Intermediate states of P-450 catalysis

The Holy Grail in the quest for a mechanistic understanding of cytochrome P-450 catalysis has been the observation of the key intermediate states of iron and oxygen that are critical to the special chemistries and reactivities observed for this class of monoxygenases. At this time point of mid-1997 there is probably a consensus that we have observed the dioxygen, peroxo, and single oxygen - iron complexes using techniques that span the range from rapid reaction methodologies to low temperature and ultra-fast x-ray diffraction. Mutant proteins, modified substrates, and altered oxygen donors have altered the rate limiting steps of catalysis to aid in the quest. Now that we may have the intermediates, what do we do with them? As Joseph of Arimathaea found, what one does with the Grail is more the problem. As the mechanistic enzymologists seeking the grail of P450 intermediates form an Order of Grail Knights, one worries that the field of discovery will become as the land around the Grail Castle at Muntsalvach: the Barren Wasteland. A purpose of this workshop should be to define the path to the city of Sarras, where the mysteries of the quest for mechanistic understanding will be revealed. Our research is supported by the National Institutes of Health.