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Title: Peptide Macrocyclization Catalyzed by a Prolyl Oligopeptidase Involved in α-Amanitin Biosynthesis

Amatoxins are ribosomally encoded and posttranslationally modified peptides that account for the majority of fatal mushroom poisonings of humans. A representative amatoxin is the bicyclic octapeptide α-amanitin, formed via head-to-tail macrocyclization, which is ribosomally biosynthesized as a 35-amino acid propeptide in Amanita bisporigera and in the distantly related mushroom Galerina marginata. Although members of the prolyl oligopeptidase (POP) family of serine proteases have been proposed to play a role in α-amanitin posttranslational processing, the exact mechanistic details are not known. In this paper, we show that a specific POP (GmPOPB) is required for toxin maturation in G. marginata. Recombinant GmPOPB catalyzed two nonprocessive reactions: hydrolysis at an internal Pro to release the C-terminal 25-mer from the 35-mer propeptide and transpeptidation at the second Pro to produce the cyclic octamer. Finally on the other hand, we show that GmPOPA, the putative housekeeping POP of G. marginata, behaves like a conventional POP.
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1]
  1. Michigan State Univ., East Lansing, MI (United States)
Publication Date:
OSTI Identifier:
1233906
Grant/Contract Number:
FG02-91ER20021
Type:
Published Article
Journal Name:
Chemistry & Biology
Additional Journal Information:
Journal Volume: 21; Journal Issue: 12; Journal ID: ISSN 1074-5521
Publisher:
Elsevier
Research Org:
Michigan State Univ., East Lansing, MI (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES