title: The mitochondrial amidoxime reducing component (mARC): involvement in metabolic reduction of N-oxides, oximes and N-hydroxyamidinohydrazones.
abstract: The mitochondrial amidoxime reducing component (mARC) is a molybdenum-containing enzyme and capable of reducing N-hydroxylated structures such as amidoxime prodrugs. In this study, we tested the involvement of mARC in the reduction of N-oxides (amitriptyline-N-oxide, nicotinamide-N-oxide), oximes ((E)-/(Z)-2,4,6-trimethylacetophenonoxime) and a N-hydroxyamidinohydrazone (guanoxabenz). All groups are reduced by mARC proteins, and the enzymes are therefore involved in the interconversion of N-oxygenated metabolites originating from cytochrome P450s and flavin-containing monooxygenases. In addition, these structures open up further options for serving as prodrugs. Thus, with respect to these reactions, testing of candidates with N-oxygenated structures should not solely be carried out in microsomal enzyme sources but as well in mitochondria. However, differences in the reduction of oximes and N-oxides between the two isoforms, namely mARC1 and mARC2, were detectable; N-oxides are exclusively reduced by mARC1. We therefore assume differences between the so far unknown 3D structures of the two proteins.
authors.affiliation: Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, Christian-Albrechts-Universität zu Kiel, Gutenbergstrasse 76, 24188 Kiel (Germany).
authors.forename: Heyka H
authors.initials: HH
authors.lastname: Jakobs
authors.forename: Danilo
authors.initials: D
authors.lastname: Froriep
authors.forename: Antje
authors.initials: A
authors.lastname: Havemeyer
authors.forename: Ralf R
authors.initials: RR
authors.lastname: Mendel
authors.forename: Florian
authors.initials: F
authors.lastname: Bittner
authors.forename: Bernd
authors.initials: B
authors.lastname: Clement
mesh_terms: D006835:Hydrazones / Q000737:chemistry*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D010091:Oximes / Q000494:pharmacology*
chemical_list: D006835:Hydrazones; D010087:Oxides; D010091:Oximes
keywords: Moco sulfurase C-terminal domain/MOSC; metabolism; mitochondrial amidoxime reducing component; nitrogene oxides; oximes