TY - JOUR
T1 - Theoretical study of the cytochrome P450 mediated metabolism of phosphorodithioate pesticides
AU - Rydberg, Patrik
PY - 2012/8/14
Y1 - 2012/8/14
N2 - The toxicity of phosphorodithioate pesticides is due to the formation of the active oxane product through desulfurization by cytochrome P450 enzymes, both in humans and insects. During this desulfurization, inhibition of cytochrome P450 and a loss of heme has been observed. Here, we study the mechanism of desulfurization and inhibition with density functional theory, using the B3LYP functional with and without dispersion correction. The results show that a reaction mechanism initiated by sulfur oxidation is most likely, with a reaction barrier of 47 kJ/mol. The sulfur oxidation is followed by a ring-closing mechanism with a barrier of 28 kJ/mol relative to the sulfur-oxidized intermediate. The enzymatic contribution to the ring-closing is very small. It is also shown that the apparent loss of heme might be due to the formation of a previously unknown inhibition complex, which changes the aromatic conjugation of the porphyrin ring. We also show that including dispersion correction has significant effects on a ring closure transition state (~30 kJ/mol), whereas effects on the other steps in the reaction are relatively small (4-15 kJ/mol).
AB - The toxicity of phosphorodithioate pesticides is due to the formation of the active oxane product through desulfurization by cytochrome P450 enzymes, both in humans and insects. During this desulfurization, inhibition of cytochrome P450 and a loss of heme has been observed. Here, we study the mechanism of desulfurization and inhibition with density functional theory, using the B3LYP functional with and without dispersion correction. The results show that a reaction mechanism initiated by sulfur oxidation is most likely, with a reaction barrier of 47 kJ/mol. The sulfur oxidation is followed by a ring-closing mechanism with a barrier of 28 kJ/mol relative to the sulfur-oxidized intermediate. The enzymatic contribution to the ring-closing is very small. It is also shown that the apparent loss of heme might be due to the formation of a previously unknown inhibition complex, which changes the aromatic conjugation of the porphyrin ring. We also show that including dispersion correction has significant effects on a ring closure transition state (~30 kJ/mol), whereas effects on the other steps in the reaction are relatively small (4-15 kJ/mol).
UR - http://www.scopus.com/inward/record.url?scp=84865099341&partnerID=8YFLogxK
U2 - 10.1021/ct300347z
DO - 10.1021/ct300347z
M3 - Journal article
C2 - 26592116
AN - SCOPUS:84865099341
SN - 1549-9618
VL - 8
SP - 2706
EP - 2712
JO - Journal of Chemical Theory and Computation
JF - Journal of Chemical Theory and Computation
IS - 8
ER -