Pyruvate Dehydrogenase, Substrate Specificity and Product Inhibition

Bremmer, Jan Ν.

doi:10.1111/j.1432-1033.1969.tb00559.x

Cited by 160 publications

(65 citation statements)

References 18 publications

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“…The increase in the malate to citrate ratio IS] in Table 3 and the stimulation of oxidative phosphorylation demonstrated in Table 5 are also consistent with the greater availability of reducing equivalents in the matrix during oxidation of octanoate. Thus the inhibition of pyruvate oxidation by octanoate could be explained by an inhibitory action of acetyl-CoA and NADH on pyruvate dehydrogenase [43,44]. However, interconversion of the active to the inactive form of the enzyme due to changes in the ATP:ADP ratio in the matrix as proposed by Reed and Wieland cannot be excluded here [45,46].…”

Section: Discussionmentioning

confidence: 99%

Regulation of Pyruvate Metabolism in Rat‐Liver Mitochondria by Adenine Nucleotides and Fatty Acids

Stucki

Brawand

Walter

1972

European Journal of Biochemistry

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Fluxes of pyruvate through the pyruvate dehydrogenase and the pyruvate carboxylase reactions in intact rat liver mitochondria were measured under various experimental conditions. When amounts of pyruvate not limiting for pyruvate dehydrogenase were present in the incubation medium, pyruvate carboxylase was found to be regulated essentially by the ATP:ADP ratio within the mitochondria1 matrix. No direct correlation between pyruvate carboxylase activity and the level of intramitochondrial acetyl-CoA could be observed under these conditions. When the ATP : ADP ratio within the matrix was decreased by elevation of the ADP concentration in the medium, a strong inhibition of the pyruvate carboxylase was observed. After addition of oleate to the medium this low ATP : ADP ratio within the matrix was increased and the inhibition of pyruvate carboxylase was partially reversed. It is demonstrated that this effect of oleate is probably caused by an inhibition of the adenine nucleotide translocase.The effects of oleate on pyruvate carboxylase were compared to those of octanoate. I n contrast to oleate, octanoate diminished the pool sue of the exchangeable adenine nucleotides, ATP and ADP, within the matrix and oxidative phosphorylation was stimulated. The reduced level of intramitochondrial ADP and the increased rate of oxidative phosphorylation elevated the ATP : ADP ratio within the matrix and partially reversed the inhibition of the pyruvate carboxylase by ADP. Thus, both fatty acids reversed the inhibition of pyruvate carboxylase by ADP via changes in the intramitochondrial ATP : ADP ratio but they did this by Wering mechanisms.Octanoate was found to be much more rapidly activated and oxidized within the matrix than oleate. Furthermore, octanoate strongly inhibited pyruvate oxidation whereas with oleate this effect was much smaller.The physiological implications of these findings are discussed in relation t o the stimulation of gluconeogenesis by fatty acids in the liver.Regulation of pyruvate metabolism is of crucial importance in intermediary metabolism as pyruvate can either be catabolized to carbon dioxide and water or be converted to glucose, fatty and amino acids, or to ketone bodies. This study deals with the regulation of pyruvate metabolism in rat liver mitochondria and its relation to gluconeogenesis.

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Section: Discussionmentioning

confidence: 99%

Regulation of Pyruvate Metabolism in Rat‐Liver Mitochondria by Adenine Nucleotides and Fatty Acids

Stucki

Brawand

Walter

1972

European Journal of Biochemistry

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“…Under these conditions, oxaloacetate required for aspartate formation can be generated via pyruvate carboxylase intramitochondrially and malate reentry into the mitochondria is no longer required for maintenance of urea synthesis [26]. Similarly, an increased oxaloacetate formation from endogenously produced pyruvate (Figs 1 C and 2) following inhibition of pyruvate dehydrogenase [20,28,291 and activation of pyruvate carboxylase [30] by elevating the mitochondrial NADHiNAD + ratio will explain why addition of 3-hydroxybutyrate, but not of acetoacetate, stimulates urea synthesis during hypotonicity (Fig. 5).…”

Section: Effect Of Hypotonicity On Urea Synthesis From Amino Acidsmentioning

confidence: 99%

Control of hepatic nitrogen metabolism and glutathione release by cell volume regulatory mechanisms

Häussinger

Läng

Bauers

et al. 1990

European Journal of Biochemistry

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1. Urea synthesis was studied in isolated perfused rat liver during cell volume regulatory ion fluxes following exposure of the liver to anisotonic perfusion media. Lowering of the osmolarity in influent perfusate from 305 mOsm/l to 225 mOsm/l (by decreasing influent [NaCl] by 40 mmol/l) led to an inhibition of urea synthesis from NH4CI (0.5 mmol/l) by about 60% and a decrease of hepatic oxygen uptake by 0.43 f 0.03 pmol g-min-[from 3.09 f 0.13 pmol g-' min-' to 2.66 0.12 pmol g -l min-' (n = 9)]. The effects on urea synthesis and oxygen uptake were observed throughout hypotonic exposure (225 mOsm/l). They persisted although volume regulatory K+ efflux from the liver was complete within 8 min and were fully reversible upon reexposure to normotonic perfusion media (305 mOsm/l). A 42% inhibition of urea synthesis from NH4Cl (0.5 mmol/l) during hypotonicity was also observed when the perfusion medium was supplemented with glucose (5 mmol/l). Urea synthesis was inhibited by only 10-20% in livers from fed rats, and was even stimulated in those from starved rats when an amino acid mixture (twice the physiological concentration) plus NH4C1 (0.2 mmol/l) was infused.2. The inhibition of urea synthesis from NH4C1 (0.5 mmol/l) during hypotonicity was accompanied by a threefold increase of citrulline tissue levels, a 50 -70% decrease of the tissue contents of glutamate, aspartate, citrate and malate, whereas 2-oxoglutarate, ATP and ornithine tissue levels, and the [3H]inulin extracellular space remained almost unaltered. Further, hypotonic exposure stimulated hepatic glutathione (GSH) release with a time course roughly paralleling volume regulatory K + efflux. NH4Cl stimulated lactate release from the liver during hypotonic but not during normotonic perfusion. In the absence of NH4Cl, hypotonicity did not significantly affect the lactate/pyruvate ratio in effluent perfusate. With NH4C1 (0.5 mmol/l) present, the lactate/pyruvate ratio increased from 4.3 to 8.2 in hypotonicity, whereas simultaneously the 3-hydroxybutyrate/acetoacetate ratio slightly, but significantly decreased.3. Addition of lactate (2.1 mmol/l) and pyruvate (0.3 mmol/l) to influent perfusate did not affect urea synthesis in normotonic perfusions, but completely prevented the inhibition of urea synthesis from NH4Cl (0.5 mmol/l) induced by hypotonicity. Restoration of urea production in hypotonic perfusions by addition of lactate and pyruvate was largely abolished in the presence of 2-cyanocinnamate (0.5 mmol/l). Addition of 3-hydroxybutyrate (0.5 mmol/l), but not of acetoacetate (0.5 mmol/l) largely reversed the hypotonicity-induced inhibition of urea synthesis from NH4Cl.4. The data are consistent with a cell-swelling-induced inhibition of the transfer of malate and reducing equivalents into the mitochondria1 compartment, thereby inhibiting urea synthesis due to a limitation of aspartate supply for argininosuccinate synthesis. They suggest that alterations of liver cell volume and/or volume regulatory responses exert marked effects on hepatic ammonia, amin...

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“…The data presented here are consistent with a tight control of one of the reactions of the tricarboxylate cycle in state 4. The acetyl-CoA which accumulates as a result would severely diminish the activity of the pyruvate dehydrogenase (Garland & Randle, 1964;Bremer, 1969), resulting in a secondary control at this stage. The data do not preclude an additional direct control on pyruvate dehydrogenase, but do impose limitations as to the magnitude of any such effect.…”

Section: Discussionmentioning

confidence: 99%

“…Previous work has suggested a control at NAD-isocitrate dehydrogenase (EC 1.1.1.41) (Hansford, 1972a) but this has to be defended in view of the existence of two prior reactions, those catalysed by pyruvate dehydrogenase and citrate synthase, both associated with large negative standard free-energy changes, and both shown to be subject to control in other animal tissues (pyruvate dehydrogenase, Garland & Randle, 1964;Von Jagow et al, 1968;Bremer, 1969;Wieland & Siess, 1970;Martinet al, 1972;Portenhauser & Wieland, 1972;citrate synthase, Smith & Williamson, 1971; LaNoue et al, 1972). The study re-ported here attempts to differentiate between control at each of these loci by establishing the steady-state concentrations of CoA, acetyl-CoA and succinylCoA (3-carboxypropionyl-CoA).…”

mentioning

confidence: 99%

The control of tricarboxylate-cycle oxidations in blowfly flight muscle. The steady-state concentrations of coenzyme A, acetyl-coenzyme A and succinyl-coenzyme A in flight muscle and isolated mitochondria

Hansford

1974

Biochemical Journal

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Pyruvate Dehydrogenase, Substrate Specificity and Product Inhibition

Cited by 160 publications

References 18 publications

Regulation of Pyruvate Metabolism in Rat‐Liver Mitochondria by Adenine Nucleotides and Fatty Acids

Regulation of Pyruvate Metabolism in Rat‐Liver Mitochondria by Adenine Nucleotides and Fatty Acids

Control of hepatic nitrogen metabolism and glutathione release by cell volume regulatory mechanisms

The control of tricarboxylate-cycle oxidations in blowfly flight muscle. The steady-state concentrations of coenzyme A, acetyl-coenzyme A and succinyl-coenzyme A in flight muscle and isolated mitochondria

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