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Three variants of the first part of the process are physiologically important. 1) A series of transport and transamination reactions convert mitochondrial oxaloacetate to cytosolic oxaloacetate which is converted to phosphoenolpyruvate by a hormonally regulated, cytosolic isoform of phosphoenolpyruvate carboxykinase. This variant allows regulated glucose synthesis from lactate. 2) Mitochondrial oxaloacetate is reduced to malate, which is exported to the cytosol and re-oxidized to oxaloacetate. This variant provides reducing equivalents to the cytosol, needed for glucose synthesis from amino acids such as alanine and glutamine. 3) Constitutively expressed mitochondrial phosphoenolpyruvate carboxykinase catalyzes the conversion of mitochondrial oxaloacetate to phosphoenolpyruvate which is then transported to the cytosol. The exact path followed by any one molecule of pyruvate through this reaction network is determined by the tissue in which the reactions are occurring, the source of the pyruvate, and the physiological stress that triggered gluconeogenesis.
In all cases, the synthesis of glucose from two molecules of pyruvate requires the generation and consumption of two reducing equivalents as cytosolic NADH + H+. For pyruvate derived from lactate (variants 1 and 3), NADH + H+ is generated with the oxidation of lactate to pyruvate in the cytosol (a reaction of pyruvate metabolism not shown in the diagram). For pyruvate derived from amino acids (variant 2), mitochondrial NADH + H+ generated by glutamate dehydrogenase (a reaction of amino acid metabolism, not shown) is used to reduce oxaloacetate to malate, which is transported to the cytosol and re-oxidized, generating cytosolic NADH + H+. The synthesis of glucose from pyruvate also requires the consumption of six high-energy phosphates, four from ATP and two from GTP.
In the second part of gluconeogenesis, cytosolic phosphoenolpyruvate, however derived, is converted to fructose 1,6-bisphosphate by reactions that are the reverse of steps of glycolysis. Hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate is catalyzed by fructose 1,6-bisphosphatase, and fructose 6-phosphate is reversibly isomerized to glucose 6-phosphate.