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Synthesis of d-Amino Acid-Containing Dipeptides Using the Adenylation Domains of Nonribosomal Peptide Synthetase

机译:使用非核糖体肽合成酶的腺苷酸化域合成含d-氨基酸的二肽

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Recent papers have reported dipeptides containing d-amino acids to have novel effects that cannot be observed with ll-dipeptides, and such dipeptides are expected to be novel functional compounds for pharmaceuticals and food additives. Although the functions of d-amino acid-containing dipeptides are gaining more attention, there are few reports on the synthetic enzymes that can accept d-amino acids as substrates, and synthetic methods for d-amino acid-containing dipeptides have not yet been constructed. Previously, we developed a chemoenzymatic system for amide synthesis that comprised enzymatic activation and a subsequent nucleophilic substitution reaction. In this study, we demonstrated the application of the system for d-amino acid-containing-dipeptide synthesis. We chose six adenylation domains as targets according to our newly constructed hypothesis, i.e., an adenylation domain located upstream from the epimerization domain may activate d-amino acid as well as l-amino acid. We successfully synthesized over 40 kinds of d-amino acid-containing dipeptides, including ld-, dl-, and dd-dipeptides, using only two adenylation domains, TycA-A from tyrocidine synthetase and BacB2-A from bacitracin synthetase. Furthermore, this study offered the possibility that the epimerization domain could be a clue to the activity of the adenylation domains toward d-amino acid. This paper provides additional information regarding d-amino acid-containing-dipeptide synthesis through the combination of enzymatic adenylation and chemical nucleophilic reaction, and this system will be a useful tool for dipeptide synthesis.IMPORTANCE Because almost all amino acids in nature are l-amino acids, the functioning of d-amino acids has received little attention. Thus, there is little information available on the activity of enzymes toward d-amino acids or synthetic methods for d-amino acid-containing dipeptides. Recently, d-amino acids and d-amino acid-containing peptides have attracted attention as novel functional compounds, and d-amino acid-activating enzymes and synthetic methods are required for the development of the d-amino acid-containing-peptide industry. This study provides additional knowledge regarding d-amino acid-activating enzymes and proposes a unique synthetic method for d-amino acid-containing peptides, including ld-, dl-, and dd-dipeptides.
机译:最近的论文报道了含有d-氨基酸的二肽具有用II-二肽无法观察到的新作用,并且这种二肽被认为是用于药物和食品添加剂的新型功能化合物。尽管含d-氨基酸的二肽的功能受到越来越多的关注,但是关于可以接受以d-氨基酸为底物的合成酶的报道很少,并且尚未构建用于含d-氨基酸的二肽的合成方法。 。以前,我们开发了用于酰胺合成的化学酶系统,该系统包括酶激活和随后的亲核取代反应。在这项研究中,我们证明了该系统在含d-氨基酸的二肽合成中的应用。根据我们新构建的假设,我们选择了六个腺苷酸化域作为靶,即位于差向异构域上游的腺苷酸化域可以激活d-氨基酸以及l-氨基酸。我们仅使用两个腺苷酸化域(来自酪氨酸合成酶的TycA-A和来自杆菌肽合成酶的BacB2-A)成功合成了40多种含d-氨基酸的二肽,包括ld-,dl-和dd-二肽。此外,该研究提供了差向异构域可能是腺苷酸化域对d-氨基酸活性的线索的可能性。本文提供了有关通过酶促腺苷酸化和化学亲核反应相结合来合成含d-氨基酸的二肽的更多信息,该系统将是二肽合成的有用工具。重要因为自然界中几乎所有氨基酸都是l-氨基酸中,d-氨基酸的功能很少受到关注。因此,关于酶对d-氨基酸的活性或含d-氨基酸的二肽的合成方法的信息很少。近来,d-氨基酸和含d-氨基酸的肽作为新型功能化合物引起了人们的注意,并且d-氨基酸活化酶和合成方法对于发展含d-氨基酸的肽工业是必需的。这项研究提供了有关d-氨基酸激活酶的更多知识,并提出了一种独特的合成方法,用于合成包含d-氨基酸的肽,包括ld-,dl-和dd-二肽。

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