Applied Microbiology and Biotechnology ( IF 3.9 ) Pub Date : 2021-02-24 , DOI: 10.1007/s00253-021-11178-1 Lauritz Harken 1 , Shu-Ming Li 1
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2,5-Diketopiperazines are the smallest cyclic peptides comprising two amino acids connected via two peptide bonds. They can be biosynthesized in nature by two different enzyme families, either by nonribosomal peptide synthetases or by cyclodipeptide synthases. Due to the stable scaffold of the diketopiperazine ring, they can serve as precursors for further modifications by different tailoring enzymes, such as methyltransferases, prenyltransferases, oxidoreductases like cyclodipeptide oxidases, 2-oxoglutarate-dependent monooxygenases and cytochrome P450 enzymes, leading to the formation of intriguing secondary metabolites. Among them, cyclodipeptide synthase-associated P450s attracted recently significant attention, since they are able to catalyse a broader variety of astonishing reactions than just oxidation by insertion of an oxygen. The P450-catalysed reactions include hydroxylation at a tertiary carbon, aromatisation of the diketopiperazine ring, intramolecular and intermolecular carbon-carbon and carbon-nitrogen bond formation of cyclodipeptides and nucleobase transfer reactions. Elucidation of the crystal structures of three P450s as cyclodipeptide dimerases provides a structural basis for understanding the reaction mechanism and generating new enzymes by protein engineering. This review summarises recent publications on cyclodipeptide modifications by P450s.
Key Points
• Intriguing reactions catalysed by cyclodipeptide synthase-associated cytochrome P 450 s
• Homo- and heterodimerisation of diketopiperazines
• Coupling of guanine and hypoxanthine with diketopiperazines
Graphical abstract
中文翻译：
环二肽合酶与细胞色素 P 450 酶组装的二酮哌嗪的修饰
2,5-二酮哌嗪是最小的环肽，包含通过两个肽键连接的两个氨基酸。它们可以在自然界中通过两种不同的酶家族生物合成，或者通过非核糖体肽合成酶，或者通过环二肽合酶。由于二酮哌嗪环的稳定支架，它们可以作为不同剪裁酶进一步修饰的前体，例如甲基转移酶、异戊烯基转移酶、环二肽氧化酶等氧化还原酶、2-酮戊二酸依赖性单加氧酶和细胞色素 P 450酶，从而形成有趣的次生代谢产物。其中，环二肽合酶相关的 P 450最近引起了极大的关注，因为它们能够催化更广泛的惊人反应，而不仅仅是通过插入氧进行氧化。P 450催化的反应包括叔碳的羟基化、二酮哌嗪环的芳构化、环二肽的分子内和分子间碳-碳和碳-氮键形成以及核碱基转移反应。阐明三个 P 450作为环二肽二聚酶的晶体结构，为理解反应机制和通过蛋白质工程产生新酶提供了结构基础。本综述总结了最近发表的有关 P 450环二肽修饰的文章。
关键点
• 环二肽合酶相关细胞色素 P 450 s催化的有趣反应
• 二酮哌嗪的同二聚和异二聚
• 鸟嘌呤和次黄嘌呤与二酮哌嗪的偶联
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