Matabaro_2022_bioRxiv__

Reference

Title : Molecular insight into the enzymatic macrocyclization of multiply backbone N-methylated peptides - Matabaro_2022_bioRxiv__
Author(s) : Matabaro E , Song H , Sonderegger L , Gherlone F , Giltrap A , Liver S , Gossert A , Kunzler M , Naismith JH
Ref : Biorxiv , : , 2022
Abstract :

The enzyme OphP is essential for the biosynthesis of the macrocyclic peptide omphalotin A, a dodecamer with 9 backbone N-methylations produced by the wood-degrading fungus Omphalotus olearius. Heterologous expression of OphP and the peptide-precursor protein OphMA in yeast, yields omphalotin A. Thus, Oph P was hypothesized to have a dual function; catalyzing both endoproteolytic release of a peptide intermediate from OphMA, and macrocyclization of the multiply alpha-N-methylated core peptide with concomitant release of a C-terminal follower peptide. In our in vitro activity assays, OphP showed robust endoproteolytic and macrocyclase activity on alpha-N-methylated peptides but was unable to cleave OphMA. The enzyme had a strong preference for hydrophobic, highly alpha-N-methylated peptides and an alpha-N-methylated glycine residue at the P1 site. OphP adopts a canonical prolyl oligopeptidase (POP) fold with a predominantly hydrophobic substrate binding cleft, and a small and hydrophobic P1 binding pocket. We demonstrate that OphP is a POP-type macrocyclase with a specificity and a substrate route to the active site different from other members of the family. These results could be exploited for the biotechnological production of macrocyclic peptides with multiple backbone N-methylations, which are interesting due to their favorable pharmacological properties.

PubMedSearch : Matabaro_2022_bioRxiv__
PubMedID:
Gene_locus related to this paper: ompol-OphP

Related information

Inhibitor Z-Pro-Prolinal
Substrate OphMA-core-peptide-15mer    OphMA-core-peptide-18mer
Gene_locus ompol-OphP
Structure 7ZAZ    7ZB0    7ZB1    7ZB2

Citations formats

Matabaro E, Song H, Sonderegger L, Gherlone F, Giltrap A, Liver S, Gossert A, Kunzler M, Naismith JH (2022)
Molecular insight into the enzymatic macrocyclization of multiply backbone N-methylated peptides
Biorxiv :

Matabaro E, Song H, Sonderegger L, Gherlone F, Giltrap A, Liver S, Gossert A, Kunzler M, Naismith JH (2022)
Biorxiv :