CHAPTER 7: Peptide Cross-links Catalyzed by Metalloenzymes in Natural Product Biosynthesis

Covalent cross-links play an important role in tailoring the structure and bioactivity of peptide natural products. While many peptide cross-links can be achieved by reactions involving heterolytic chemistries, some require radical mechanisms to activate otherwise inert bonds. This type of one-electron chemistry is found in the biosynthesis of two of our most important antibiotics, penicillin and vancomycin, in addition to small peptide products, such as the antibiotic subtilosin A, the redox co-factor pyrroloquinoline quinone, and the putative bacterial signaling molecule streptide. This chapter takes a look at the structures and mechanisms of the three known classes of metalloenzymes that carry out the one-electron reactions required to form the C–C, C–N, C–O, and C–S bonds that make up the cross-links in these molecules.