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)

PET observations of reduced cerebral glucose metabolism in AD could be explained by a defect in key energy metabolizing enzymes. In particular, levels of two enzymes, cytochrome oxidase (CO) and alpha-ketoglutarate dehydrogenase complex (alpha KGDHC) are generally assumed to be reliably reduced in postmortem brain of patients with AD. How strong is the evidence that brain CO and alpha KGDHC are reduced in AD? In our study CO activity and alpha KGDHC activity and protein subunit levels were measured in cerebral cortex of 19-29 AD patients and 29 control subjects. We found that mean CO activity in cerebral cortex was reduced by 16-26% in the AD group but with almost complete overlap between control and patient ranges. Since our publication in 1992, mean brain CO activity in AD was modestly reduced in 9 independent studies (p < 0.05 in 5). Activity of alpha KGDHC varied widely in control/AD subjects and is not useful as an enzyme marker. Cerebral cortical protein levels of E1-3 subunits, which showed much less variance, were reduced by 23-41% but with large overlap between control/patient groups. We concluded that decreased (i.e., below normal) brain CO and alpha KGDHC is a feature of some, but not all patients with AD. The possible causes and significance of the enzyme changes are discussed.
Ann N Y Acad Sci 1997 Sep 26
PMID:Brain energy metabolizing enzymes in Alzheimer's disease: alpha-ketoglutarate dehydrogenase complex and cytochrome oxidase. 932 93

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.
J Neurosci 2004 Sep 08
PMID:Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species. 1535 89