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

Enzyme activities of a alpha-ketoglutarate dehydrogenase complex (alpha KGDHC) and one of its constituent subunits, dihydrolipoamide dehydrogenase (E3), are reported to be reduced in non-CNS tissues of some patients with Friedreich's ataxia (FA); however, the results are highly conflicting. To determine whether an enzyme abnormality occurs in brain, we measured immunoreactive levels of the three alpha KGDHC subunits, namely, alpha-ketoglutarate dehydrogenase (E1), dihydrolipoamide succinyltransferase (E2) and E3 in postmortem frontal, occipital and cerebellar cortices of 18 control subjects, 9 patients with FA and, for comparison, 12 patients with spinocerebellar ataxia type 1 (SCA1). Decreased (-20 to -31%) levels of E3 were observed in all three examined areas of the patients with FA with the changes statistically significant in cerebellar and frontal cortices. The E3 reduction could be explained by a loss of alpha KGDHC or other dehydrogenase complexes (e.g. pyruvate dehydrogenase complex) which utilize this subunit. In SCA1, enzyme changes were limited to E2 in cerebellar (-26%) and frontal (-19%) cortices. Although the E3 and E2 reductions are only slight, and may represent secondary events, the changes in this key Krebs cycle enzyme could exacerbate degenerative processes in both of the spinocerebellar ataxia disorders.
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PMID:Immunoreactive levels of alpha-ketoglutarate dehydrogenase subunits in Friedreich's ataxia and spinocerebellar ataxia type 1. 873 79

Mitochondria-produced reactive oxygen species (ROS) are thought to contribute to cell death caused by a multitude of pathological conditions. The molecular sites of mitochondrial ROS production are not well established but are generally thought to be located in complex I and complex III of the electron transport chain. We measured H(2)O(2) production, respiration, and NADPH reduction level in rat brain mitochondria oxidizing a variety of respiratory substrates. Under conditions of maximum respiration induced with either ADP or carbonyl cyanide p-trifluoromethoxyphenylhydrazone,alpha-ketoglutarate supported the highest rate of H(2)O(2) production. In the absence of ADP or in the presence of rotenone, H(2)O(2) production rates correlated with the reduction level of mitochondrial NADPH with various substrates, with the exception of alpha-ketoglutarate. Isolated mitochondrial alpha-ketoglutarate dehydrogenase (KGDHC) and pyruvate dehydrogenase (PDHC) complexes produced superoxide and H(2)O(2). NAD(+) inhibited ROS production by the isolated enzymes and by permeabilized mitochondria. We also measured H(2)O(2) production by brain mitochondria isolated from heterozygous knock-out mice deficient in dihydrolipoyl dehydrogenase (Dld). Although this enzyme is a part of both KGDHC and PDHC, there was greater impairment of KGDHC activity in Dld-deficient mitochondria. These mitochondria also produced significantly less H(2)O(2) than mitochondria isolated from their littermate wild-type mice. The data strongly indicate that KGDHC is a primary site of ROS production in normally functioning mitochondria.
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PMID:Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species. 1535 89

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