A response to stress within the human body involves the C11-hydroxylation of 11-deoxycorticosterone (DOC) to corticosterone by the enzyme cytochrome P450 CYP11B2 (Figure 1). The inhibition of this pathway is a target for stress management techniques, and there are many postulated inhibitors of the enzyme. The phytochemical sutherlandioside B (SU1) of Sutherlandia frutescens lowers corticosterone and acts as a natural inhibitor (Sergent, 2009). Additional naturally occurring inhibitors of CYP11B2 include ethyl caffeate and labiatenic acid which are sourced from Bidens pilosa and Rosmarinus officinalis (Menard et al., 2014). Our research explores the mechanistic qualities of the enzymatic hydroxylation of deoxycorticosterone via CYP11B2 to further understand possible inhibition mechanisms. An initial study was performed on a small model system containing the iron/parent porphyrin complex, the apical ligand methyl sulfide and a hydrocarbon propane. This study provided a foundation for electronic structure and spin distributions with chemical accuracy. The system was computed at the quantum mechanical level. Results suggest a stepwise radical mechanism that initializes with hydrogen abstraction and subsequent hydroxyl group migration. A more realistic model system was developed from the crystal structure of CYP11B2 Cytochrome P450 complexed to deoxycorticosterone (PDB 4DVQ). We employed multilevel methods (ONIOM) for accurate computation of the system. The active site contained the iron-porphyrin complex with a cysteine ligand and the steroid deoxycorticosterone, which were treated with density functional theory. Critical amino acid residues were carefully selected to obtain a region surrounding the active site and were described using semi-empirical methods. The propane-oxidation model provided the foundation for the ONIOM study, which establishes how thermochemical parameters are affected by the enzymatic environment.

Your body’s response to stress: The enzymatic oxidation of deoxycorticosterone by cytochrome P450 CYP11B2

ACS Fall 2021

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