The role of mitochondria in modifying calcium-sensitive cytoplasmic metabolic activities. Modification of pyruvate kinase activity

Meli, J.; Bygrave, Fyfe L.

doi:10.1042/bj1280415

Cited by 36 publications

(11 citation statements)

References 25 publications

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“…Inhibition of the L form ofpyruvate kinase by ATP and GTP was shown to be due solely to the removal of the Mg2+ from the assay medium and it would appear most unlikely that these nucleotide triphosphates could act as the physiological inhibitors of the enzyme. Gevers & Krebs (1966) suggested that the extrusion of Ca2+ out of, and the influx of Mg2+ into, mitochondria during gluconeogenesis could be an effective method of controlling pyruvate kinase activity, and Meli & Bygrave (1972), by altering the [Mg2+]/[Ca2+] ratio in rat liver mitochondria were able to switch on and off pyruvate kinase activity alternately and rapidly. It would appear from our studies that the nature of the ionic environment could be the major mode for the control of the activity of the L form of pyruvate kinase.…”

Section: Discussionmentioning

confidence: 99%

Kinetic studies on the regulation of rabbit liver pyruvate kinase

Irving

Williams

1973

Biochemical Journal

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Two kinetically distinct forms of pyruvate kinase (EC 2.7.1.40) were isolated from rabbit liver by using differential ammonium sulphate fractionation. The L or liver form, which is allosterically activated by fructose 1,6-diphosphate, was partially purified by DEAE-cellulose chromatography to give a maximum specific activity of 20 units/mg. The L form was allosterically activated by K(+) and optimum activity was recorded with 30mm-K(+), 4mm-MgADP(-), with a MgADP(-)/ADP(2-) ratio of 50:1, but inhibition occurred with K(+) concentrations in excess of 60mm. No inhibition occurred with either ATP or GTP when excess of Mg(2+) was added to counteract chelation by these ligands. Alanine (2.5mm) caused 50% inhibition at low concentrations of phosphoenolpyruvate (0.15mm). The homotropic effector, phosphoenolpyruvate, exhibited a complex allosteric pattern (n(H)=2.5), and negative co-operative interactions were observed in the presence of low concentrations of this substrate. The degree of this co-operative interaction was pH-dependent, with the Hill coefficient increasing from 1.1 to 3.2 as the pH was raised from 6.5 to 8.0. Fructose 1,6-diphosphate interfered with the activation by univalent ions, markedly decreased the apparent K(m) for phosphoenolpyruvate from 1.2mm to 0.2mm, and transformed the phosphoenolpyruvate saturation curve into a hyperbola. Concentrations of fructose 1,6-diphosphate in excess of 0.5mm inhibited this stimulated reaction. The M or muscle-type form of the enzyme was not activated by fructose 1,6-diphosphate and gave a maximum specific activity of 0.3 unit/mg. A Michaelis-Menten response was obtained when phosphoenolpyruvate was the variable substrate (K(m)=0.125mm), and this form was inhibited by ATP, as well as alanine, even in the presence of excess of Mg(2+).

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Section: Discussionmentioning

confidence: 99%

Kinetic studies on the regulation of rabbit liver pyruvate kinase

Irving

Williams

1973

Biochemical Journal

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“…A large variety of cytosolic (1)(2)(3)(4)(5), mitochondrial (6)(7)(8), and microsomal enzymes (9)(10)(11) have been found to be calcium-sensitive. There is also mounting evidence which suggests that a common target of hormonal action is the redistribution of ions, especially intracellular calcium (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

The effect of glucagon on the kinetics of hepatic mitochondrial calcium uptake

1981

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Previous work by this and other laboratories has shown that glucagon administration stimulates calcium uptake by subsequently isolated hepatic mitochondria. This stimulation of hepatic mitochondrial Ca2+ uptake by in vivo administration of glucagon was further characterized in the present report. Maximal stimulation of mitochondrial Ca2+ accumulation was achieved between 6-10 min after the intravenous injection of glucagon into intact rats. Under control conditions, Ca2+ uptake was inhibited by the presence of Mg2+ in the incubation medium. Glucagon treatment, however, appeared to obliterate the observed inhibition by Mg2+ of mitochondrial Ca2+ uptake. Kinetic experiments revealed the usual sigmoidicity associated with initial velocity curves for mitochondrial calcium uptake. Glucagon treatment did not alter this sigmoidal relationship. Glucagon treatment significantly increased the V max for Ca2+ uptake from 292 +/- 22 to 377 +/- 34 nmoles Ca2+/min per mg protein (n = 8) but did not affect the K 0.5, (6.5-8.6 microM). Since the major kinetic change in mitochondrial Ca2+ uptake evoked by glucagon is an increase in V max, the enhancement mechanism is likely to be an increase either in the number of active transport sites available to Ca2+ or in the rate of Ca2+ carrier movement across the mitochondrial membranes.

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“…Ca2+ ions influence a number of enzymic reactions in the cell (for reviews, see Bianchi, 1968;Rasmussen, 1970;, including steps in the glycolytic (Bygrave, 1967;Meli & Bygrave, 1972), gluconeogenic (Kimmich & Rasmussen, 1969;Roobol & Alleyne, 1973), phospholipid (Roberts & Bygrave, 1973) and protein-biosynthetic pathways (Rao et al, 1974). It has been proposed that mitochondria play an important role in regulating the distribution of intracellular Ca2+ (Spencer & Bygrave, 1973;Borle, 1973;).…”

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confidence: 99%

Stimulation of hepatic mitochondrial calcium transport by elevated plasma insulin concentrations

Dorman

Barritt

Bygrave

1975

Biochemical Journal

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The effect of insulin (injected intraperitoneally) on the transport of Ca2+ by hepatic mitochondria from rats was investigated. 2. Elevated concentrations of plasma insulin within the physiological range (10-100muunits/ml) stimulate the initial rate of Ca2+ transport into mitochondria at 4 degrees C by about 75% and prolong by approx. tenfold the time for which the mitochondria retain the accumulated Ca2+. 3. The prolonged retention of Ca2+ is observed under the conditions where hypoglycaemia is significantly decreased by the simultaneous injection of glucose and insulin. 4. A good correlation is observed between the effects on Ca2+ transport and the decrease in blood glucose concentration when the amount of insulin injected was varied. 5. The effects of insulin on mitochondrial Ca2+ transport are apparent at about 30 min after the injection, and are inhibited by cycloheximide. 6. There is little change in mitochondrial energy transduction after the administration of insulin. 7. The results are briefly discussed in relation to the mechanisms of Ca2+ transport across the inner mitochondrial membrane and the role of mitochondria in modifying intracellular Ca2+ concentrations with reference to the mechanism(s) by which insulin affects cellular metabolism.

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The role of mitochondria in modifying calcium-sensitive cytoplasmic metabolic activities. Modification of pyruvate kinase activity

Cited by 36 publications

References 25 publications

Kinetic studies on the regulation of rabbit liver pyruvate kinase

Kinetic studies on the regulation of rabbit liver pyruvate kinase

The effect of glucagon on the kinetics of hepatic mitochondrial calcium uptake

Stimulation of hepatic mitochondrial calcium transport by elevated plasma insulin concentrations

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