Influence of L-Tryptophan and Its Metabolites on Gluconeogenesis in the Isolated, Perfused Liver<sup>*</sup>

Veneziale, Carlo M.; Walter, Paul; Kneer, Nancy; Lardy, Henry A.

doi:10.1021/bi00859a034

Cited by 226 publications

(71 citation statements)

References 22 publications

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“…However, local accumulation of kynurenine metabolites, in particular, quinolinic acid, following IDO induction may also represent a potentially detrimental event. In fact, quinolinic acid is a potent excitotoxin, and its overproduction has been linked to neuronal damage occurring in brain inflammation (17), initiation of lipid peroxidation (33), and other conditions (3,42). Indeed, quinolinic acid concentration was significantly increased by T. gondii infection (S. Fujigaki and K. Saito, unpublished observation).…”

Section: Discussionmentioning

confidence: 99%

l-Tryptophan-l-Kynurenine Pathway Metabolism Accelerated byToxoplasmagondiiInfection Is Abolished in Gamma Interferon-Gene-Deficient Mice: Cross-Regulation between Inducible Nitric Oxide Synthase and Indoleamine-2,3-Dioxygenase

et al. 2002

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Section: Discussionmentioning

confidence: 99%

l-Tryptophan-l-Kynurenine Pathway Metabolism Accelerated byToxoplasmagondiiInfection Is Abolished in Gamma Interferon-Gene-Deficient Mice: Cross-Regulation between Inducible Nitric Oxide Synthase and Indoleamine-2,3-Dioxygenase

et al. 2002

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“…Cobalt (0.07 parts/106) is not sufficiently abundant in liver [15] to activate this enzyme. Cadmium (2 parts/106) and especially manganese (1.2 parts/106) do not appear to render the enzyme sufficiently susceptible to quinolinate to account for the striking inhibition of gluconeogenesis at the stage of P-pyruvate carboxylase [2,4]. It is possible that the activity of this enzyme, from the normal animal and measurable in the absence of added divalent transition metals, is partly Mn2+-activated.…”

Section: Influence Of Tryptophan Metabolites Analogs and Metal Chelamentioning

confidence: 99%

“…I n view of the strong inhibition by quinolinate of gluconeogenesis at the stage of P-pyruvate carboxylase [2,4,16,17], Fe2+ seems to be the most likely activator of this enzyme in the intact liver. This conclusion is also supported by the similarity in behavior of the enzyme in the liver supernatant fractions from tryptophan-treated rats and from normal rats supplemented with Fe2+ in vitro (Fig.3).…”

Section: Influence Of Tryptophan Metabolites Analogs and Metal Chelamentioning

confidence: 99%

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Response of Phosphopyruvate Carboxylase to Tryptophan Metabolites and Metal Ions

Snoke

Johnston

Lardy

1971

European Journal of Biochemistry

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Tryptophan, administered to rats, inhibits gluconeogenesis, but increases the activity of hepatic phosphopyruvate carboxylase when assayed in vitro. Quinolinate, a metabolite of tryptophan, inhibits gluconeogenesis in perfused livers, and inhibits phosphopyruvate carboxylase in liver cytosol from tryptophan-treated rats but not from normal rats.Metal The elevated phosphopyruvate carboxylase activity in cytosol of tryptophan-treated rats was lowered in vitro by quinolinate to the same extent as was the activity of the Fe2+-treated enzyme from normal rats. Ferrous iron is proposed as the physiologically important cation and quinolinate the important metabolite responsible for altering the activity of phoshopyruvate carboxylase in vivo following tryptophan administration.Tryptophan administered to rats enhances the activity of several hepatic enzymes that participate in gluconeogenesis. Among these, phosphopyruvate carboxylase responds in an unusual fashion ; the measurable activity is rapidly increased but the reaction catalyzed by this enzyme appears to be blocked in the intact rat 11-31. The observed elevation of P-pyruvate carboxylase activity is the result of two processes, first a rapid activation of existing enzyme and then a slower increase in activity as new enzyme is synthesized [3]. Tryptophan, at levels as high as 1.7 mM, did not affect the enzymic activity in vitro. However, 50 to 100pM MnCl, or FeCl, added to reaction mixtures containing 6 mM MgCI, activated P-pyruvate carboxylase to levels seen with the enzyme from livers of tryptophantreated rats [3]. The P-pyruvate carboxylase from the latter source was not activated by Mn2+ [3].Ray et al. [2] demonstrated that inhibition of gluconeogenesis after tryptophan administration to fasted rats occurred at the P-pyruvate carboxylase step. Metabolite crossover-type plots showed that the concentrations of gluconeogenic intermediates before the P-pyruvate carboxylase step were higher, while metabolites after that step were lower than the Enzyme. Phosphopyruvate carboxylase or GTP : oxaloacetate carboxy-lyase (transphosphorylating) (EC 4.1.1.32).concentrations of corresponding metabolites in livers of control animals. Veneziale et al.[a] perfused isolated livers from fasted rats with various metabolites of tryptophan and found that compounds in the pathway to nicotinic acid ribonucleotide also inhibited glucose production. Quinolinate, the precursor of nicotinic acid ribonucleotide, blocked gluconeogenesis and activated P-pyruvate carboxylase and was suggested to be the agent responsible for the effect of tryptophan.The key role that P-pyruvate carboxylase plays in gluconeogenesis and the need for information on the regulation of this enzyme led to further investigation of the interaction of metal ions and tryptophan metabolites on enzyme activity in vitro. MATERIALS AND METHODSMale albino rats weighing 160 to 200g (Badger Research Corporation, Madison, Wisconsin) were maintained on water and Rockland chow ad libitum. Animals were fasted for 24 h before sacrit...

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“…The hypoglycemic effect of tryptophan is produced by inhibition of hepatic gluconeogenesis at the reaction catalyzed by phosphoenolpyruvate carboxykinase (EC 4.1 .1.32) and under the condition, contents of were metabolites of tricarboxylic acid cycle in liver markedly increased [ 1,2]. It was shown in the previous study [3] that the intraperitoneal administration of tryptophan to rats produced an increase in the hepatic lipogenesis.…”

Section: Introductionmentioning

confidence: 99%

Effect of tryptophan on fatty acid synthesis in rat liver

1973

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Influence of L-Tryptophan and Its Metabolites on Gluconeogenesis in the Isolated, Perfused Liver^*

Cited by 226 publications

References 22 publications

l-Tryptophan-l-Kynurenine Pathway Metabolism Accelerated byToxoplasmagondiiInfection Is Abolished in Gamma Interferon-Gene-Deficient Mice: Cross-Regulation between Inducible Nitric Oxide Synthase and Indoleamine-2,3-Dioxygenase

l-Tryptophan-l-Kynurenine Pathway Metabolism Accelerated byToxoplasmagondiiInfection Is Abolished in Gamma Interferon-Gene-Deficient Mice: Cross-Regulation between Inducible Nitric Oxide Synthase and Indoleamine-2,3-Dioxygenase

Response of Phosphopyruvate Carboxylase to Tryptophan Metabolites and Metal Ions

Effect of tryptophan on fatty acid synthesis in rat liver

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Influence of L-Tryptophan and Its Metabolites on Gluconeogenesis in the Isolated, Perfused Liver*

Cited by 226 publications

References 22 publications

l-Tryptophan-l-Kynurenine Pathway Metabolism Accelerated byToxoplasmagondiiInfection Is Abolished in Gamma Interferon-Gene-Deficient Mice: Cross-Regulation between Inducible Nitric Oxide Synthase and Indoleamine-2,3-Dioxygenase

l-Tryptophan-l-Kynurenine Pathway Metabolism Accelerated byToxoplasmagondiiInfection Is Abolished in Gamma Interferon-Gene-Deficient Mice: Cross-Regulation between Inducible Nitric Oxide Synthase and Indoleamine-2,3-Dioxygenase

Response of Phosphopyruvate Carboxylase to Tryptophan Metabolites and Metal Ions

Effect of tryptophan on fatty acid synthesis in rat liver

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Influence of L-Tryptophan and Its Metabolites on Gluconeogenesis in the Isolated, Perfused Liver^*