STRUCTURAL MODELS FOR MOLYBDOENZYMES

University Of Arizona, Tucson AZ

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Abstract

Molybdenum is an essential trace element for all forms of life, and over 30 molybdoenzymes are known that catalyze oxidation-reduction reactions that are essential in the metabolism of carbon, nitrogen and sulfur. In humans molybdoenzymes play physiologically vital roles in the oxidation of sulfite to sulfate (sulfite oxidase) and in certain aspects of purine metabolism (xanthine oxidase). Fatal simultaneous deficiencies in the activities of both of these enzymes due to an inborn deficiency of a "molybdenum cofactor" have been well documented in children. Point defects in the sulfite oxidase protein itself can also produce the severe neurological symptoms of sulfite oxidase deficiency. These symptoms include dislocated ocular lenses, mental retardation, and, in severe cases, attenuated growth of the brain and early death. Development of methods to clone and express human sulfite oxidase has revealed several different clinical point mutations that result in isolated sulfite oxidase deficiency. The X-ray structure of the highly homologous chicken liver sulfite oxidase provides a molecular basis for interpreting the fatal point mutations of the human enzyme. The research proposed here addresses the fundamental properties of sulfite oxidase by an integrated program of biochemical, biophysical and model compound studies. Emphasis will be given to the use of electron spin echo envelope modulation (ESEEM) spectroscopy to probe the molybdenum environment; to developing pulsed electron-electron double resonance (ELDOR) spectroscopy to probe the molybdenum-iron interaction; and to studying the factors that control the rates of intramolecular electron transfer between the molybdenum and iron centers in native and mutant sulfite oxidase proteins.