[79] Chemical properties and synthesis of fluoro analogs of compounds related to substrates of the citric acid cycle

Kun, Ernest; Dummel, Robert J.

doi:10.1016/0076-6879(69)13087-6

Cited by 25 publications

(9 citation statements)

References 35 publications

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“…Fluoro-homologues of dicarboxylic acids were prepared by published synthetic and enzymatic methods [17,18] Table 1 illustrates the effects of fluorocarboxylic acids on rates of glucose formation from pyruvate, lactate or fructose by cells obtained from the livers of fasted animals. Initial studies were conducted with monofluorooxaloacetate, an inhibitor of malate dehydrogenase [S], and difluorooxaloacetate, an inhibitor of aspartate aminotransferase [8].…”

Section: Methodsmentioning

confidence: 99%

Rate-Limiting Steps of Gluconeogenesis in Liver Cells as Determined with the Aid of Fluoro-Dicarboxylic Acids

Berry

Kun

1972

Eur J Biochem

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Fluoromalate (an inhibitor of malate dehydrogenase and the malate carrier) or difluorooxaloacetate (an inhibitor of aspartate aminotransferase) inhibited gluconeogenesis from both pyruvate and lactate, but had no effect on glucose formation from fructose or endogenous substrates. When cells were incubated with both fluorocarboxylic acids simultaneously, an additive effect on the inhibition of glucose formation from lactate was observed, but the inhibition was not additive when pyruvate was the glucogenic precursor. Pyruvate removal was reduced I5 O/ , , , by difluorooxaloacetate and 44O/, by fluoromalate. Lactate production from pyruvate was inhbited 36O/, by fluoromalate but was almost unaffected by ditluorooxaloacetate.The results suggest that both malate-oxaloacetate and glutamate-aspartate shuttles participate, but to different extents, in glucose formation from either pyruvate or lactate. The malateoxaloacetate shuttle predominates during gluconeogenesis from pyurvate whereas the glutamateaspartate shuttle is of greater importance when lactate is the gluconeogenic precursor. However, the inhibition by fluoromalate of glucose formation from lactate indicates that not all the reducing equivalents arising during lactate oxidation are directly available for the reductive step of gluconeogenesis.Neither of the two shuttles seems to compensate for inhibition of the alternative system. This lack of compensation implies that each shuttle is working close to or a t its maximal capacity. Hence, transfer processes between mitochondria and cytoplasm must be considered as potential rate-limiting and regulatory sites for gluconeogenesis. The failure of fluoromalate to inhibit ethanol oxidation suggests that alternatives to the malate-oxaloacetate shuttle exist for the transfer to the mitochondria of reducing equivalents generated in the cytoplasmic compartment.

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Section: Methodsmentioning

confidence: 99%

Rate-Limiting Steps of Gluconeogenesis in Liver Cells as Determined with the Aid of Fluoro-Dicarboxylic Acids

Berry

Kun

1972

Eur J Biochem

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“…Monofluoromethylated amino acids such as D ‐fluoroalanine are well known to act as “suicide substrates” causing inactivation of the enzyme by alkylative capture of the aminoacrylate‐pyridoxal‐P species 4j. Monofluoroacetic acid is responsible for “lethal synthesis” and it blocks the tricarboxylic acid cycle (Krebs cycle) 4f–h…”

Section: Methodsmentioning

confidence: 99%

2‐Fluoro‐1,3‐benzodithiole‐1,1,3,3‐tetraoxide: A Reagent for Nucleophilic Monofluoromethylation of Aldehydes

et al. 2010

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Matter of choice: The title compound (FBDT), a cyclic analogue of 1‐fluorobis(phenylsulfonyl)methane (FBSM), was developed as a reagent for the nucleophilic monofluoromethylation of aldehydes. By choice of an appropriate base it is possible to achieve selective 1,2‐ or 1,4‐addition of FBDT to conjugated aldehydes. The method was applied to the synthesis of a fluorinated isostere of osmundalactone.

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“…Fluoro homologues of dicarboxylic acids were prepared by published methods (Kun & Dummel, 1969;Skilleter et al, 1972). Collagenase and hyaluronidase were products of Worthington Biochemical Corp., Freehold, N.J., U.S.A. All other enzymes and cofactors were obtained from Boehringer Mannheim Corp., New York, N.Y., U.S.A. [1-_4C]-Ethanol (2mCi/mmol) was obtained from New England Nuclear Corp., Boston, Mass., U.S.A. Male Sprague-Dawley rats weighing between 300 and 350g were used in these experiments.…”

Section: Methodsmentioning

confidence: 99%

Effects of bicarbonate on intercompartmental reducing-equivalent translocation in isolated parenchymal cells from rat liver

Berry

Werner

Kun

1974

Biochemical Journal

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1. Incubation of isolated liver cells in a medium containing bicarbonate raises malate concentrations almost sixfold compared with values obtained in a bicarbonate-free phosphate medium. The malate concentration of about 0.3mm in bicarbonate medium is of the same order as the K(m) for malate dehydrogenase. 2. The utilization of ethanol, glyercol and sorbitol was increased by 20-35% in bicarbonate medium. 3. Fluoromalate, a specific inhibitor of malate dehydrogenase and the malate carrier, inhibited or ethanol oxidation by 23%, glycerol uptake by 20% and sorbitol uptake by 42% in bicarbonate medium, but had a much smaller inhibitory action in phosphate medium. In consequence fluoromalate almost abolished the stimulatory effects of bicarbonate on substrate utilization. 4. Difluoro-oxaloacetate, a specific inhibitor of aspartate aminotransferase, had about one-half the inhibitory activity of fluoromalate. The two inhibitors in combination were less effective than fluoromalate by itself. 5. It is concluded that bicarbonate stimulates the utilization of reduced substrates, which are oxidized in the cytoplasmic compartment of the liver cell, by increasing the activity of rate-limiting malate dehydrogenase-dependent intercompartmental hydrogen shuttles. Both malate-oxaloacetate and malate-aspartate systems are involved in these hydrogen-translocation processes.

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[79] Chemical properties and synthesis of fluoro analogs of compounds related to substrates of the citric acid cycle

Cited by 25 publications

References 35 publications

Rate-Limiting Steps of Gluconeogenesis in Liver Cells as Determined with the Aid of Fluoro-Dicarboxylic Acids

Rate-Limiting Steps of Gluconeogenesis in Liver Cells as Determined with the Aid of Fluoro-Dicarboxylic Acids

2‐Fluoro‐1,3‐benzodithiole‐1,1,3,3‐tetraoxide: A Reagent for Nucleophilic Monofluoromethylation of Aldehydes

Effects of bicarbonate on intercompartmental reducing-equivalent translocation in isolated parenchymal cells from rat liver

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