Products Cited in Publications Worldwide Leader-Independent C-Terminal Modification by a Radical S-Adenosyl-l-methionine Maturase Enables Macrocyclic GLP-1-Like Peptides

Leader-Independent C-Terminal Modification by a Radical S-Adenosyl-l-methionine Maturase Enables Macrocyclic GLP-1-Like Peptides

Pedigo, Jacob K; Eastman, Karsten AS; Bandarian, Vahe

DOI:

Abstract

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a rapidly expanding family of natural products in which biosynthetic maturase enzymes tailor ribosomal precursors into bioactive products. Classical RiPP maturation relies on an N-terminal leader sequence in the precursor peptide and a complementary RiPP-recognition element in the enzyme to guide substrate binding. Herein, we interrogated PapB, a radical S-adenosyl-l-methionine RiPP maturase known to introduce thio(seleno)-ether cross-links and discovered that its catalytic reach extends well beyond this paradigm. PapB efficiently processes substrates that lack any canonical leader sequence, demonstrating bona fide leader-independent activity. To highlight the practical value of this capability, we applied PapB to three therapeutically relevant analogues of glucagon-like peptide pathway agonists to generate C-terminal cyclic structures. In every case, the enzyme achieved complete conversion of the linear to the thioether macrocyclized peptide. These results establish PapB as a versatile, plug-and-play biocatalyst for late-stage macrocyclization of structurally diverse peptides, opening a direct route to conformationally constrained therapeutic candidates without the need for leader tags.

Keywords

peptides ; enzymes ; radical SAM ; macrocyclization ; mass spectrometry ; GLP-1

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S-Adenosyl-L-methionine chloride 2HCl

A86251786867-01-875%

S-Adenosyl-L-methionine chloride 2HCl

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