Quantitative Structure−Activity Relationship Based Quantification of the Impacts of Enzyme−Substrate Binding on Rates of Peroxidase-Mediated Reactions of Estrogenic Phenolic Chemicals

Abstract

The initial rates of horseradish peroxidase (HRP)-mediated enzymatic reactions of 15 assorted aqueous phase phenolic chemicals were studied. The associated reaction rate constants were found to correlate quantitatively with two independent variables: the highest-occupied molecular orbital energy (E(HOMO)) defining the intrinsic redox reactivities of the phenolic substrates and the distance between a substrate and the deltaN of HIS42's imidazole ring in an HRP/substrate binding complex, obtained through molecular simulations. Highly correlated quantitative structure-activity relationship (QSAR) equations were thus developed. This work provides insights into the impacts that HRP/substrate binding may have on HRP-mediated reactions. Additionally, the QSAR equations developed in the work may serve as a basis to further explore the potential use of HRP-mediated reactions in the treatment of estrogenic contaminants, and they constitute an important tool for redesign and screening of potential proteomic modifications to the wild-type HRP structure intended to enhance reactivity toward selected substrates.

Chemical kinetics and interactions involved in horseradish peroxidase-mediated oxidative polymerization of phenolic compounds

“…Similar observations can be made with data published previously by Auriol et al, 2007. Interestingly, k cat is positively correlated with E HOMO (Colosi et al, 2006), which makes sense because k cat and E HOMO relate to the maximum reaction rate potential. It is also determined that k r does not correlate well with E HOMO as shown by Figure 10.…”

“…Sakurado et al 1990 andBrewster et al 1991 r eported fairly strong correlations with coefficient of 0.86 a nd 0.89 r espectively between compound II reactivity and the E LUMO for sets of substituted phenols. However, Hosoya et al 1983 andColosi et al 2006 reported no significant correlation for a set of similar substrates.…”

“…Correlations between k cat and the energy of the lowest unoccupied molecular orbital (E LUMO ) have also produced mixed results for substituted phenols (Sakurada et al, 1990, Brewster et al, 1991, Hosoya et al, 1983, Colosi et al, 2006. Sakurado et al 1990 andBrewster et al 1991 r eported fairly strong correlations with coefficient of 0.86 a nd 0.89 r espectively between compound II reactivity and the E LUMO for sets of substituted phenols.…”

“…The flexible amino acids residues were HIS42, ARG38, PHE41, and ASN70. The binding distance was between the substrate's phenolic proton and the imidazole δN on the HIS42 residue as suggested previously (Colosi et al, 2006).…”

QSAR studies on the depuration rates of polycyclic aromatic hydrocarbons, polybrominated diphenyl ethers and polychlorinated biphenyls in mussels (Elliptio complanata)

“…Quantum chemical parameters such as E HOMO , E LUMO , qH þ and q À were proved successful in many QSAR studies for characterizing intermolecular electrostatic interactions [26]. The electrophilicity index !…”