h at37℃, the product was obtained with a conversion rate of93%(mol/mol). y-Glutamyltranspeptidase was reversibly inhibited only when phenylhydrazine concentration was above300mM.
A new method for the synthesis of β-N-(γ-L(+)-glutamyl)-4-carboxyphenylhydrazine, a precursor of agaritine, is presented. This compound was prepared from L-glutamine and4-hydrazinobenzoic acid through the transpeptidation reaction catalyzed by the Escherichia coli y-glutamyltransferase. The optimum reaction conditions for the production of β-N-(γ-L(+)-glutamyl)-4-carboxyphenylhydrazine were50mM L-glutamine,500mM4-hydrazinobenzoic acid and40U γ-glutamyltransferase/mL at pH8and37℃for24h. The product was obtained with a conversion rate of90%(mol/mol). γ-Glutamyltransferase activity was not inhibited by4-hydrazinobenzoic acid at concentrations up to1000mM. This simple and efficient method would facilitate the synthesis of glutamyl phenylhydrazine analogues, including agaritine.
Enantiomerically pure chiral amines are highly valuable functionalized molecules with a wide range of applications including intermediates for the synthesis of pharmaceutical and agrochemical active ingredients, resolving agents for the separation of enantiomers via diastereomeric salt formation, and ligands for asymmetric synthesis using either transition metal catalysis or organocatalysis. Compared with chemical synthesis and kinetic resolution, the option of preparing chiral amines using biocatalytic approaches is now viewed as attractive as a result of recent developments in biocatalyst availability, methods for improving biocatalyst stability, and the inherent high selectivity and catalytic activity that can be obtained through enzyme catalysis. Eight α-keto acids were synthesized to investigate the characteristics of these enzymes including aspartate aminotransferase, leucine dehydrogenase. For aspartate aminotransferase, the conversion rates of phenylpyruvate and o-methoxyphenylpyruvate substrates were higher than o-hydroxyphenylpyruvate and p-dimethylamino phenylpyruvate. And4-methyl-2-oxovaleric acid and5-methyl-2-oxohexanoic acid were catalyzed well using aspartate aminotransferase when compared with the two other alkyl a-keto acids among which the highest conversion ratio was about sixty percent of the phenylpyruvate. In addition,3-hydroxyacetophenone was considered as the substrate of aspartate aminotransferase to prepare the intermediate of rivastigmine, however, it was unfortunate that the enzyme activity of3-hydroxyacetophenone was less than those a-keto acids which the conversion rate was not higher than40%even in the present of10%DMSO.
Leucine dehydrogenase was successfully applied for the synthesis of L-leucine and L-tertiary leucine. The necessary NADH regeneration was performed with formate dehydrogenase with formate as the ultimate hydrogen source. It has been demonstrated that in-situ coenzyme regeneration is in principle economically feasible. In this study, a structural gene (leudh) encoding leucine dehydrogenase from B. sphaericus IFO3525was cloned into Escherichia coli cells and sequenced. And a formate dehydrogenase gene from candida boidinii was cloned, sequenced and over-expressed in E. coli. The available a-keto acids described above were tested as substrates in the coupled reaction system of leucine dehydrogenase and formate dehydrogenase. Key factors such as pH, temperature, and NAD usage were all investigated. The alkyl a-keto acids all reacted well at pH9、30℃、1mM NAD after24h, of which the conversion rates were all approximately90%. However, the phenyl a-keto acids did not proceed smoothly except for phenylpyruvate.
The number of examples of drugs and drug intermediates prepared by biocatalytic approaches has significantly increased over the past years, so that this study only got a start in biocatalysis and implied a further development of suitable enzymes for asymmetric organic synthesis in the future.
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