关于苯乙酸神经毒性的可能机制：苯乙酰辅酶A对胆碱乙酰转移酶的抑制作用。

On the possible mechanism of phenylacetate neurotoxicity: inhibition of choline acetyltransferase by phenylacetyl-CoA.

作者信息

Potempska A, Loo Y H, Wisniewski H M

出版信息

J Neurochem. 1984 May;42(5):1499-501. doi: 10.1111/j.1471-4159.1984.tb02819.x.

DOI:10.1111/j.1471-4159.1984.tb02819.x

Abstract

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.

摘要

在体外研究了苯乙酸、苯丁酸和苯乙酰辅酶A对胆碱乙酰转移酶和S-乙酰辅酶A合成酶活性的影响。发现苯乙酰辅酶A是胆碱乙酰转移酶的一种非常有效的抑制剂，对乙酰辅酶A具有竞争性，其抑制常数（Ki）为3.1×10⁻⁷M。相比之下，需要毫摩尔浓度的苯乙酸和苯丁酸才能抑制该酶的活性。10⁻³ - 10⁻²M浓度的这三种试剂对S-乙酰辅酶A合成酶的活性影响很小。目前，研究结果表明，在苯丙酮尿症中，苯乙酸通过其代谢产物苯乙酰辅酶A发挥神经毒性作用，这可能会严重降低乙酰辅酶A的可用性。