کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8478906 | 1551258 | 2018 | 37 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Human dihydrolipoamide dehydrogenase (E3) deficiency: Novel insights into the structural basis and molecular pathomechanism
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کلمات کلیدی
ThDPDHLAHDX-MSPDHcMSUDGCsDihydrolipoamide dehydrogenaseHRPflavin adenine dinucleotideDCPIPKGDHCalpha-ketoglutarate dehydrogenase complexnuclear magnetic resonance - رزونانس مغناطیسی هستهای2,6-dichlorophenolindophenol - 2،6-dichlorophenolindophenolNAD+/NADH - NAD + / NADHROS - ROSalpha-ketoglutarate - آلفا کتوگلووتراتEDTA - اتیلن دی آمین تترا استیک اسید Ethylenediaminetetraacetic acid - اتیلینیدامین تتراستیک اسیدFAD - بدMaple syrup urine disease - بیماری ادرار شربت افراNMR - تشدید مغناطیسی هستهای Thiamin diphosphate - تیامین دی فسفاتPathogenic mutation - جهش پاتوژنdihydrolipoic acid - دی هیدرولیپوئیک اسیدMolecular dynamics - دینامیک ملکولی یا پویایی مولکولیGlycine cleavage system - سیستم شکاف گلیسینLADH - لادوLipoic acid - لیپوئیک اسیدbranched-chain α-keto acid dehydrogenase complex - مجتمع α-کتاسید هیدروژناز زنجیره ای زنجیره ایHuman origin - منشاء انسانیwild-type - نوع وحشیHorseradish peroxidase - پراکسیداز هوررادیشpyruvate dehydrogenase complex - پیرووات دهیدروژناز پیچیدهliquid chromatography - کروماتوگرافی مایع
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
بیولوژی سلول
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neurochemistry International - Volume 117, July 2018, Pages 5-14
Journal: Neurochemistry International - Volume 117, July 2018, Pages 5-14
نویسندگان
Attila Ambrus, Vera Adam-Vizi,