Contribution of the Cytosol and Mitochondrial Pathways to Phosphoenolpyruvate Formation during Gluconeogenesis

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Abstract
Gluconeogenesis was compared in liver slices from guinea pigs and rats to assess the significance of the different distribution patterns of phosphoenolpyruvate carboxykinase. Preferential formation of phosphoenolpyruvate in the cytosol or mitochondria was determined by addition of compounds (tryptophan, quinolinic acid, n-butylmalonate and amino oxyacetic acid) which inhibit cytosolic phosphoenolpyruvate carboxykinase or decrease the availability of substrate precursors such as malate and aspartate. During active gluconeogenesis these inhibitors are all effective. In particular, quinolinic acid at a concentration of 10 mM inhibits glucose formation about 90% in rat liver and produces a 60% inhibition in guinea pig liver. A study of avian liver phosphoenolpyruvate carboxykinase which is predominantly a mitochondrial enzyme, revealed a cytosol component during embryogenesis when there is a requirement for active gluconeogenesis. These results indicate that during maximum gluconeogenesis, the formation of phosphoenolpyruvate in the cytosol assumes a significant proportion of the carbon pathway, even in those animals which have the capacity to synthesize large amounts of this important precursor of glucose in the mitochondria.

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