Effects of hypoglycin on certain aspects of glucose and fatty acid metabolism in the rat

McKerns, Kenneth W.; Bird, Harris H.; Kaleita, E.; Coulomb, B.S.; Renzo, E.C. De

doi:10.1016/0006-2952(60)90096-4

Cited by 29 publications

(7 citation statements)

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“…The mechanism of the inhibition of fatty acid oxidation by pent-4-enoic acid, first described by Yardley (Yardley, 1964;Yardley & Godfrey, 1963, 1967, is therefore of considerable interest (Corredor et al, 1967;Senior et al, 1968;Bressler et al, 1969;Fukami & Williamson, 1971;Sherratt et al, 1971). McKerns et al (1960) originally proposed that inhibition of fatty acid oxidation by compounds related to hypoglycin might be caused either by the accumulation of their metabolically inert CoA derivatives, which sequester CoA necessary for normal metabolism, or by the specific inhibition of an enzyme of ,-oxidation. Most authors have concluded that inhibition of oxidation of fatty acid and pyruvate by pent-4-enoic acid is caused by sequestration of CoA as pent-4-enoyl-CoA and as its oxidation product, acryloyl-CoA (Bressler et al, 1969;Fukami &Williamson, 1971).…”

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Biochemical effects of the hypoglycaemic compound pent-4-enoic acid and related non-hypoglycaemic fatty acids. Effects of the free acids and their carnitine esters on coenzyme A-dependent oxidations in rat liver mitochondria

Holland

Sherratt

1973

Biochemical Journal

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1. The synthesis of pent-4-enoyl-l-carnitine, cyclopropanecarbonyl-l-carnitine and cyclobutanecarbonyl-l-carnitine is described. 2. Pent-4-enoate strongly inhibits palmitoyl-l-carnitine oxidation in coupled but not in uncoupled mitochondria. Pent-4-enoyl-l-carnitine strongly inhibits palmitoyl-l-carnitine oxidation in uncoupled mitochondria. Prior intramitochondrial formation of pent-4-enoyl-CoA is therefore necessary for inhibition. 3. There was a small self-limiting pulse of oxidation of pent-4-enoyl-l-carnitine during which the ability to inhibit the oxidation of subsequently added palmitoyl-l-carnitine developed. 4. Pent-4-enoate and pent-4-enoyl-l-carnitine are equally effective inhibitors of the oxidation of all even-chain acylcarnitines of chain length C(4)-C(16). Pent-4-enoyl-l-carnitine also inhibits the oxidation of pyruvate and of 2-oxoglutarate. 5. Pent-4-enoate strongly inhibits the oxidation of palmitate but not that of octanoate. This is presumably due to competition between octanoate and pent-4-enoate for medium-chain acyl-CoA ligase. 6. There was less inhibition of the oxidation of pyruvate by pent-4-enoyl-l-carnitine, and of palmitoyl-l-carnitine by cyclopropanecarbonyl-l-carnitine, after pre-incubation with 10mm-arsenate. This suggests that these inhibitions were caused either by depletion of free CoA or by increase of acyl-CoA concentrations, since arsenate deacylates intramitochondrial acyl-CoA. There was little effect on the inhibition of palmitoyl-l-carnitine oxidation by pent-4-enoyl-l-carnitine. 7. Penta-2,4-dienoate strongly inhibited palmitoyl-l-carnitine oxidation in coupled mitochondria; acrylate only inhibited slightly. 8. Pent-4-enoate (0.1mm) caused a rapid and almost complete decrease in free CoA and a large increase in acid-soluble acyl-CoA when incubated with coupled mitochondria. Cyclopropanecarboxylate caused a similar decrease in CoA, with an equivalent rise in acid-soluble acyl-CoA concentrations. n-Pentanoate caused extensive lowering of CoA and a large increase in acid-soluble acyl-CoA and acetyl-CoA concentrations. Octanoate caused a 50% lowering of CoA and an increase in acid-soluble acyl-CoA and acetyl-CoA concentrations. 9. Cyclopropanecarboxylate and n-pentanoate were less potent inhibitors of palmitate oxidation than was pent-4-enoate. 10. It is concluded that pent-4-enoate causes a specific inhibition of beta-oxidation after the formation intramitochondrially of its metabolites.

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Biochemical effects of the hypoglycaemic compound pent-4-enoic acid and related non-hypoglycaemic fatty acids. Effects of the free acids and their carnitine esters on coenzyme A-dependent oxidations in rat liver mitochondria

Holland

Sherratt

1973

Biochemical Journal

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“…In victims of vomiting sickness there is severe or total depletion of liver glycogen and fatty infiltration of the liver (Hill, 1953;Jelliffe & Stuart, 1954). These effects of hypoglycin have been obtained in laboratory animals (Patrick, 1954;Leppla & Holt, 1956;Holt & Holt, 1958Chen, Anderson, McCowen & Harris, 1957;McKerns, Bird, Kaleita, Coulomb & De Renzo, 1960). Hypoglycin inhibited conversion of glucose into liver glycogen in rats (Patrick, 1954), but did not affect glycogen phosphorylase (EC 2.4.1.1) or glucose 6-phosphohydrolase (EC 3.1.3.9) activity in Table 1 0H2-CH-002H…”

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confidence: 87%

“…rat liver homogenates (Feng & Patrick, 1958). It had no effect on glycolysis in vitro (McKerns et al 1960;Patrick, 1962). Net glucose oxidation in intact rats was unaffected (McKerns et al 1960), or decreased (Holt, Holt & Bohm, 1966) by hypoglycin treatment.…”

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confidence: 95%

“…It had no effect on glycolysis in vitro (McKerns et al 1960;Patrick, 1962). Net glucose oxidation in intact rats was unaffected (McKerns et al 1960), or decreased (Holt, Holt & Bohm, 1966) by hypoglycin treatment. Patrick (1966) reported that hypoglycin at relatively high concentration inhibited gluconeogenesis in rat kidney and liver slices.…”

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confidence: 96%

“…Hypoglycin caused a large rise in serum free fatty acid concentrations in rats and very strongly inhibited the oxidation of palmitate and stearate in intact rats (Holt & Benedict, 1959;McKerns et al 1960). Oxidation of short-chain fatty acids was not inhibited.…”

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Biochemical effects of the hypoglycaemic compound pent-4-enoic acid and related non-hypoglycaemic fatty acids. Oxidative phosphorylation and mitochondrial oxidation of pyruvate, 3-hydroxybutyrate and tricarboxylic acid-cycle intermediates

Senior

Sherratt

1968

Biochemical Journal

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1. The effects of the hypoglycaemic compound pent-4-enoic acid, and of four structurally related non-hypoglycaemic compounds (pent-2-enoic acid, pentanoic acid, cyclopropanecarboxylic acid and cyclobutanecarboxylic acid), on several reactions in rat liver mitochondria were determined. 2. The use of manometric techniques for measurements of oxidations and of phosphorylation is critically discussed. 3. Pent-4-enoic acid and pentanoic acid uncoupled oxidative phosphorylation at low concentrations, but usually by not more than about 50%. 4. All the compounds, except cyclobutanecarboxylic acid, strongly inhibited the oxidation of pyruvate and 2-oxoglutarate, but the oxidations of succinate, citrate and 3-hydroxybutyrate were not strongly inhibited. 5. All the compounds, except cyclobutanecarboxylic acid, inhibited decarboxylation of [1-(14)C]pyruvate with ferricyanide as electron acceptor. 6. All the compounds, except pent-2-enoic acid, caused mitochondrial swelling after a time-lag.

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Toxic Amino Acids: Their Action as Antimetabolites

Fowden¹,

Lewis²,

Tristram³

1967

Advances in Enzymology - And Related Areas of Molecular Biology

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Effects of hypoglycin on certain aspects of glucose and fatty acid metabolism in the rat

Cited by 29 publications

References 15 publications

Biochemical effects of the hypoglycaemic compound pent-4-enoic acid and related non-hypoglycaemic fatty acids. Effects of the free acids and their carnitine esters on coenzyme A-dependent oxidations in rat liver mitochondria

Biochemical effects of the hypoglycaemic compound pent-4-enoic acid and related non-hypoglycaemic fatty acids. Effects of the free acids and their carnitine esters on coenzyme A-dependent oxidations in rat liver mitochondria

Biochemical effects of the hypoglycaemic compound pent-4-enoic acid and related non-hypoglycaemic fatty acids. Oxidative phosphorylation and mitochondrial oxidation of pyruvate, 3-hydroxybutyrate and tricarboxylic acid-cycle intermediates

Toxic Amino Acids: Their Action as Antimetabolites

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