The fourth molybdenum containing enzyme mARC: cloning and involvement in the activation of N-hydroxylated prodrugs

  • J Med Chem. 2008 Dec 25;51(24):8173-7. doi: 10.1021/jm8010417.
Sanja Gruenewald  1 ,  Bettina Wahl ,  Florian Bittner ,  Helen Hungeling ,  Stephanie Kanzow ,  Joscha Kotthaus ,  Ulrike Schwering ,  Ralf R Mendel ,  Bernd Clement
Affiliations
  • 1. Pharmaceutical Institute, Department of Pharmaceutical and Medicinal Chemistry, Christian-Albrechts-University of Kiel, Gutenbergstrasse 76, D-24118 Kiel, Germany.
PMID: 19053771 DOI: 10.1021/jm8010417
Abstract

The recently discovered mammalian molybdoprotein mARC1 is capable of reducing N-hydroxylated compounds. Upon reconstitution with cytochrome b(5) and b(5) reductase, benzamidoxime, pentamidine, and diminazene amidoximes, N-hydroxymelagatran, guanoxabenz, and N-hydroxydebrisoquine are efficiently reduced. These substances are amidoxime/N-hydroxyguanidine prodrugs, leading to improved bioavailability compared to the active amidines/guanidines. Thus, the recombinant enzyme allows prediction about in vivo reduction of N-hydroxylated prodrugs. Furthermore, the prodrug principle is not dependent on Cytochrome P450 enzymes.