Vamecq J, Vallee L, Fontaine M, Lambert D, Poupaert J, Nuyts J P
North France Center for the Study of Childhood Epilepsy, Hôpital B, Centre Hospitalier Régional Universitaire de Lille, France.
FEBS Lett. 1993 May 10;322(2):95-100. doi: 10.1016/0014-5793(93)81545-b.
In rat liver homogenates fortified with the appropriate cofactors (ATP and CoA), valproic acid induced H2O2 production rates by far lower than those recorded on the straight medium-chain fatty acid n-octanoic acid. Using directly the CoA esters of these carboxylic acids as substrates for the rat liver H2O2-generating enzyme activities, valproyl-CoA, and n-octanoyl-CoA were found to induce similar oxidation rates. In the rat liver homogenates, cyanide-insensitive valproyl-CoA and octanoyl-CoA oxidations occurred at rates similar to those of valproyl-CoA and octanoyl-CoA oxidase(s), respectively. Studies on fractions obtained from rat liver postnuclear supernatants by isopycnic centrifugation on a linear sucrose density gradient disclose that the density distribution of valproyl-CoA oxidase superimposes to those of catalase, fatty acyl-CoA oxidase and cyanide-insensitive fatty acyl-CoA oxidation, three peroxisomal marker activities. By contrast, the cyanide-insensitive valproyl-CoA oxidation does not adopt the typical peroxisomal distribution of these activities but rather exhibits a mitochondrial localization with, however, a minor peroxisomal component. Interestingly enough, the comparative study of rat tissue distribution, inducibility by clofibrate and sensitivity to deoxycholate indicated that valproyl-CoA oxidase is an enzyme distinct from fatty acyl-CoA oxidase and bile acyl-CoA oxidase. Taken as a whole, the results presented here support the occurrence of a peroxisomal oxidation of the CoA ester of valproic acid and its delta 4-enoic derivate which might be characterized by two major features: initiation by an acyl-CoA oxidase distinct from fatty and bile acyl-CoA oxidases, and inability to complete the beta-oxidation cycle which would not proceed, at significant rates, further than the beta-hydroxyacyl-CoA dehydrogenation step in peroxisomes.
在添加了适当辅因子（ATP和辅酶A）的大鼠肝脏匀浆中，丙戊酸诱导产生过氧化氢的速率远低于在直链中链脂肪酸正辛酸上记录的速率。直接使用这些羧酸的辅酶A酯作为大鼠肝脏产生过氧化氢的酶活性的底物时，发现丙戊酰辅酶A和正辛酰辅酶A诱导的氧化速率相似。在大鼠肝脏匀浆中，对氰化物不敏感的丙戊酰辅酶A和辛酰辅酶A氧化分别以与丙戊酰辅酶A和辛酰辅酶A氧化酶相似的速率发生。通过在线性蔗糖密度梯度上进行等密度离心对大鼠肝脏核后上清液获得的组分进行研究发现，丙戊酰辅酶A氧化酶的密度分布与过氧化氢酶、脂肪酰辅酶A氧化酶和对氰化物不敏感的脂肪酰辅酶A氧化这三种过氧化物酶体标记活性的密度分布重叠。相比之下，对氰化物不敏感的丙戊酰辅酶A氧化并不呈现这些活性典型的过氧化物酶体分布，而是表现出线粒体定位，不过有少量过氧化物酶体成分。有趣的是，对大鼠组织分布、氯贝丁酯诱导性和对脱氧胆酸盐敏感性的比较研究表明，丙戊酰辅酶A氧化酶是一种不同于脂肪酰辅酶A氧化酶和胆汁酰辅酶A氧化酶的酶。总体而言，此处呈现的结果支持丙戊酸的辅酶A酯及其δ4 - 烯酸衍生物存在过氧化物酶体氧化，其可能具有两个主要特征：由一种不同于脂肪酰辅酶A氧化酶和胆汁酰辅酶A氧化酶的酰基辅酶A氧化酶引发，且无法完成β - 氧化循环，在过氧化物酶体中该循环不会以显著速率进行到β - 羟酰基辅酶A脱氢步骤之后。
