Cytochrome P450 Enzyme Mechanisms

In this chapter, we examine the oxygen activation mechanisms used by cytochrome P450 enzymes (CYPs) and related heme-thiolate enzymes. A particular emphasis is placed on new insight gleaned from recent spectroscopic and kinetic interrogations on the structure and reactivity of iron-oxygen intermediates in the catalytic cycle, many of which have been recently identified. We explore how the tuning of ferryl species, either through the nature of the axial ligand or non-covalent effects can be used to afford reactions ranging from catabolic metabolism to highly specific biosynthetic pathways. Following a progression through a current view of the CYP catalytic cycle, we discuss a few instances where deviation from the canonical hydrogen atom transfer (HAT)/oxygen rebound pathway occurs to afford novel C–C cleavage and C–C coupling outcomes. Together, these examples serve to demonstrate the flexibility of iron-oxo intermediates for challenging transformations.