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A fundamental catalytic difference between zinc and manganese dependent enzymes revealed in a bacterial isatin hydrolase

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  • Theis Sommer, Universitetet i Oslo
  • ,
  • Kaare Bjerregaard-Andersen, Universitetet i Oslo
  • ,
  • Lalita Uribe, Universität Mainz
  • ,
  • Michael Etzerodt
  • Gregor Diezemann, Universität Mainz
  • ,
  • Jürgen Gauss, Universität Mainz
  • ,
  • Michele Cascella, Universitetet i Oslo
  • ,
  • J. Preben Morth, Norwegian Center of Molecular Medicine, Universitetet i Oslo, Institute for Experimental Medical Research, University of Oslo, Enzyme and Protein Chemistry, Technical University of Denmark

The catalytic mechanism of the cyclic amidohydrolase isatin hydrolase depends on a catalytically active manganese in the substrate-binding pocket. The Mn2+ ion is bound by a motif also present in other metal dependent hydrolases like the bacterial kynurenine formamidase. The crystal structures of the isatin hydrolases from Labrenzia aggregata and Ralstonia solanacearum combined with activity assays allow for the identification of key determinants specific for the reaction mechanism. Active site residues central to the hydrolytic mechanism include a novel catalytic triad Asp-His-His supported by structural comparison and hybrid quantum mechanics/classical mechanics simulations. A hydrolytic mechanism for a Mn2+ dependent amidohydrolases that disfavour Zn2+ as the primary catalytically active site metal proposed here is supported by these likely cases of convergent evolution. The work illustrates a fundamental difference in the substrate-binding mode between Mn2+ dependent isatin hydrolase like enzymes in comparison with the vast number of Zn2+ dependent enzymes.

Original languageEnglish
Article number13104
JournalScientific Reports
Number of pages11
Publication statusPublished - 30 Aug 2018

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