2021 Fiscal Year Final Research Report
Characterization of peptide cyclization mediated by penicillin-binding protein-type thioesterases and its protein engineering
Project/Area Number |
19K16390
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 47050:Environmental and natural pharmaceutical resources-related
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Research Institution | Hokkaido University |
Principal Investigator |
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Project Period (FY) |
2019-04-01 – 2022-03-31
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Keywords | 環状ペプチド / 生合成 / 非リボソームペプチド / 環化酵素 / 生体触媒 / 酵素工学 / 放線菌 |
Outline of Final Research Achievements |
SurE, a novel peptide cyclase involved in the biosynthesis of nonribosomal macrolactams produced by actinomycetes, was analyzed to elucidate its substrate selectivity and its structural basis; biochemical and structural comparison between SurE and two homologous enzymes was performed to clarify the structure that generates differences in substrate selectivity. Based on the findings obtained, we succeeded in logically modifying the substrate selectivity of the enzyme. Furthermore, we investigated the synthesis scheme of the enzyme substrate and established a highly efficient synthetic method. The modified solid phase peptide synthesis combined with sequential enzymatic cyclization realized seamless chemoenzymatic synthesis of cyclic peptides.
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Free Research Field |
天然物化学
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Academic Significance and Societal Importance of the Research Achievements |
ペプチドの環化反応は、代謝安定性や標的特異性が向上する創薬上重要な修飾反応である。一方で、有機合成的な環化反応は、多量の廃棄物や分離困難な副生成物を生じる問題を抱えている。本研究では、独自に発見した新規ペプチド環化酵素の触媒利用を目指し、この有用酵素ファミリーに関する基礎的知見を数多く獲得した。得られた知見は、有機合成的手法の課題を克服した環境調和性の高いペプチド環化反応の実現に向けた基盤となると考えられる。
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