On the possible mechanism of phenylacetate neurotoxicity: inhibition of choline acetyltransferase by phenylacetyl-CoA.
The influence of phenylacetate, phenylbutyrate, and phenylacetyl-CoA on the activity of choline acetyltransferase and S-acetyl-CoA synthetase was investigated in vitro. Phenylacetyl-CoA was found to be a very potent inhibitor of choline acetyltransferase, competitive for acetyl-CoA with Ki of 3.1 X 10(-7)M. In contrast, millimolar concentrations of phenylacetate and phenylbutyrate were required to inhibit the activity of the enzyme. Activity of S-acetyl-CoA synthetase was affected only slightly by the three agents in concentrations of 10(-3)-10(-2)M. At this time, results are interpreted to suggest that in phenylketonuria, phenylacetate exerts its neurotoxic action through its metabolic product, phenylacetyl-CoA, which could severely decrease the availability of acetyl-CoA.
D000106:Acetate-CoA Ligase / Q000037:antagonists & inhibitors; D000105:Acetyl Coenzyme A / Q000031:analogs & derivatives* / Q000633:toxicity; D002795:Choline O-Acetyltransferase / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D007700:Kinetics; D009498:Neurotoxins; D010648:Phenylacetates / Q000633:toxicity*; D010661:Phenylketonurias / Q000378:metabolism; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D012441:Saccharomyces cerevisiae / Q000201:enzymology
D009498:Neurotoxins; D010648:Phenylacetates; D000105:Acetyl Coenzyme A; C037816:phenylacetyl-coenzyme A; D002795:Choline O-Acetyltransferase; D000106:Acetate-CoA Ligase; C025136:phenylacetic acid