Chemistry Weekly Seminar - Dr. Graham George

Title: The active site and catalytic mechanism of arsenite oxidase

Arsenic contamination in the environment arises from both natural and anthropogenic sources. In environmental terms, arsenic can have serious consequences, and in humans, exposure substantially increases the risks of cancer. This is most prevalent when the more toxic trivalent forms, are concerned such as arsenite As(OH)₃. Respiratory arsenite oxidases conduct the environmentally important conversion of more toxic arsenite to the much less toxic arsenate. The enzymes are thought to be ancient, originating before the divergence of the Archaea and the Bacteria. We have investigated the nature of the molybdenum active site of the arsenite oxidase from the Alphaproteobacterium Rhizobium sp. str. NT-26 using a combination of X-ray absorption spectroscopy and computational chemistry. Our analysis indicates an oxidized Mo(VI) active site with a structure that is far from equilibrium. We propose that this is an entatic state imposed by the protein on the active site through relative orientation of the two molybdopterin cofactors, in a variant of the Rây-Dutt twist of classical coordination chemistry, which we call the “pterin twist” hypothesis. The implications of this hypothesis for other putatively ancient molybdopterin based enzymes will be discussed.