Quantum Mechanics/Molecular Mechanics Studies on the Relative Reactivities of Compound I and II in Cytochrome P450 Enzymes.

The cytochromes P450 are drug metabolizing enzymes in the body that typically react with substrates through a monoxygenation reaction. During the catalytic cycle two reduction and protonation steps generate a high-valent iron (IV)-oxo heme cation radical species called Compound I. However, with sufficient reduction equivalents present, the catalytic cycle should be able to continue to the reduced species of Compound I, called Compound II, rather than a reaction of Compound I with substrate.

Understanding How Prolyl-4-hydroxylase Structure Steers a Ferryl Oxidant toward Scission of a Strong C-H Bond.

Prolyl-4-hydroxylase (P4H) is a non-heme iron hydroxylase that regio- and stereospecifically hydroxylates proline residues in a peptide chain into R-4-hydroxyproline, which is essential for collagen cross-linking purposes in the human body. Surprisingly, in P4H, a strong aliphatic C-H bond is activated, while thermodynamically much weaker aliphatic C-H groups, that is, at the C and C positions, are untouched. Little is known on the origins of the high regio- and stereoselectivity of P4H and many non-heme and heme enzymes in general, and insight into this matter may be relevant to Biotechnology as well as Drug Development.