9sov
CorZ in complex with SAH and myxarylin, Methyltransferase
Structural highlights
Publication Abstract from PubMedBiarylitides are a new class of ribosomally synthesized and post-translationally modified peptides (RiPPs) featuring the smallest reported precursor peptide and cytochrome P450-mediated cross-links. Here, we report the complete in vitro reconstitution of the myxobacterial biarylitide, myxarylin. We demonstrate that cross-linking is the first step and acts as a gatekeeper for downstream processing. The cytochrome P450 enzyme P450(BytO) from the myxarylin biosynthetic gene cluster exhibits remarkable substrate tolerance, allowing biosynthesis of new-to-nature thioamidated biarylitides through an unprecedented modular precursor peptide engineering approach. Surprisingly, changes in the precursor peptide sequence resulted in a shift in the installation of the P450(BytO)-mediated modification from the expected C- to the N-terminus. Leader peptide removal follows cross-linking and is likely carried out by a prolyl oligopeptidase (POP), a member of the serine protease family. The last step of the pathway involves N-terminal methylation, which also prevents premature degradation of the pathway intermediates by the POP. The crystal structure of the methyltransferase in complex with SAH and myxarylin allowed us to rationalize its substrate selectivity and guide protein engineering to expand its substrate scope. Myxarylin: Total In Vitro Biosynthesis, Expansion of Substrate Scope, and Bioengineered Thioamidated Biarylitides.,Sikandar A, Vianey L, Schliessmann K, Shen Q, Mackay CL, Haeckl FPJ, Urlacher VB, Naismith JH, Muller R J Am Chem Soc. 2026 Feb 25;148(7):6970-6980. doi: 10.1021/jacs.5c17257. Epub 2026 , Feb 13. PMID:41687121[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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