Problems in the Bioinorganic Chemistry of Molybdenum and Tungsten

Harvard University, Cambridge MA

Investigators

Abstract

This award in the Inorganic, Bioinorganic and Organometallic Chemistry program supports research by Professor Richard H. Holm at Harvard University that centers on transformations catalyzed by the molybdenum and tungsten oxotransferases and hydroxylases. Many of these reactions are pure oxygen atom (oxo) transfer processes, in which an oxygen atom is inserted or removed (oxotransferases) while others utilize metalcoordinated hydroxide in the catalytic reaction (hydroxylases). The tungsten-containing enzymes are usually found in hyperthermophilic bacteria and archaea. In practically all cases, the ultimate source or sink of oxygen atoms is water. The catalytic centers contain mononuclear molybdenum or tungsten atoms bound to one or two pyranopterindithiolene ligands. The experimental approach involves the synthesis of low molecular weight analogues of the catalytic sites of enzymes and their utilization in reactivity investigations. The research builds upon synthetic and reactivity results with analogues of the catalytic sites of enzymes that contain two pyranopterindithiolene ligands and reduce organic S-oxides and N-oxides by atom transfer. The natural ligand is represented by a synthetic dithiolene, which functions as an ene-1,2-dithiolate when bound to molybdenum or tungsten and closely simulates the electronic environment engendered by the native coordination. A new and possibly general method of synthesis of dithiolene complexes is proposed in order to examine analogue reactions of the enzymes selenate reductase, arsenite oxidase, formate dehydrogenase, acetylene hydratase, aldehyde oxidase, and carbon monoxide dehydrogenase. Other systems include the transhydroxylases and ethylbenzene dehydrogenase. Functional analogue systems that transform substrates as do enzymes (but not necessarily in the same reaction rate domain) with metal sites credibly similar to those of the enzymes and providing close approaches to enzyme-site geometric and electronic structures, are the focus of this research. Molybdenum and tungsten enzymes are implicated in global cycles thet process carbon, nitrogen, sulfur, arsenic, and selenium. Certain enzymes such as the sulfite and xanthine oxidases occur in humans; their malfunction leads to significant health risks. For example, the absence of sulfite oxidase can lead to mental retardation. Reduced ability to biosynthesize the pyranopterindithiolene ligand will lead to deficiencies in all molybdoenzymes with accompanying diseases including neurological syndromes. The broader potential impact of the proposed research derives from a better understanding of the structure, function, and mechanism of biological molybdenum/tungsten centers at all levels, and an integration of that information into improved interpretation of geochemical and environmental cycles of the these elements and those contained in enzymatic substrates.