Disease relevance of OGDH

• The human OGDH has 37% sequence identity with 933 amino acid residues of the Escherichia coli OGDH and 40% sequence identity with 1014 residues of the yeast OGDH [1].
• We conclude that brain protein and activity levels of alpha-ketoglutarate dehydrogenase complex are reduced in patients with AD who have onset after 50 years and suggest that these changes, which are also observed in other human brain disorders, may represent a nonspecific consequence of different neurodegenerative processes [2].
• The activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC) declines in brains of patients with several neurodegenerative diseases [3].
• Immunoreactive levels of alpha-ketoglutarate dehydrogenase subunits in Friedreich's ataxia and spinocerebellar ataxia type 1 [4].
• Nitrosomonas europaea and Methylococcus capsulatus, which lack the functional enzyme, were found to contain the coding sequences for the E1 and E2 subunits of alpha-ketoglutarate dehydrogenase [5].

Psychiatry related information on OGDH

• Brain protein and alpha-ketoglutarate dehydrogenase complex activity in Alzheimer's disease [2].
• Results of this study demonstrate significant reductions of TPP-dependent enzymes [pyruvate dehydrogenase complex, alpha-ketoglutarate dehydrogenase (alpha KGDH), and transketolase] in autopsied cerebellar vermis samples from alcoholic patients with the clinical and neuropathologically confirmed diagnosis of Wernicke-Korsakoff Syndrome (WKS) [6].

High impact information on OGDH

• The specified region of the inner E2 core domain was highly homologous to the region of the E2 subunit of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase [7].
• Of the 14 serum samples obtained from patients with primary biliary cirrhosis, 13, 11, and 2 samples tested positive by immunoblot for the E2 subunits of pyruvate, branched-chain ketoacid, and alpha-ketoglutarate dehydrogenase, respectively [8].
• Dihydrolipoamide succinyltransferase (DLST) is a subunit enzyme of the alpha-ketoglutarate dehydrogenase complex of the Krebs cycle [9].
• Thus, structural roles which are mediated by a specific gene product, protein X in PDC and possibly also the E2 subunit, are performed by similar structural elements located on the E1 enzyme of the OGDC [10].
• The genome sequence of Mtb H37Rv predicts the presence of a complete tricarboxylic acid cycle, but we recently found that alpha-ketoglutarate dehydrogenase (KDH) activity is lacking in Mtb lysates [11].

Chemical compound and disease context of OGDH

• Inhibition of alpha-ketoglutarate dehydrogenase activity by a distinct population of autoantibodies recognizing dihydrolipoamide succinyltransferase in primary biliary cirrhosis [12].
• Deficiency of dihydrolipoyl dehydrogenase (a component of the pyruvate and alpha-ketoglutarate dehydrogenase complexes): a cause of congenital chronic lactic acidosis in infancy [13].
• Activities of rate limiting enzymes of the citric acid cycle (alpha-ketoglutarate dehydrogenase) and oxidation of free fatty acids (carnitine palmitoyltransferase II) were 48% and 21% lower than in controls, but the mean phosphofructokinase activity was unchanged in congestive heart failure [14].
• We measured the activity of the alpha-ketoglutarate dehydrogenase complex (alpha-KGDHC), a rate-limiting Krebs cycle enzyme, in postmortem brain samples from 38 controls and 30 neuropathologically confirmed Alzheimer's disease (AD) cases, in both the presence and absence of thiamine pyrophosphate (TPP), the enzyme's cofactor [15].
• We established one Epstein-Barr virus-transformed B cell hybrid clone producing human mAb of the IgG class to the 2-oxoglutarate dehydrogenase complex (OGDC) for the first time from the peripheral B lymphocytes of a patient with primary biliary cirrhosis (PBC) [16].

Biological context of OGDH

• Comparison of the deduced amino acid sequence of the human OGDH with experimentally determined segments of porcine OGDH comprising 308 amino acid residues shows 93% sequence identity [1].
• We have cloned a human cDNA encoding OGDH from a fetal liver cDNA library by plaque hybridization with a mixture of oligonucleotide probes designed from the amino acid sequences of porcine OGDH [1].
• alpha-Ketoglutarate dehydrogenase (E1k), also designated oxoglutarate dehydrogenase (OGDH; EC 1.2.4.2), is a component of the enzyme complex that catalyzes the conversion of alpha-ketogluterate to succinyl coenzyme A, a critical step in the Krebs tricarboxylic acid cycle [17].
• Using DNAs from human x rodent somatic cell hybrids that segregate human chromosomes in conjunction with fluorescence in situ hybridization, human OGDH was assigned to chromosome arm 7p, an area that corresponds to the boundary between bands 7p13 and 7p14 [18].
• The human OGDH gene contains 22 exons spanning approx. 85 kb [18].

Anatomical context of OGDH

• Genomic clones covering the entire sequence of the gene encoding human 2-oxoglutarate dehydrogenase (OGDH) were isolated by screening leukocyte and placenta genomic libraries with radio- and digoxigenin (DIG)-labeled human OGDH cDNAs [18].
• Muscle biopsy samples were taken from the vastus lateralis for the determination of fiber type composition (I, IIa, IIb), fiber type area, and assay of the following enzymes: malate dehydrogenase (MDH), 3-hydroxyacyl CoA dehydrogenase (HADH) and oxoglutarate dehydrogenase (OGDH) [19].
• Overall, the results indicate that along with the abundant natural peptides p2Ca and p2Cb, the QL9 and other OGDH peptides of various lengths, sharing a conserved C-terminal sequence, are also processed and presented with L(d) as allogeneic ligands for T cells expressing 2C TCR [20].
• Abnormality of the alpha-ketoglutarate dehydrogenase complex in fibroblasts from familial Alzheimer's disease [21].
• In contrast, formation of aspartate from [U-(14)C]glucose in awake rats (which reflects the passage of (14)C through the whole TCA cycle) and activities of pyruvate dehydrogenase, citrate synthase, alpha-ketoglutarate dehydrogenase, and fumarase in white structures were 10-23% of cortical values, optic nerve showing the lowest values [22].

Associations of OGDH with chemical compounds

• 2-Oxoglutarate dehydrogenase (lipoamide) (( OGDH: 2-oxoglutarate:lipoamide 2-oxidoreductase (decarboxylating and acceptor-succinylating), EC 1.2.4.2 )) is a component enzyme of the 2-oxoglutarate dehydrogenase complex [1].
• The results of primer extension analysis imply that the OGDH transcription start point is a thymine residue 55 bp upstream from the ATG start codon [18].
• Human 2-oxoglutarate dehydrogenase (OGDH) is an E1-component of the OGDH multi-enzyme complex and catalyzes both the ThDP-dependent decarboxylation of 2-oxoglutarate and the subsequent reductive succinylation of the lipoyl moiety which is covalently bound to the E2 component, dihydrolipoamide succinyltransferase [23].
• In the present study, the effects of 4-hydroxy-2-nonenal (HNE) on highly purified pyruvate dehydrogenase complex (PDC) and its catalytic components in vitro and on PDC, alpha-ketoglutarate dehydrogenase complex (KGDC), and the branched-chain alpha-keto acid dehydrogenase complex (BCKDC) activities in cultured human HepG2 cells were investigated [24].
• One of these peptides, QLSPFPFDL (QL9), elicits more vigorous cytolytic responses than two previously identified naturally processed peptides with overlapping sequences, LSPFPFDL (p2Ca) and VAITRIEQLSPFPFDL (p2Cb), from OGDH [20].

Physical interactions of OGDH

• Subunit interactions in the mammalian alpha-ketoglutarate dehydrogenase complex. Evidence for direct association of the alpha-ketoglutarate dehydrogenase and dihydrolipoamide dehydrogenase components [25].
• Significant decreases (-39%) in alpha-ketoglutarate dehydrogenase complex/glutamate dehydrogenase ratio and significant increases (+36%) in tissue MDA levels were observed in the SFC in PSP; no differences in complex I or complex IV activities were detected [26].
• Deficient activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC) has been documented in Alzheimer disease (AD) brain and fibroblasts [27].

Enzymatic interactions of OGDH

• Analysis of the pattern of release of E1 and E1' polypeptides from the OGDC during tryptic inactivation suggests that both polypeptide chains of individual E1 homodimers must be cleaved to permit the dissociation of the E1 and E3 components [25].

Regulatory relationships of OGDH

• The oxidation-sensitive Kreb's cycle enzyme alpha-ketoglutarate dehydrogenase was inactivated by SIN-1, in a manner that could be significantly attenuated by gamma-tocopherol (at <10 microM) but not by alpha-tocopherol [28].

Other interactions of OGDH

• No significant difference was noted in the activities of oxidative enzymes [malate dehydrogenase (MDH), oxoglutarate dehydrogenase (OGDH), and 3-hydroxyacyl-CoA dehydrogenase (HADH)] [29].
• KGDHC consists of multiple copies of E1k, E2k, and E3 [3].
• The dihydrolipoamide succinyltransferase (DLST) gene of the alpha-ketoglutarate dehydrogenase complex (alpha-KGDC) was isolated from a rat genomic DNA library and sequenced [30].
• Significant biochemical changes occurred in saline-treated stimulated rats compared with shams: with reductions in glutathione, alpha-ketoglutarate dehydrogenase, aconitase, citrate synthase, and complex I activities [31].
• Exclusion of OGDH and BMP4 as candidate genes in two siblings with autosomal recessive DOOR syndrome [32].

Analytical, diagnostic and therapeutic context of OGDH

• Resting muscle was sampled by needle biopsy from m. vastus lateralis and analyzed for fiber type diameter, fiber type percentage, 2-oxoglutarate dehydrogenase (OGDH) activity, and phosphofructokinase (PFK) activity [33].
• Immunoblotting demonstrated no abnormalities in the E1k and E3 components [21].
• Interaction between the alpha-ketoglutarate dehydrogenase complex and NAD+-dependent isocitrate dehydrogenase was detected with a variety of techniques including polyethylene glycol precipitation, ultracentrifugation, and centrifugal gel filtration on a Sepharose 6B column [34].
• Forty-four hours later, the hippocampi were extracted and prepared for electrochemical high-performance liquid chromatography (HPLC), to measure reduced glutathione levels, and for spectrophotometric assays to measure activities of mitochondrial enzymes (aconitase, alpha-ketoglutarate dehydrogenase, citrate synthase, complex I, and complex II/III) [31].
• Antibodies against pyruvate dehydrogenase, branched-chain alpha-ketoacid dehydrogenase and alpha-ketoglutarate dehydrogenase complexes were detected by immunoblot and quantified by enzyme-linked immunosorbent assay [8].

References