Coenzyme A esters of 2-aryloxyphenoxypropionate herbicides and 2-arylpropionate antiinflammatory drugs are potent and stereoselective inhibitors of rat liver acetyl-CoA carboxylase.
The CoA esters of diclofop, haloxyfop and fluazifop are up to 425-fold more potent than the corresponding unconjugated herbicides as inhibitors of rat liver acetyl-CoA carboxylase (EC 6.4.1.2); the most potent inhibitor is (R)-fluazifopyl-CoA2 (Ki = 0.03 microM). The binding site is stereoselective for (R)-diclofop, the herbicidally active enantiomer, and for (R)-diclofopyl-CoA. The CoA esters of the antiinflammatory drugs ibuprofen and fenoprofen also strongly inhibit this carboxylase. (S)-Ibuprofenyl-CoA (Ki = 0.7 microM), the CoA ester of the enantiomer with antiinflammatory activity, is 15-fold more potent as an inhibitor than (R)-ibuprofenyl-CoA. These results suggest that some of the biological effects of these herbicides and antiinflammatory drugs in animals may be due to the inhibition of acetyl-CoA carboxylase by their acyl-CoA derivatives.
Kemal
C
C
Department of Entomological Sciences, University of California, Berkeley 94720.
Casida
J E
JE
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D000818:Animals; D001665:Binding Sites; D003065:Coenzyme A / Q000737:chemistry*; D004095:Dihydropyridines / Q000494:pharmacology; D004952:Esters / Q000737:chemistry*; D005279:Fenoprofen / Q000737:chemistry / Q000494:pharmacology*; D055768:Halogenated Diphenyl Ethers; D006540:Herbicides / Q000737:chemistry / Q000494:pharmacology*; D007052:Ibuprofen / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D010647:Phenyl Ethers / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004095:Dihydropyridines; D004952:Esters; D055768:Halogenated Diphenyl Ethers; D006540:Herbicides; D010647:Phenyl Ethers; D011725:Pyridines; C054176:haloxyfop; C050582:fluazifop; C012891:dichlorfop-methyl; D000103:Acetyl-CoA Carboxylase; D005279:Fenoprofen; D003065:Coenzyme A; D007052:Ibuprofen