Structure and biosynthesis of a macrocyclic peptide containing an unprecedented lysine-to-tryptophan crosslink.
Structure and biosynthesis of a macrocyclic peptide containing an unprecedented lysine-to-tryptophan crosslink.
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链球菌利用肽信号作为种内交流的手段。这些肽可以包含不寻常的翻译后修饰，为扩大我们对自然化学和生物合成谱的理解提供了机会。在这里，我们结合了天然产物发现和机械酶学的工具来报道链球菌大环肽的结构和生物合成。我们发现，在赖氨酸和色氨酸的侧链中，两个未激活的碳之间存在共价键，这是一种前所未有的翻译后修饰。从遗传学和生物化学的角度研究了肽的生物合成。前者暗示了一个新的含有SPASM结构域的自由基SAM酶StrB，而后者揭示了StrB包含两个[4Fe-4S]簇，并在一个步骤中安装了不寻常的赖氨酸-色氨酸交联。StrB通过分子内拼接赖氨酸和色氨酸的侧链，为生物合成大环肽提供了一条新的途径。
Streptococcal bacteria use peptide signals as a means of intraspecies communication. These peptides can contain unusual post-translational modifications providing opportunities for expanding our understanding of Nature's chemical and biosynthetic repertoires. Herein we have combined tools from natural products discovery and mechanistic enzymology to report the structure and biosynthesis of streptide, a streptococcal macrocyclic peptide. We show that streptide bears an unprecedented post-translational modification involving a covalent linkage between two unactivated carbons within the side chains of lysine and tryptophan. The biosynthesis of streptide was addressed by genetic and biochemical studies. The former implicated a new SPASM domain-containing radical SAM enzyme, StrB, while the latter revealed that StrB contains two [4Fe-4S] clusters and installs the unusual lysine-to-tryptophan crosslink in a single step. By intramolecularly stitching together the side chains of lysine and tryptophan, StrB provides a new route for biosynthesizing macrocyclic peptides.