Disease relevance of Citric Acid Cycle

• A mitochondrial-like aconitase in the bacterium Bacteroides fragilis: implications for the evolution of the mitochondrial Krebs cycle [1].
• Parallel operation of the PEP-glyoxylate cycle and the tricarboxylic acid cycle was identified in the bacterium Escherichia coli under conditions of glucose hunger in a slow-growing continuous culture [2].
• In Pseudomonas putida, benzoate and 3-chlorobenzoate are converted to catechol and 3-chlorocatechol, respectively, which are then catabolized to tricarboxylic acid cycle intermediates via the catBCA and clcABD pathways [3].
• At a later time during the anoxia, intracellular pH decreased rapidly, consistent with a fall in cerebral metabolic rate for O2 and reduced flux through the tricarboxylic acid cycle [4].
• The Mendelian tumour syndromes hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary paragangliomatosis with phaeochromocytomas (HPGL) result from mutations in nuclear genes (FH and SDHB/C/D, respectively) that encode Krebs cycle enzymes [5].

Psychiatry related information on Citric Acid Cycle

• 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 [6].

High impact information on Citric Acid Cycle

• Here we show, through a combination of mapping critical recombinants, identifying individuals with germline mutations and screening known and predicted transcripts, that this gene encodes fumarate hydratase, an enzyme of the tricarboxylic acid cycle [7].
• As a result of a block in the Krebs cycle, these cells are auxotrophs for carbon dioxide and asparagine [8].
• In mitochondria, electrons derived from the oxidation of succinate by the tricarboxylic acid cycle enzyme succinate-ubiquinone oxido-reductase are transferred directly to the quinone pool [9].
• A protein with kinase and phosphatase activities involved in regulation of tricarboxylic acid cycle [10].
• Sequence analysis revealed that the product of this gene, named Indy (for I'm not dead yet), is most closely related to a mammalian sodium dicarboxylate cotransporter-a membrane protein that transports Krebs cycle intermediates [11].

Chemical compound and disease context of Citric Acid Cycle

• In Escherichia coli, the branch point between the Krebs cycle and the glyoxylate bypass is regulated by the phosphorylation of isocitrate dehydrogenase (IDH) [12].
• Recently, germline mutations in the FH gene, the product of which (fumarate hydratase) catalyzes the conversion of fumarate to malate in the Krebs cycle, have been detected in a distinct hereditary tumor syndrome, which is characterized by uterine and skin leiomyomatosis and papillary renal cancer [13].
• Our results suggest that extracts of R. typhi that contain demonstrable enzymes involved in the catabolism of glutamate and tricarboxylic acid cycle intermediates, unlike Coxiella burnetti, lack detectable glycolytic activity [14].
• The citrate synthase activity of Acetobacter xylinum cells grown on glucose was the same as of cells grown on intermediates of the tricarboxylic acid cycle [15].
• The effects of adult-onset hypothyroidism on the metabolic compartmentation of the cerebral tricarboxylic acid cycle and the gamma-aminobutyric acid (GABA) shunt have been investigated by 13C nuclear magnetic resonance spectroscopy [16].

Biological context of Citric Acid Cycle

• As a crucial nexus for the cell, mitochondria are involved in numerous essential aspects of cell function, from energy production via the respiratory chain to steroid biosynthesis, heme assembly, pyrimidine biosynthesis, the tricarboxylic acid cycle, and apoptosis [17].
• The circulatory effects of selective metabolic inhibition of glycolysis and of the tricarboxylic acid cycle by iodoacetate and fluoroacetate were studied in intact chloralose-anesthetized dogs [18].
• We therefore applied a new isotopic approach that theoretically overcomes these limitations and permits quantification of Krebs cycle carbon exchange and the individual contributions of gluconeogenesis and glycogenolysis to overall glucose output [19].
• The channeling of isocitrate through the glyoxylate bypass is regulated via the phosphorylation/dephosphorylation of isocitrate dehydrogenase, the enzyme of the tricarboxylic acid cycle which competes for a common substrate with isocitrate lyase [20].
• Enrichment of the glutamate C5 position shows the existence of a futile cycle in which phosphoenolpyruvate, formed from oxaloacetate, returns to the Krebs cycle through pyruvate and acetyl CoA[21]

Anatomical context of Citric Acid Cycle

• BACKGROUND: Pyruvate, as an intermediate in the Krebs cycle, is an important source of energy for myocardium and improves contractility of normal, hypoxic, and postischaemic animal myocardium [22].
• Krebs cycle intermediates such as succinate, citrate, and alpha-ketoglutarate are transferred across plasma membranes of cells by secondary active transporters that couple the downhill movement of sodium to the concentrative uptake of substrate [23].
• We now demonstrate that overexpression of frataxin in mammalian cells causes a Ca(2+)-induced up-regulation of tricarboxylic acid cycle flux and respiration, which, in turn, leads to an increased mitochondrial membrane potential (delta psi(m)) and results in an elevated cellular ATP content [24].
• To determine whether a high level of glutamatergic activity is present in human cortex, the rates of the tricarboxylic acid cycle, glutamine synthesis, and the glutamate/glutamine cycle were determined in the human occipital/parietal lobe at rest [25].
• Uptake rates of 0.1 mM citrate and alpha-ketoglutarate were inhibited by greater than 90% by 10 mM succinate, malate, fumarate, or oxaloacetate, indicating the presence in the brush border membrane of a transport system highly specialized for the renal conservation of intermediates of the tricarboxylic acid cycle [26].

Associations of Citric Acid Cycle with chemical compounds

• This indicated that lactate was metabolized directly via pyruvate to enter the tricarboxylic acid cycle [27].
• Compounds transported by MFS permeases include simple sugars, oligosaccharides, inositols, drugs, amino acids, nucleosides, organophosphate esters, Krebs cycle metabolites, and a large variety of organic and inorganic anions and cations [28].
• The pathogenesis in these instances seems to consist of an initial synergistic insult on the liver by mixed types of viruses and subsequent breakdown of urea cycle, Krebs cycle, and possible other hepatic functions [29].
• At this glucose concentration, there was no measurable accumulation of lactate in sensitized spleen cells, but Krebs cycle activity was detectable [30].
• Inhibition of viral replication by nitric oxide and its reversal by ferrous sulfate and tricarboxylic acid cycle metabolites [31].

Gene context of Citric Acid Cycle

• Dihydrolipoamide succinyltransferase (DLST) is a subunit enzyme of the alpha-ketoglutarate dehydrogenase complex of the Krebs cycle [32].
• The nuclear-encoded Krebs cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDHB, -C and -D), act as tumour suppressors [33].
• A nuclear gene encoding the tricarboxylic acid cycle enzyme citrate synthase has previously been isolated (M. Suissa, K. Suda, and G. Schatz, EMBO J. 3:1773-1781, 1984) and is referred to here as CIT1 [34].
• In conclusion, our model proposes that in response to reduction in hepatocyte glycogen storage, the TTR-Foxa2 TG mice survive by maintaining sufficient serum levels of glucose through gluconeogenesis using deaminated amino acids with dicarboxylate products of peroxisomal lipid beta-oxidation shuttled through the tricarboxylic acid cycle [35].
• This finding suggests that constitutively activated GDH enhances oxidation of glutamate, which is intracellularly converted from glutamine to alpha-ketoglutarate, a tricarboxylic acid cycle substrate, which thereby stimulates insulin secretion [36].

Analytical, diagnostic and therapeutic context of Citric Acid Cycle

• Immediately after perfusion with estrogen-containing medium, a continuous enhancement in the rates of glucose consumption, lactate production by glycolysis, and glutamate synthesis by the Krebs cycle occurred with a persistent 2-fold increase at 4 hr [37].
• Since drIndy is a transporter for tricarboxylic acid-cycle intermediates, dysfunction of the Indy gene may lead to decreased production of metabolic energy in cells, analogous to caloric restriction [38].
• High-pressure liquid chromatography was used to demonstrate that, in the presence of glucose, uniformly labeled [14C]palmitic acid was converted to intermediates of the tricarboxylic acid cycle and glyoxylate shunt [39].
• PCR with degenerate primers for three key genes in the reverse tricarboxylic acid cycle and form I and form II of ribulose 1,5-bisphosphate carboxylase/oxygenase (Calvin cycle marker gene) were utilized to demonstrate the abundance of the reverse tricarboxylic acid cycle genes in diverse vent samples [40].
• The increased production of lactate and the flux of glucose through the Krebs cycle and the reduction in glutamine consumption seems to be involved in the immunosuppression presented in the TB and PNX animals [41].

References