Journal
CHEMISTRY & BIOLOGY
Volume 21, Issue 12, Pages 1610-1617Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2014.10.015
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Funding
- NIH General Medical Sciences [1R01-GM088274]
- Division of Chemical Sciences, Geosciences and Biosciences, Office of Basic Energy Sciences, Office of Science, U.S. Department of Energy [DE-FG02-91ER20021]
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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 alpha-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 alpha-amanitin posttranslational processing, the exact mechanistic details are not known. Here, 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. On the other hand, we show that GmPOPA, the putative housekeeping POP of G. marginata, behaves like a conventional POP.
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