Studies of the mechanism of the hypoglycemic action of 4-pentenoic acid.

Corredor, Carlos; Brendel, Klaus; Bressler, Rubin

doi:10.1073/pnas.58.6.2299

Cited by 51 publications

(26 citation statements)

References 23 publications

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“…These same in vivo effects have been observed in experimental animals after injection of hypoglycin A (13,14). Several groups of investigators subsequently concluded that the hypoglycemia and depletion of glycogen were due to the decreased gluconeogenesis resulting from impairment of long chain fatty acid metabolism (15)(16)(17). In these studies, (Fig.…”

supporting

confidence: 56%

“…These structures are believed to be necessary for their hypoglycemic action (9) and, also, for their inhibition of long-chain fatty acid oxidation (17,20). However, there is a striking difference in the structure of these two compounds, namely the presence of the cyclopropane ring.…”

Section: Discussionmentioning

confidence: 99%

“…The acctumulation of N-isovalerylglycine in the medium when liver slices were incubated with [2- Bressler and co-workers have suggested that the inhibition of long chain fatty acid oxidation by methylenecyclopropylacetic acid and 4-PE is due to the ability of these inhibitors to form nonmetabolizable esters with CoA and (-)-carnitine (17,20). As a result, free CoA and (-)-carnitine become less available.…”

Section: Discussionmentioning

confidence: 99%

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Hypoglycin A: A Specific Inhibitor of Isovaleryl CoA Dehydrogenase

Tanaka

Miller

Isselbacher

1971

Proc. Natl. Acad. Sci. U.S.A.

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Evidence is presented for the specific in vivo and in vitro inhibition of isovaleryl CoA dehydrogenation by hypoglycin A and its derivative, a-ketomethylenecyclopropylpropionic acid. a-MethylbutyrylCoA dehydrogenation was also impaired, but the degree of inhibition was much lower. Isobutyryl CoA dehydrogenation was not inhibited. 4-Pentenoic acid inhibited none of these reactions. It is concluded that isovaleryl CoA is dehydrogenated by a specific enzyme, isovaleryl CoA dehydrogenase, contrary to previous assumptions that it is dehydrogenated by green acyl CoA dehydrogenase. The present concept agrees with our previous findings in isovaleric acidemia, a genetic disorder in which a specific defect of isovaleryl CoA dehydrogenase was observed. It was also demonstrated that isovaleric acidemia can be induced in experimental animals by the administration of hypoglycin A. Furthermore, some symptoms of "the vomiting sickness of Jamaica" appear to be due to isovaleric acid accumulation secondary to the ingestion of hypoglycin A.Isovaleric acidemia is a genetic defect of leucine metabolism (1-4) in which isovaleric acid accumulates in blood in large amounts. Based on the biochemical findings in this hereditary disorder, we proposed that isovaleryl CoA is dehydrogenated by a specific enzyme, isovaleryl CoA dehydrogenase (1,3) and that this enzyme is deficient in patients with isovaleric acidemia ( Fig. 1). It was previously believed that isovaleryl CoA, butyryl CoA, and hexanoyl CoA were dehydrogenated by a single enzyme, acyl CoA dehydrogenase (5,6).It has subsequently been shown that oxidation of leucine is inhibited by hypoglycin A (7,8). In contrast, oxidation of valine and isoleucine are not significantly inhibited by this compound (8). However, the specific step in the pathway of leucine metabolism that is inhibited by hypoglycin A has not been precisely identified.Hypoglycin A is an unusual amino acid having the structure of a-aminomethylenecyclopropylpropionic acid (9). It has been extracted from unripe fruits of ackee grown in Jamaica and has been identified as the cause of the "vomiting sickness of Jamaica" (10). Extreme hypoglycemia (11) In vivo experimentsAmino acids were given by stomach tube 30 min after intramuscular injection of the inhibitor. The blood samples were drawn by heart puncture 150 min after injection of the inhibitor. Short chain fatty acid analyses were performed by gasliquid chromatography (GLC) (1).In vitro experiments Incubations were for 3 hr at 37°C. The tissues and the incubation medium were homogenized after acidification with 0.5 ml of 2 N H2SO4 and extracted with 20 vol of chloroform-methanol 2:1. The filtered extract was separated into two phases by mixing with 0.2 N NaOH (0.2 vol of the extract). Unlabeled carrier was added to the homogenate before extraction.Only the upper alkaline layer, which contains most of the water soluble salts of carboxylic acids and acidic conjugates, was analyzed. The steam-distillable fractions after acid hydrolysis were designated as total fr...

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supporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hypoglycin A: A Specific Inhibitor of Isovaleryl CoA Dehydrogenase

Tanaka

Miller

Isselbacher

1971

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, a-bromopalmitate [34], 4-pentenoic acid [35] and (+)-acyl carnitine derivatives [6,36], inhibitors of fatty acid oxidation, result in a decrease of gluconeogenesis. Exton and Park [13], based on calculated yields of ATP from pyruvate oxidation, have concluded that glucose formation from pyruvate could proceed in the absence of liver lipid breakdown.…”

Section: Discussionmentioning

confidence: 99%

The Role of Endogenous Lipid in Gluconeogenesis and Ketogenesis of Perfused Rat Liver

Menahan

Wieland²

1969

European Journal of Biochemistry

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1. The oral antidiabetic glycodiazine (2-benzene sulfonamido-5-~-methoxyethoxy pyrimidine), an inhibitor of hepatic lipolysis, was used to investigate the metabolic role of liver lipid in glucogenesis in the perfused livers of fasted (24-30 h) rats. I n a concentration of 10 mM, glycodiazine inhibited almost completely endogenous ketone body formation.2 . Perfusion with pyruvate as substrate, in the presence of glycodiazine, resulted in a higher rate of pyruvate oxidation and suppressed the rate of glucose synthesis in comparison to livers perfused with pyruvate alone. Thus, maximal rates of gluconeogenesis from pyruvate would seem to require an adequate supply and oxidation of fatty acids.3. Oleate, even in the presence of glycodiazine, stimulates glucose synthesis from pyruvate. Uptake of and ketone body formation from oleate were also not affected by glycodiazine. These results allow the conclusion that glycodiazine specifically inhibits liver lipolysis.4. Glucagon (57 nM), although having no significant effect on gluconeogenesis from pyruvate a t this concentration, overcame the inhibitory effects of glycodiazine on glucose formation and suppressed the elevated pyruvate oxidation which results from the inhibition of endogenous lipid mobilization.5. Glucagon, in the absence of added substrates, stimulated gluconeogenesis, urea production and ketogenesis. The increase in gluconeogenesis due to glucagon was not impaired by glycodiazine. This indicates that intermediates arising from fatty acid oxidation do not limit the rate of gluconeogenesis under these conditions.

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“…Pent-4-enoate is usually regarded as an inhibitor of the fl-oxidation of fatty acids (Corredor et al, 1967;Senior & Sherratt, 1978a,b;Senior et al, 1968;Brendel et al, 1969;Fukami & Williamson, 1971). Its effects seem to be tissue-specific, however.…”

mentioning

confidence: 99%

Effects of pent-4-enoate on cellular redox state, glycolysis and fatty acid oxidation in isolated perfused rat heart

Hiltunen

Jauhonen

Savolainen

et al. 1978

Biochemical Journal

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The metabolic effects of pent-4-enoate were studied in beating and potassium-arrested perfused rat hearts. The addition of 0.8imM-pent-4-enoate to the fluid used to perfuse a potassium-arrested heart resulted in a 70 % increase in the 02 consumption and a 66 % decrease in the glycolytic flux as measured in terms of the de-tritiation of [3-3H]glucose, although the proportion of the 02 consumption attributable to glucose oxidation decreased from an initial 30 % to 10 %. The pent-4-enoate-induced increase in 02 consumption was only 15 % in the beating heart. In the potassium-arrested heart, pent-4-enoate stimulated palmitate oxidation by more than 100% when measured in terms of the production of "4CO2 from [1-14C]palmitate, but in the beating heart palmitate oxidation was inhibited. Perfusion of the heart with pent-4-enoate had no effect on the proportion of pyruvate dehydrogenase found in the active form, in spite of large changes in the CoASH and acetyl-CoA concentrations and changes in their concentration ratios. The effects of pent-4-enoate on the cellular redox state were dependent on the ATP consumption of the heart. In the beating heart, pent-4-enoate caused a rapid mitochondrial NAD+ reduction that subsequently faded out, so that the final state was more oxidized than the initial state. The arrested heart, however, remained in a more reduced state than initially, even after the partial re-oxidation that followed the initial rapid NAD+ reduction. The ability of pent-4-enoate to increase or decrease fatty acid oxidation can be explained on the basis of the differential effects of pent-4-enoate on the concentration of citric acid-cycle intermediates under conditions of high or low ATP consumption of the myocardial cell. The proportion of the fatty acids in the fuel consumed by the heart is probably primarily determined by the regulatory mechanisms of glycolysis. When pent-4-enoate causes an increase in the citric acid-cycle intermediates, feedback inhibition of glycolysis results in an increase in the oxidation of fatty acids.

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Studies of the mechanism of the hypoglycemic action of 4-pentenoic acid.

Cited by 51 publications

References 23 publications

Hypoglycin A: A Specific Inhibitor of Isovaleryl CoA Dehydrogenase

Hypoglycin A: A Specific Inhibitor of Isovaleryl CoA Dehydrogenase

The Role of Endogenous Lipid in Gluconeogenesis and Ketogenesis of Perfused Rat Liver

Effects of pent-4-enoate on cellular redox state, glycolysis and fatty acid oxidation in isolated perfused rat heart

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