Gliotoxin Biosynthesis: Structure, Mechanism, and Metal Promiscuity of Carboxypeptidase GliJ

ACS Chemical Biology
Antoine MarionEva M Huber

Abstract

The formation of glutathione (GSH) conjugates, best known from the detoxification of xenobiotics, is a widespread strategy to incorporate sulfur into biomolecules. The biosynthesis of gliotoxin, a virulence factor of the human pathogenic fungus Aspergillus fumigatus, involves attachment of two GSH molecules and their sequential decomposition to yield two reactive thiol groups. The degradation of the GSH moieties requires the activity of the Cys-Gly carboxypeptidase GliJ, for which we describe the X-ray structure here. The enzyme forms a homodimer with each monomer comprising one active site. Two metal ions are present per proteolytic center, thus assigning GliJ to the diverse family of dinuclear metallohydrolases. Depending on availability, Zn2+, Fe2+, Fe3+, Mn2+, Cu2+, Co2+, or Ni2+ ions are accepted as cofactors. Despite this high metal promiscuity, a preference for zinc versus iron and manganese was noted. Mutagenesis experiments revealed details of metal coordination, and molecular modeling delivered insights into substrate recognition and processing by GliJ. The latter results suggest a reaction mechanism in which the two scissile peptide bonds of one gliotoxin precursor molecule are hydrolyzed sequentially and in a given ...Continue Reading

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Citations

Jul 26, 2019·Angewandte Chemie·Joshua A BaccileFrank C Schroeder
Jun 30, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ilya Lyagin, Elena Efremenko
Dec 11, 2019·International Journal of Molecular Sciences·Hyewon SeoCheol-Won Yun
Aug 25, 2020·Chembiochem : a European Journal of Chemical Biology·Daniel H ScharfChristian Hertweck
Apr 29, 2021·Angewandte Chemie·Kirstin ScherlachEva M Huber
Mar 3, 2020·Journal of Natural Products·Meng-Hua WangZhong-Mei Zou

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