Hertz R, Berman I, Bar-Tana J
Department of Human Nutrition and Metabolism, Faculty of Medicine, Hebrew University, Israel.
Eur J Biochem. 1994 Apr 1;221(1):611-5. doi: 10.1111/j.1432-1033.1994.tb18773.x.
Most peroxisomal proliferators consist of a carboxylic group attached to a hydrophobic backbone yielding an amphipathic carboxylate molecule. The respective CoA derivatives of peroxisomal proliferators, formed by ATP-dependent CoA thioesterification catalyzed by long-chain-acyl-CoA synthase, have been repeatedly considered as the immediate inducers of peroxisome and other genes. In this study, the putative requirement for prior CoA thioesterification of peroxisomal proliferators was evaluated by analyzing the induced expression of a reporter plasmid promoted by the peroxisomal acyl-CoA-oxidase promoter in cells transiently cotransfected with expression vectors for the peroxisome-proliferator-activated receptor and the long-chain-acyl-CoA synthase. Transcriptional activation of peroxisomal acyl-CoA oxidase by peroxisomal proliferators was inhibited in the presence of transfected functional acyl-CoA synthase. The inhibitory effect was negatively correlated with the capacity of the acyl-CoA synthase to catalyze CoA thioesterification of the respective proliferator. Hence, the immediate inducer is the peroxisomal proliferator free acid rather than the respective CoA derivative or a metabolite derived from the peroxisomal-proliferator-CoA intermediate.
大多数过氧化物酶体增殖剂由连接在疏水主链上的羧基组成，形成两亲性羧酸酯分子。过氧化物酶体增殖剂的相应辅酶A衍生物由长链酰基辅酶A合酶催化的ATP依赖性辅酶A硫酯化反应形成，一直被认为是过氧化物酶体和其他基因的直接诱导剂。在本研究中，通过分析在与过氧化物酶体增殖物激活受体和长链酰基辅酶A合酶的表达载体瞬时共转染的细胞中，由过氧化物酶体酰基辅酶A氧化酶启动子促进的报告质粒的诱导表达，评估了过氧化物酶体增殖剂预先进行辅酶A硫酯化的假定需求。在转染的功能性酰基辅酶A合酶存在的情况下，过氧化物酶体增殖剂对过氧化物酶体酰基辅酶A氧化酶的转录激活受到抑制。抑制作用与酰基辅酶A合酶催化相应增殖剂的辅酶A硫酯化的能力呈负相关。因此，直接诱导剂是过氧化物酶体增殖剂游离酸，而不是相应的辅酶A衍生物或源自过氧化物酶体增殖剂-辅酶A中间体的代谢物。
