Structural alterations by five disease-causing mutations in the low-pH conformation of human dihydrolipoamide dehydrogenase (hLADH) analyzed by molecular dynamics - Implications in functional loss and modulation of reactive oxygen species generation by pathogenic hLADH forms.
Structural alterations by five disease-causing mutations in the low-pH conformation of human dihydrolipoamide dehydrogenase (hLADH) analyzed by molecular dynamics - Implications in functional loss and modulation of reactive oxygen species generation by pathogenic hLADH forms.
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DOI：
10.1016/j.bbrep.2015.04.006
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发表时间：
2015-07-01
影响因子：
2.7
通讯作者：
Adam-Vizi, Vera
中科院分区：
文献类型：
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作者：
Ambrus, Attila;Mizsei, Reka;Adam-Vizi, Vera
人二氢脂酰胺脱氢酶（hLADH）是人α -酮戊二酸脱氢酶复合物（α - kgdhc）和其他几种脱氢酶复合物的黄酶组分（E3）。hLADH的致病性突变导致严重的代谢性疾病（E3缺乏的非典型形式），通常升级为心脏病或神经学表现，甚至过早死亡；病理一般伴有乳酸性酸中毒。在酸中毒（pH 5.5-6.8）条件下，hLADH呈现出独特的构象，生理活性和生成活性氧（ROS）的能力较低。我们的实验室已经证明，选择的致病突变除了降低hLADH的生理活性外，还显著刺激hLADH产生ROS，特别是在较低的pH下，这可能在各自病例中e3缺乏症的发病机制中发挥作用。此前，我们通过分子动力学（MD）模拟生成了低ph hLADH结构，并分析了8种hLADH致病突变在该结构中引起的结构变化。在缺乏高分辨率突变结构的情况下，这些信息对于hLADH蛋白分子发病机理的机制研究至关重要。本文通过分子动力学模拟分析了5种hLADH致病突变对hLADH低ph构象的结构改变；这些致病的hLADH突变体的结构以前从未被研究过。
Human dihydrolipoamide dehydrogenase (hLADH) is a flavoenzyme component (E3) of the human alpha-ketoglutarate dehydrogenase complex (alpha-KGDHc) and few other dehydrogenase complexes. Pathogenic mutations of hLADH cause severe metabolic diseases (atypical forms of E3 deficiency) that often escalate to cardiological or neurological presentations and even premature death; the pathologies are generally accompanied by lactic acidosis. hLADH presents a distinct conformation under acidosis (pH 5.5-6.8) with lower physiological activity and the capacity of generating reactive oxygen species (ROS). It has been shown by our laboratory that selected pathogenic mutations, besides lowering the physiological activity of hLADH, significantly stimulate ROS generation by hLADH, especially at lower pH, which might play a role in the pathogenesis of E3-deficiency in respective cases. Previously, we generated by molecular dynamics (MD) simulation the low-pH hLADH structure and analyzed the structural changes induced in this structure by eight of the pathogenic mutations of hLADH. In the absence of high resolution mutant structures these pieces of information are crucial for the mechanistic investigation of the molecular pathogeneses of the hLADH protein. In the present work we analyzed by molecular dynamics simulation the structural changes induced in the low-pH conformation of hLADH by five pathogenic mutations of hLADH; the structures of these disease-causing mutants of hLADH have never been examined before.