Molybdenum (Mo) is critical to the health of nearly every organism on earth. Humans have an absolute requirement for several molybdenum enzymes and one in particular is critical for proper embryo development to maturity. Inherited diseases in humans result in compromised molybdenum enzymes causing pervasive neurological problems at best and infant fatalities at worst. Despite fifty years'of research on molybdenum enzymes, the function and certain structural aspects of the unique ligand chelating Mo in these proteins remain a mystery. This ligand is a pterin-substituted dithiolene chelate and is found only in molybdenum and the related tungsten enzymes. Human diseases resulting from molybdoenzyme disfunction have been linked to errors in the pterin-dithiolene biosynthetic path which underscores the pivotal role of the ligand in enzyme function. This project will undertake a detailed study of the chemical behavior and reactivity of a Mo-pyranopterin- dithiolene model complex designed to be nearly identical to the Mo site in the enzymes. The goal is to understand how conformation and redox changes at the pterin influence the electronic structure of the entire pterin-dithiolene ligand coordinated to Mo in the enzymes. Of particular interest is establishing the pyran ring reactivity towards scission and how the gamut of known pterin redox chemistry is altered when pterin is fused to a pyran ring and a dithiolene ligand. Specific objectives are: (a) to determine those factors that influence pyran ring cyclization and cleavage on pterin-dithiolene ligands chelated to Mo;(b) to understand the redox chemistry and properties of pyranopterin dithiolene ligands using chemical and electrochemical methods;(c) to probe the electronic effects of pterins at different levels of reduction on the Mo-dithiolene unit;and (d) to accomplish full spectroscopic and structural characterization of all model compounds. The results are critical to a complete understanding of how the Mo site functions and how the pterin-dithiolene might be involved in dysfunctional enzymes. It is expected that these studies will: a) reveal what chemical reactivity exists for pterin-dithiolene ligands within the Mo enzymes, and this understanding will b) provide insights for how the protein environment could influence pterin behavior;(c) provide spectroscopic and structural benchmarks to aid interpretation of similar results from the enzymes and (d) describe fundamental chemistry of the active site chemistry of Mo and W enzymes to be exploited for possible future therapies.
The relationship of molybdenum to human health is far less well known by the general public than that of familiar essential metals iron, copper and zinc. In humans, rare inherited diseases result in compromised molybdenum enzymes causing pervasive neurological problems at best and infant fatalities at worst. The goal of this project is to gain a more detailed understanding of how the unique ligand environment of molybdenum in molybdoenzymes is critical to the enzyme activity.
|Williams, Benjamin R; Gisewhite, Douglas; Kalinsky, Anna et al. (2015) Solvent-Dependent Pyranopterin Cyclization in Molybdenum Cofactor Model Complexes. Inorg Chem 54:8214-22|
|Basu, Partha; Burgmayer, Sharon J Nieter (2015) Recent developments in the study of molybdoenzyme models. J Biol Inorg Chem 20:373-83|
|Williams, Benjamin R; Fu, Yichun; Yap, Glenn P A et al. (2012) Structure and reversible pyran formation in molybdenum pyranopterin dithiolene models of the molybdenum cofactor. J Am Chem Soc 134:19584-7|
|Basu, Partha; Burgmayer, Sharon J N (2011) Pterin chemistry and its relationship to the molybdenum cofactor. Coord Chem Rev 255:1016-1038|
|Matz, Kelly G; Mtei, Regina P; Rothstein, Rebecca et al. (2011) Study of molybdenum(4+) quinoxalyldithiolenes as models for the noninnocent pyranopterin in the molybdenum cofactor. Inorg Chem 50:9804-15|
|Matz, Kelly G; Mtei, Regina P; Leung, Belinda et al. (2010) Noninnocent dithiolene ligands: a new oxomolybdenum complex possessing a donor-acceptor dithiolene ligand. J Am Chem Soc 132:7830-1|