Xanthine Dehydrogenase Active Site: Chiral Switching and Substrate Coordination

Abstract

Analysis of electronic, structural and mechanistic parameters of the enzyme-substrate reaction of xanthine oxidase, a member of the xanthine dehydrogenase class of mono-molybdopterin oxidoreductive enzymes, shows that the molybdenum center in the enzyme active site acts as a reversible chiral switch. The metal center cycles from the (S)-absolute configuration, SPY-5-42-A, in the fully oxidized state, Mo(VI), to the (R)-absolute configuration, SPY-5-43-C, for the fully reduced metal center, Mo(IV). This process is complemented by induction of chirality at the substrate carbon center (pro-SC → SC) and is involved in the control of coordination and, likely, protonation of imino-centers of conjugated heterocyclic substrates in the enzyme active site.