Kandy Sanath K, Pasquale Michael A, Chekan Jonathan R
Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC, USA.
Nat Chem Biol. 2025 Feb;21(2):168-181. doi: 10.1038/s41589-024-01795-y. Epub 2025 Jan 15.
Peptide cyclization is a defining feature of many bioactive molecules, particularly in the ribosomally synthesized and post-translationally modified peptide (RiPP) family of natural products. Although enzymes responsible for N- to C-terminal macrocyclization, lanthipeptide formation or heterocycle installation have been well documented, a diverse array of cyclases have been discovered that perform crosslinking of aromatic side chains. These enzymes form either biaryl linkages between two aromatic amino acids or a crosslink between one aliphatic amino acid and one aromatic amino acid. Incredibly, nature has evolved multiple routes to install these crosslinks. While enzymes such as cytochromes P450 and radical S-adenosylmethionine (rSAM) enzymes are well known from other pathways, this role in RiPP biosynthesis has only recently been appreciated. Others, such as burpitide cyclases and DUF3328 (UstY) family proteins, come from eukaryotes and are relatively uncharacterized enzyme classes. This Review covers the emerging theme of aromatic amino acid side-chain crosslinking in RiPPs by focusing on the newly discovered enzymes responsible for catalyzing these challenging reactions.
肽环化是许多生物活性分子的一个决定性特征，特别是在核糖体合成和翻译后修饰的肽（RiPP）类天然产物中。尽管负责N端到C端大环化、羊毛硫肽形成或杂环安装的酶已有充分记载，但已发现了多种能进行芳香族侧链交联的环化酶。这些酶要么在两个芳香族氨基酸之间形成联芳基键，要么在一个脂肪族氨基酸和一个芳香族氨基酸之间形成交联。令人惊讶的是，自然界已经进化出多种途径来形成这些交联。虽然细胞色素P450和自由基S-腺苷甲硫氨酸（rSAM）酶等在其他途径中已为人熟知，但它们在RiPP生物合成中的作用直到最近才被认识到。其他的，如burpitide环化酶和DUF3328（UstY）家族蛋白，来自真核生物，是相对未被充分表征的酶类。本综述通过聚焦于新发现的负责催化这些具有挑战性反应的酶，涵盖了RiPPs中芳香族氨基酸侧链交联这一新兴主题。
