Department of Chemistry, University of North Florida, 1 UNF Dr, Jacksonville, FL 32224, USA.
Org Biomol Chem. 2019 Feb 27;17(9):2305-2314. doi: 10.1039/c8ob03063d.
Microorganisms are remarkable chemists, with enzymes as their tools for executing multi-step syntheses to yield myriad natural products. Microbial synthetic aptitudes are illustrated by the structurally diverse 2,5-diketopiperazine (DKP) family of bioactive nonribosomal peptide natural products. Nonribosomal peptide synthetases (NRPSs) have long been recognized as catalysts for formation of DKP scaffolds from two amino acid substrates. Cyclodipeptide synthases (CDPSs) are more recently recognized catalysts of DKP assembly, employing two aminoacyl-tRNAs (aa-tRNAs) as substrates. CDPS-encoding genes are typically found in genomic neighbourhoods with genes encoding additional biosynthetic enzymes. These include oxidoreductases, cytochrome P450s, prenyltransferases, methyltransferases, and cyclases, which equip the DKP scaffold with groups that diversify chemical structures and confer biological activity. These tailoring enzymes have been characterized from nine CDPS-containing biosynthetic pathways to date, including four during the last year. In this review, we highlight these nine DKP pathways, emphasizing recently characterized tailoring reactions and connecting new developments to earlier findings. Featured pathways encompass a broad spectrum of chemistry, including the formation of challenging C-C and C-O bonds, regioselective methylation, a unique indole alkaloid DKP prenylation strategy, and unprecedented peptide-nucleobase bond formation. These CDPS-containing pathways also provide intriguing models of metabolic pathway evolution across related and divergent microorganisms, and open doors to synthetic biology approaches for generation of DKP combinatorial libraries. Further, bioinformatics analyses support that much unique genetically encoded DKP tailoring potential remains unexplored, suggesting opportunities for further expansion of Nature's biosynthetic spectrum. Together, recent studies of DKP pathways demonstrate the chemical ingenuity of microorganisms, highlight the wealth of unique enzymology provided by bacterial biosynthetic pathways, and suggest an abundance of untapped biosynthetic potential for future exploration.
微生物是出色的化学家，它们利用酶作为工具，执行多步合成反应，从而产生无数的天然产物。微生物的合成能力体现在结构多样的 2,5-二酮哌嗪（DKP）家族生物活性非核糖体肽天然产物中。非核糖体肽合酶（NRPSs）长期以来一直被认为是从两个氨基酸底物形成 DKP 支架的催化剂。环二肽合酶（CDPSs）是最近被认可的 DKP 组装催化剂，它使用两个氨酰-tRNA（aa-tRNA）作为底物。CDPS 编码基因通常存在于与编码其他生物合成酶的基因相邻的基因组区域中。这些酶包括氧化还原酶、细胞色素 P450s、 prenyltransferases、methyltransferases 和 cyclases，它们为 DKP 支架提供了多样化化学结构并赋予生物活性的基团。迄今为止，已经从九个包含 CDPS 的生物合成途径中对这些修饰酶进行了特征描述，其中包括去年的四个。在这篇综述中，我们重点介绍了这九个 DKP 途径，强调了最近表征的修饰反应，并将新发现与早期发现联系起来。特色途径涵盖了广泛的化学，包括形成具有挑战性的 C-C 和 C-O 键、区域选择性甲基化、独特的吲哚生物碱 DKP prenylation 策略以及前所未有的肽-核苷键形成。这些包含 CDPS 的途径还为相关和不同微生物的代谢途径进化提供了有趣的模型，并为生成 DKP 组合文库的合成生物学方法打开了大门。此外，生物信息学分析支持，大量独特的遗传编码 DKP 修饰潜力仍未被探索，这表明未来有机会进一步扩展自然界的生物合成谱。总之，最近对 DKP 途径的研究表明了微生物的化学智慧，突出了细菌生物合成途径提供的独特酶学的丰富性，并表明未来有大量未开发的生物合成潜力可供探索。
