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Inhibition Isocitric acid

Polarographic studies of a mitochondrial fraction from Hymenolepis diminuta showed that of four substrates tested, DL-glycerol-3-phosphate was the most rapidly oxidized, but the highest respiratory control ratio (1.7) was obtained with dl-isocitric acid. With isocitrate as substrate oxyclozanide at 1.61 nM stimulated O uptake and relieved oligomycin inhibition of adinosine diphosphate-stimulated respiration, but at concentrations above 2 pM progressively inhibited O uptake. Rafoxanide, niclosamide, 3,4,5-tribromo-salicylanilide, nitroxynil, resorantel, di-chlorophen, and 2,4-dinitrophenol exhibited effects similar to those of oxyclozanide on the respiration in cestode mitochondria. The relative potencies were compared and the possible mode of action discussed [38]. [Pg.84]

CJ-15,183 (44) has been isolated from the fermentation culture of the fungus, Aspergillus aculeatus CL38916 as a squalene synthase inhibitor. The compound potently inhibited rat liver and human squalene synthases. In addition, it showed antifungal activities against filamentous fungi and yeast. The structure was elucidated to be an aliphatic tetracarboxylic acid compound consisting of an alkyl y-lactone, malic acid and isocitric acid moieties by spectroscopic analyses [69]. [Pg.773]

As fatty acids are produced under conditions of high energy, the high NADH/NAD" ratio in the mitochondria inhibits isocitrate dehydrogenase, which leads to citrate accumulation within the mitochondrial matrix. As the citrate accumulates, it is transported out into the cytosol to donate carbons for fatty acid synthesis. [Pg.670]

Rapid p-oxidation of fatty acids in perfused liver (DeBeer et a/., 1974) and in isolated mitochondria (Lopes-Cardozo and Van den Bergh, 1972) has been shown to suppress the operation of citric acid cycle apparently from the elevation of mitochondrial NADH/NAD ratio which restricts oxaloaceta-te availability for citrate synthase and simultaneously inhibits isocitrate oxidation (Lenartowicz et a/., 1976). Considerable support for an earlier postulate that oxaloacetate availability normally determines the rate of citrate synthesis has become available. Thus, because of marked protein binding, the concentration of free, as opposed to total, oxaloacetate in matrix of liver mitochondria is now estimated to be near the of citrate synthase (Siess et al., 1976 Brocks eta ., 1980). The antiketogenic effect of alanine (Nosadini et a/., 1980) and of 3-mercaptopicolinate, an inhibitor of phosphoenolpy-ruvate carboxykinase (Blackshear et a/., 1975), is believed to be exerted, at least in part, from their ability to raise hepatic oxaloacetate concentration. And, in pyruvate carboxylase deficiency, expected to impair oxaloacetate supply, concentration of ketone bodies is elevated (Saudubray et a/., 1976). [Pg.373]

Citrate is isomerized to isocitrate by the enzyme aconitase (aconitate hydratase) the reaction occurs in two steps dehydration to r-aconitate, some of which remains bound to the enzyme and rehydration to isocitrate. Although citrate is a symmetric molecule, aconitase reacts with citrate asymmetrically, so that the two carbon atoms that are lost in subsequent reactions of the cycle are not those that were added from acetyl-CoA. This asymmetric behavior is due to channeling— transfer of the product of citrate synthase directly onto the active site of aconitase without entering free solution. This provides integration of citric acid cycle activity and the provision of citrate in the cytosol as a source of acetyl-CoA for fatty acid synthesis. The poison fluo-roacetate is toxic because fluoroacetyl-CoA condenses with oxaloacetate to form fluorocitrate, which inhibits aconitase, causing citrate to accumulate. [Pg.130]

The catalytic efficiency of this enzyme to hydrolyze 5-fluoro-5,6-dihydro-uracil was found to be approximately twice that toward 5,6-dihydrouracil [152], 2-Fluoro-/3-alanine can either be eliminated via the bile after conjugation with bile acids, or be converted to fluoroacetate (4.238) [153], The latter metabolite is transformed to fluorocitrate, a potent inhibitor of the aconi-tase-catalyzed conversion of citrate to isocitrate. This inhibition probably explains the clinical neurotoxicity of 5-fluorouracil [154] [155],... [Pg.159]

Isocitrate dehydrogenase inhibited by NADH (causing the citric acid cyde to stop when the ETC stops in the anaerobic cell). [Pg.186]

Fluoroacetate produces its toxic action by inhibiting the citric acid cycle. The fluorine-substituted acetate is metabolized to fluoroci-trate that inhibits the conversion of citrate to isocitrate. There is an accumulation of large quantities of citrate in the tissue, and the cycle is blocked. The heart and central nervous system are the most critical tissues involved in poisoning by a general inhibition of oxidative energy metabolism. ... [Pg.635]

Phosphorylation of an enzyme can affect catalysis in another way by altering substrate-binding affinity. For example, when isocitrate dehydrogenase (an enzyme of the citric acid cycle Chapter 16) is phospho-rylated, electrostatic repulsion by the phosphoryl group inhibits the binding of citrate (a tricarboxylic acid) at the active site. [Pg.230]

Some bacteria, including E. coli, have the full complement of enzymes for the glyoxylate and citric acid cycles in the cytosol and can therefore grow on acetate as their sole source of carbon and energy. The phosphoprotein phosphatase that activates isocitrate dehydrogenase is stimulated by intermediates of the citric acid cycle and glycolysis and by indicators of reduced cellular energy supply (Fig. 16-23). The same metabolites inhibit the protein kinase activity of the bifunctional polypeptide. Thus, the accumulation of intermediates of... [Pg.624]

The same intermediates of glycolysis and the citric acid cycle that activate isocitrate dehydrogenase are allosteric inhibitors of isocitrate lyase. When energy-yielding metabolism is sufficiently fast to keep the concentrations of glycolytic and citric acid cycle intermediates low, isocitrate dehydrogenase is inactivated, the inhibition of isocitrate lyase is relieved, and isocitrate flows into the glyoxylate pathway, to be used in the biosynthesis of carbohydrates, amino acids, and other cellular components. [Pg.625]

Acetyl CoA Carboxylase Acetyl CoA carboxylase catalyzes the first and rate-Umiting step of fatty acid synthesis carboxylation of acetyl CoA to malonyl CoA. The mammalian enzyme is activated allostericaUy by citrate and isocitrate, and inhibited by long-chain fatty acyl CoA derivatives. It is also activated in response to insulin and inactivated in response to glucagon. [Pg.330]

The activity of an enzyme may be inhibited by the presence of a toxic metabolite. Sodium fluoroacetate, known as rat poison 1080, is extremely toxic to animals. The toxic action, however, is not due to sodium fluoroacetate itself but to a metabolic conversion product, flu-orocitrate, formed through a reaction commonly known as "lethal synthesis," as shown in Figure 5.3. The resulting fluorocitrate is toxic because it is inhibitory to aconitase, the enzyme responsible for the conversion of citrate into czs-aconitate and then into isocitrate in the tricarboxylic acid cycle. Inhibition of aconitase results in citrate accumulation. The cycle stops for lack of metabolites, leading to disruption of energy metabolism. [Pg.122]

Stimulation of lip-hydroxylase activity by Krebs-cycle acids is inhibited by CN and AmytalS. With rat adrenal homogenates, Amytal is not active in presence of isocitrate or Ca and the CN effect is reversed by isocitrate + NADPH. Oligomycin is inactive but Antimycin A, ferricy-anide and dinitrophenol act like Amytal. This supports the concept of a link between the classical electron transfer chain and the P-if50 containing hydroxylating system. [Pg.268]


See other pages where Inhibition Isocitric acid is mentioned: [Pg.489]    [Pg.156]    [Pg.462]    [Pg.357]    [Pg.135]    [Pg.1419]    [Pg.358]    [Pg.1419]    [Pg.189]    [Pg.622]    [Pg.112]    [Pg.181]    [Pg.953]    [Pg.958]    [Pg.1016]    [Pg.285]    [Pg.343]    [Pg.183]    [Pg.473]    [Pg.517]    [Pg.66]    [Pg.85]    [Pg.929]    [Pg.1272]    [Pg.357]    [Pg.1607]    [Pg.2453]    [Pg.458]    [Pg.78]    [Pg.85]    [Pg.492]    [Pg.778]   
See also in sourсe #XX -- [ Pg.154 ]




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