This review summarizes our present view on the molecular pathogenesis of human (h) E3-deficiency caused by a variety of genetic alterations with a special emphasis on the moonlighting biochemical phenomena related to the affected (dihydro)lipoamide dehydrogenase (LADH, E3, gene: dld), in particular the generation of reactive oxygen species (ROS). E3-deficiency is a rare autosomal recessive genetic disorder frequently presenting with a neonatal onset and premature death; the highest carrier rate of a single pathogenic dld mutation (1:94–1:110) was found among Ashkenazi Jews. Patients usually die during acute episodes that generally involve severe metabolic decompensation and lactic acidosis leading to neurological, cardiological, and/or hepatological manifestations. The disease owes its severity to the fact that LADH is the common E3 subunit of the alpha-ketoglutarate (KGDHc), pyruvate (PDHc), and branched-chain α-keto acid dehydrogenase complexes and is also part of the glycine cleavage system, hence the malfunctioning of LADH simultaneously incapacitates several central metabolic pathways. Nevertheless, the clinical pictures are usually not unequivocally portrayed through the loss of LADH activities and imply auxiliary mechanisms that exacerbate the symptoms and outcomes of this disorder. Enhanced ROS generation by disease-causing hE3 variants as well as by the E1-E2 subcomplex of the hKGDHc likely contributes to selected pathogeneses of E3-deficiency, which could be targeted by specific drugs or antioxidants; lipoic acid was demonstrated to be a potent inhibitor of ROS generation by hE3 in vitro. Flavin supplementation might prove to be beneficial for those mutations triggering FAD loss in the hE3 component. Selected pathogenic hE3 variants lose their affinity for the E2 component of the hPDHc, a mechanism which warrants scrutiny also for other E3-haboring complexes.

这篇综述总结了我们目前对由多种遗传改变引起的人（h）E3缺乏的分子发病机理的看法，特别着重于与受影响的（二氢）脂酰胺脱氢酶（LADH，E3，基因）相关的月光生化现象：dld），特别是活性氧（ROS）的产生。E3缺乏症是一种罕见的常染色体隐性遗传疾病，经常表现为新生儿发作和过早死亡。单个病原体dld的最高载带率在Ashkenazi犹太人中发现了突变（1：94–1：110）。患者通常在急性发作期间死亡，急性发作通常涉及严重的代谢失代偿和乳酸性酸中毒，导致神经，心脏和/或肝病表现。该疾病的严重性是由于LADH是α-酮戊二酸（KGDHc），丙酮酸（PDHc）和支链α-酮酸脱氢酶复合物的常见E3亚基，并且也是甘氨酸裂解系统的一部分，因此LADH的功能障碍同时使一些中枢代谢途径丧失功能。尽管如此，通常不会通过LADH活性的丧失来明确地描绘出临床情况，并且暗示了加剧这种疾病的症状和结局的辅助机制。引起疾病的hE3变体以及hKGDHc的E1-E2亚复合物增强的ROS产生可能导致E3缺乏症的某些病原体，这可能是特定药物或抗氧化剂所针对的；硫辛酸被证明是hE3产生ROS的有效抑制剂体外。黄素补充剂可能被证明对那些在hE3组分中触发FAD丢失的突变有益。选定的致病性hE3变体失去了对hPDHc E2成分的亲和力，该机制也需要对其他携带E3的复合物进行仔细研究。