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Model systems for flavoenzyme activity molecular recognition in multiple oxidation states

Eric C Breinlinger, University of Massachusetts Amherst


Flavoenzymes mediate a large number of oxidation and reduction reactions throughout nature. This wide variety of catalytic transformations is accomplished by virtue of a versatile flavin cofactor (usually FAD or FMN). The variety and nature of each individual non-covalent interaction has a specific effect on cofactor binding and reactivity. These non-covalent interactions are studied in the oxidized and one electron reduced states using model compounds to replicate enzymatic interactions. The effects of hydrogen bonding and aromatic stacking were examined in the oxidized and reduced states. The flavin undergoes hydrogen bonding to the oxidized state and is governed mainly by hydrogen bond donor ability and sterics of the model receptor. Hydrogen bonding is significantly enhanced in the one electron reduced state indicating selective recognition by hydrogen bonding of the reduced state with respect to the oxidized flavin. Aromatic stacking recognizes (binds) strongly the oxidized flavin and increases with increased aromatic overlap of flavin and aromatic stacking group. Reduction of the flavin is disfavored by aromatic stacking and thus reduces the association of the model receptor with the reduced flavin (as compared to association with the oxidized flavin.) A model for electrostatic interactions with the pyrimidine of flavin is examined. When linked to a primary recognition unit, electrostatic moieties (heteroatoms) are found to interact favorably with the electron deficient flavin. These interactions are a model for the positioning of main chain carbonyl groups in close proximity to the flavin aromatic face. Size and polarizability of the heteroatom governs the strength of interaction while reduction of the flavin has a mitigating effect. The electrostatic surface of the flavin is not uniform and distinct areas of this surface are found to interact differentially with dipoles. Positioning of the dipole with respect to the quadrupole of the flavin is found to modulate recognition of the flavin by approximately 0.5 Kcal/mol. Many of the reactions that flavoenzymes catalyze are the conversion between thiols and disulfides. A model for the interaction of thiols and disulfides with the flavin is developed. Preliminary results of these studies are discussed.

Subject Area

Organic chemistry

Recommended Citation

Breinlinger, Eric C, "Model systems for flavoenzyme activity molecular recognition in multiple oxidation states" (1998). Doctoral Dissertations Available from Proquest. AAI9909151.