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首页> 外文期刊>Advanced synthesis & catalysis >Actions of Tryptophan Prenyltransferases Toward Fumiquinazolines and their Potential Application for the Generation of Prenylated Derivatives by Combining Chemical and Chemoenzymatic Syntheses
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Actions of Tryptophan Prenyltransferases Toward Fumiquinazolines and their Potential Application for the Generation of Prenylated Derivatives by Combining Chemical and Chemoenzymatic Syntheses

机译:色氨酸异戊二烯基转移酶对氟喹唑啉类的作用及其在化学和化学酶促合成中产生烯丙基化衍生物的潜在应用

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摘要

Dimethylallyltryptophan synthases (DMATSs) catalyze regiospecific transfer reactions of a prenyl moiety from dimethylallyl diphosphate to various positions of the indole ring of tryptophan. For example, FgaPT2, 5-DMATS, and 7-DMATS from Aspergillus fungi catalyze tryptophan prenylation at C-4, C-5, and C-7, while 5-DMATS(Sc) and 6-DMATS(Sa) from Streptomyces strains are tryptophan C-5 and C-6 prenyltransferases, respectively. In this study, our objective is to demonstrate the possibility of producing prenylated analogues of ardeemin fumiquinazoline (FQ) (1a), a precursor of the multidrug resistance (MDR) export pump inhibitor ardeemin, by using DMATSs. All ardeemin FQ stereoisomers were chemically synthesized and used as substrates for enzyme assays with DMATSs. Biochemical investigations revealed different features of these enzymes toward ardeemin FQ analogues, regarding activity and prenylation position. Isolation and structural elucidation showed that 7-DMATS catalyzed mainly regiospecific prenylation at C-7, which is also observed for its natural substrate l-tryptophan. Up to four prenylated derivatives were identified in the reaction mixtures of other enzymes. In total, 18 new prenylated ardeemin FQ analogues were obtained in this study. Molecular modelling of ardeemin FQ analogues with the crystal structure of FgaPT2 led to the identification of two potential amino acid residues for guidance of the prenylation position. The two generated mutants FgaPT2_M328L and FgaP-T2_Y398F showed significant prenylation shifts with 1a.
机译:二甲基烯丙基色氨酸合酶(DMATS)催化异戊二烯基部分从二甲基烯丙基二磷酸到色氨酸吲哚环的各个位置的区域特异性转移反应。例如,曲霉属真菌的FgaPT2、5-DMATS和7-DMATS在C-4,C-5和C-7处催化色氨酸异戊二烯化,而链霉菌菌株的5-DMATS(Sc)和6-DMATS(Sa)分别是色氨酸C-5和C-6异戊二烯基转移酶。在这项研究中,我们的目的是证明使用DMATS生产多药耐药性(MDR)出口泵抑制剂ardeemin的前体的ardeemin fumiquinazoline(FQ)(1a)的异戊二烯基类似物的可能性。化学合成所有ardeemin FQ立体异构体,并用作DMATS酶分析的底物。生化研究表明,这些酶对ardeemin FQ类似物的活性和异戊烯化位置有不同的特征。分离和结构解析表明,7-DMATS主要在C-7催化区域特异性的异戊二烯化,这也是其天然底物1-色氨酸的现象。在其他酶的反应混合物中最多鉴定出四个烯丙基化衍生物。在这项研究中,总共获得了18种新的烯丙基化的ardeemin FQ类似物。具有FgaPT2晶体结构的ardeemin FQ类似物的分子模型导致鉴定出两个潜在的氨基酸残基,用于指导异戊二烯化位置。生成的两个突变体FgaPT2_M328L和FgaP-T2_Y398F表现出显着的烯丙基化位移,为1a。

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