TRANSITION STRUCTURE AND REACTIVE COMPLEXES FOR HYDRIDE TRANSFER IN AN ISOALLOXAZINE-NICOTINAMIDE COMPLEX - ON THE CATALYTIC MECHANISM OF GLUTATHIONE-REDUCTASE - AN AB-INITIO MO SCF STUDY

An analysis is presented of the catalytic mechanism of glutathione red uctase based upon a theoretically characterized saddle point of index one obtained for a model representing the active groups of the flavine and nicotinamide adenine dinucleotide phosphate, namely, an isoalloxa zine and nicotinamide rings, The isoalloxazine rings appears deformed into a butterfly conformation in the saddle point of index one. The bu tterfly conformation is retained along the path leading to a reduced i soalloxazine (N5-H) forcing the transferred hydrogen to stick into the nicotinamide binding site, this geometric feature suggests the existe nce of a transposed hydride transfer path where the NS-proton goes bac k to a lysine residue leaving the electrons on FAD. This mechanism is discussed and proposed as an alternative catalytic pathway in glutathi one reductase to the standard electron transfer one, These results hel p to understand the riddle created by the changing kinetic behavior of glutathione reductase when, for instance, 2,4,6-trinitro-benzene sulf onate is used to study in vitro kinetics or when specific site directe d mutagenesis is performed.