Department of Neurology, Martin-Luther-University Halle-Wittenberg, Ernst-Grube Str. 40, 06120 Halle (Saale), Germany.
Molecules. 2020 Apr 13;25(8):1784. doi: 10.3390/molecules25081784.
Carnitine palmitoyltransferase (CPT) catalyzes the transfer of long- and medium-chain fatty acids from cytoplasm into mitochondria, where oxidation of fatty acids takes place. Deficiency of CPT enzyme is associated with rare diseases of fatty acid metabolism. CPT is present in two subforms: CPT I at the outer mitochondrial membrane and carnitine palmitoyltransferase II (CPT II) inside the mitochondria. Deficiency of CPT II results in the most common inherited disorder of long-chain fatty acid oxidation affecting skeletal muscle. There is a lethal neonatal form, a severe infantile hepato-cardio-muscular form, and a rather mild myopathic form characterized by exercise-induced myalgia, weakness, and myoglobinuria. Total CPT activity (CPT I + CPT II) in muscles of CPT II-deficient patients is generally normal. Nevertheless, in some patients, not detectable to reduced total activities are also reported. CPT II protein is also shown in normal concentration in patients with normal CPT enzymatic activity. However, residual CPT II shows abnormal inhibition sensitivity towards malonyl-CoA, Triton X-100 and fatty acid metabolites in patients. Genetic studies have identified a common p.Ser113Leu mutation in the muscle form along with around 100 different rare mutations. The biochemical consequences of these mutations have been controversial. Hypotheses include lack of enzymatically active protein, partial enzyme deficiency and abnormally regulated enzyme. The recombinant enzyme experiments that we recently conducted have shown that CPT II enzyme is extremely thermoliable and is abnormally inhibited by different emulsifiers and detergents such as malonyl-CoA, palmitoyl-CoA, palmitoylcarnitine, Tween 20 and Triton X-100. Here, we present a conceptual overview on CPT II deficiency based on our own findings and on results from other studies addressing clinical, biochemical, histological, immunohistological and genetic aspects, as well as recent advancements in diagnosis and therapeutic strategies in this disorder.
肉碱棕榈酰转移酶（CPT）催化长链和中链脂肪酸从细胞质转移到线粒体，在那里脂肪酸发生氧化。CPT 酶的缺乏与罕见的脂肪酸代谢疾病有关。CPT 有两种亚型：位于外线粒体膜的 CPT I 和线粒体内的肉碱棕榈酰转移酶 II（CPT II）。CPT II 的缺乏导致最常见的长链脂肪酸氧化遗传障碍，影响骨骼肌。有致命的新生儿型、严重的婴儿型肝心肌型和相对轻微的肌病型，其特征为运动诱导的肌肉疼痛、无力和肌红蛋白尿。CPT II 缺乏症患者肌肉中的总 CPT 活性（CPT I + CPT II）通常正常。然而，也有报道称在一些患者中无法检测到降低的总活性。CPT II 蛋白在 CPT 酶活性正常的患者中也以正常浓度显示。然而，在患者中，残留的 CPT II 对丙二酰辅酶 A、Triton X-100 和脂肪酸代谢物的抑制敏感性异常。遗传研究已经确定了肌肉型中常见的 p.Ser113Leu 突变，以及大约 100 种不同的罕见突变。这些突变的生化后果一直存在争议。假设包括缺乏具有酶活性的蛋白质、部分酶缺乏和异常调节的酶。我们最近进行的重组酶实验表明，CPT II 酶非常热不稳定，并且被不同的乳化剂和清洁剂（如丙二酰辅酶 A、棕榈酰辅酶 A、棕榈酰肉碱、吐温 20 和 Triton X-100）异常抑制。在这里，我们根据自己的发现以及其他研究的结果，介绍了关于 CPT II 缺乏症的概念概述，这些研究涉及临床、生化、组织学、免疫组织化学和遗传方面，以及该疾病的最新诊断和治疗策略进展。
