The fourth molybdenum containing enzyme mARC: cloning and involvement in the activation of N-hydroxylated prodrugs.
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.
Gruenewald
Sanja
S
Pharmaceutical Institute, Department of Pharmaceutical and Medicinal Chemistry, Christian-Albrechts-University of Kiel, Gutenbergstrasse 76, D-24118 Kiel, Germany.
Wahl
Bettina
B
Bittner
Florian
F
Hungeling
Helen
H
Kanzow
Stephanie
S
Kotthaus
Joscha
J
Schwering
Ulrike
U
Mendel
Ralf R
RR
Clement
Bernd
B
D000818:Animals; D001550:Benzamidines / Q000737:chemistry; D002417:Cattle; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003001:Cloning, Molecular; D042966:Cytochrome-B(5) Reductase / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D008982:Molybdenum / Q000737:chemistry*; D010088:Oxidoreductases / Q000737:chemistry* / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D013696:Temperature
D001550:Benzamidines; D008024:Ligands; D011355:Prodrugs; D011994:Recombinant Proteins; C053561:benzamidoxime; D008982:Molybdenum; D010088:Oxidoreductases; C534493:amidoxime reducing component, human; D042966:Cytochrome-B(5) Reductase