Macrocyclization of backbone N-methylated peptides by a prolyl oligopeptidase with a distinctive substrate recognition mechanism
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2025-08-21
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Journal Article
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yes
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Abstract
Macrocyclization and multiple backbone N-methylations can significantly improve the pharmacological properties of peptides. Since chemical synthesis of such compounds is often challenging, enzyme-based production platforms are an interesting option. Here, we characterized OphP, a serine peptidase involved in the cyclization of omphalotins, a group of ribosomally produced dodecapeptides with multiple backbone N-methylations. OphP displays robust peptidase and macrocyclase activity towards multiply alpha-N-methylated peptides of various lengths and composition derived from the omphalotin precursor protein OphMA. In addition, OphP processes, with lower efficiency, peptides unrelated to OphMA, containing a MeGly, MeAla or Pro residue at the P1 site. Structural analysis reveals that OphP adopts a canonical prolyl oligopeptidase fold but, unlike other enzymes of this enzyme family, recognizes its substrates by their hydrophobic and multiply backbone N-methylated core rather than by the follower peptide. The activity of OphP could be harnessed for the enzymatic production of therapeutic peptides.
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published
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Volume
16 (31)
Pages / Article No.
14196 - 14206
Publisher
Royal Society of Chemistry
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08838 - Künzler, Markus (Tit.-Prof.)
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173097 - Molecular dissection of the chemical defense system of multicellular fungi against predation (SNF)