Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P36957 (KGDHC)
 17 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dihydrolipoamide dehydrogenase (LADH) is a flavo-enzyme that serves as a subunit of alpha-ketoglutarate dehydrogenase complex (alpha-KGDHC). Reactive oxygen species (ROS) generation by alpha-KGDHC has been assigned to LADH (E3 subunit) and explained by the diaphorase activity of E3. Dysfunctions of alpha-KGDHC and concurrent ROS production have been implicated in neurodegeneration, ischemia-reperfusion, and other pathological conditions. In this work we investigated the in-depth details of ROS generation by isolated LADH and alpha-KGDHC. We found a parallel generation of superoxide and hydrogen peroxide by the E3 subunit of alpha-KGDHC which could be blocked by lipoic acid (LA) acting on a site upstream of the E3 subunit. The pathologically relevant ROS generation (at high NADH/NAD+ ratio and low pH) in the reverse mode of alpha-KGDHC could also be inhibited by LA. Our results contradict the previously proposed mechanism for pH-dependent ROS generation by LADH, showing no disassembling of the E3 functional homodimer at acidic pH using a physiologically relevant method for the examination. It is also suggested that LA could be beneficial in reducing the cell damage related to excessive ROS generation under pathological conditions.
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PMID:Inhibition of the alpha-ketoglutarate dehydrogenase-mediated reactive oxygen species generation by lipoic acid. 1939 31

Mitochondrial dysfunction and oxidative stress are involved in Alzheimer disease (AD) pathogenesis. In human AD brains, the activity of the alpha-ketoglutarate dehydrogenase enzyme complex (alpha-KGDHC) is reduced. KGDHC is mostly involved in NADH production. It can also participate in oxidative stress and reactive oxygen species (ROS) production. The mitochondrial dihydrolipoyl succinyltransferase enzyme (DLST) is a key subunit specific to the alpha-KGDHC. In cultured cells, reduction of DLST increased H(2)O(2)-induced ROS generation and cell death. Thus, we asked whether partial genetic deletion of DLST could accelerate the onset of AD pathogenesis, using a transgenic mouse model of amyloid deposition crossed with DLST(+/-) mice. Tg19959 mice, which carry the human amyloid precursor protein with two mutations, develop amyloid deposits and progressive behavioral abnormalities. We compared Tg19959 mice to Tg19959-DLST(+/-) littermates at 2-3 months of age and studied the effects of DLST deficiency on amyloid deposition, spatial learning and memory, and oxidative stress. We found that alpha-KGDHC activity was reduced in DLST(+/-) mice. We also found that DLST deficiency increased amyloid plaque burden, Abeta oligomers, and nitrotyrosine levels and accelerated the occurrence of spatial learning and memory deficits in female Tg19959 mice. Our data suggest that alpha-KGDHC may be involved in AD pathogenesis through increased mitochondrial oxidative stress.
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PMID:Mitochondrial dihydrolipoyl succinyltransferase deficiency accelerates amyloid pathology and memory deficit in a transgenic mouse model of amyloid deposition. 1959 66