Theoretical and isotope effect studies on cytochrome P-450 mediated aromatic oxidation

Thesis/Dissertation · Thu Jan 01 04:00:00 EST 1987

OSTI ID:5276882

Korzekwa, K R

Both theoretical and experimental approaches were used to probe the mechanism of cytochrome P-450 mediated aromatic oxidation. The theoretical studies used semiempirical molecular orbital calculations (MNDO) to model possible addition-rearrangement pathways and to clarify the role of epoxide intermediates during phenol formation. Both biradical and protonated cationic pathways leading to epoxides, ketones, and phenols were characterized for a series of substituted benzenes and naphthalene. The heats of formation and other thermodynamic properties of the geometry optimized products, intermediate, and transition states provided free energies of activation and allowed the calculation of kinetic isotope effects. The results of this study indicated that biradical pathways show little or no substituent effects and the order or reaction rates is epoxide > ketone > phenol. The cationic pathways show marked substituent effects and the order of reaction rates is reversed with phenol > ketone > epoxide. The experimental studies involved the measurement of isotope effects associated with the metabolism of a series of deuterated chlorobenzenes. Positive isotope effects were observed for the meta hydroxylation of 3,5-/sup 2/H/sub 2/-,2,4,6-/sup 2/H/sub 3/-, and /sup 2/H/sub 5/-chlorobenzenes, whereas inverse isotope effects were measured for the ortho and para hydroxylation of 2,4,6-/sup 2/H/sub 3/-chlorobenzene.

• Research Organization: Washington Univ., Seattle (USA)
• OSTI ID: 5276882
• Country of Publication: United States
• Language: English

Related Subjects

550501 -- Metabolism-- Tracer Techniques
560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
AROMATICS
BIOLOGICAL PATHWAYS
CHLORINATED AROMATIC HYDROCARBONS
DEUTERIUM
ENZYMES
EPOXIDES
HALOGENATED AROMATIC HYDROCARBONS
HYDROGEN ISOTOPES
HYDROXY COMPOUNDS
ISOTOPE EFFECTS
ISOTOPES
KETONES
LIGHT NUCLEI
METABOLISM
MIXED-FUNCTION OXIDASES
NUCLEI
ODD-ODD NUCLEI
ORGANIC CHLORINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
OXIDOREDUCTASES
OXYGENASES
PHENOL
PHENOLS
STABLE ISOTOPES