Glucose 6-phosphate hydrolysis by glucose 6-phosphatase bypasses the irreversible hexokinase/glucokinase reaction and provides an energetically favorable pathway for the formation of free glucose (Fig. 10.6). The liver is the primary organ that produces free glucose from glucose 6-phosphate. This process requires a complex of two proteins found only in gluconeogenic tissue: glucose 6-phosphate translocase, which transports glucose 6-phosphate across the endoplasmic reticular (ER) membrane, and glucose 6-phosphatase, which removes the phosphate, producing free glucose (see Fig. 10.6). [Note: These ER membrane proteins are also required for the final step of glycogen degradation (see p. 130). Glycogen storage diseases Ia and Ib, caused by deficiencies in the phosphatase and the translocase, respectively, are characterized by severe fasting hypoglycemia, because free glucose is unable to be produced from either gluconeogenesis or glycogenolysis.] Specific transporters are responsible for moving the free glucose into the cytosol and then into blood.
F. Summary of the reactions of glycolysis and gluconeogenesis
Of the 11 reactions required to convert pyruvate to free glucose, 7 are catalyzed by reversible glycolytic enzymes (Fig. 10.7). The 3 irreversible reactions (catalyzed by hexokinase/glucokinase, PFK-1, and PK) are circumvented by reactions catalyzed by glucose 6-phosphatase, fructose 1,6-bisphosphatase, PC, and PEPCK. In gluconeogenesis, the equilibria of the reversible glycolytic reactions are pushed toward glucose synthesis as a result of the essentially irreversible formation of PEP, fructose 6-phosphate, and glucose by the gluconeogenic enzymes. [Note: The stoichiometry of gluconeogenesis from two pyruvate molecules couples the cleavage of six high-energy phosphate bonds and the oxidation of two NADH with the formation of one glucose molecule (see Fig. 10.7).]
IV. REGULATION
The moment-to-moment regulation of gluconeogenesis is determined primarily by the circulating level of glucagon and by the availability of gluconeogenic substrates. In addition, slow adaptive changes in enzyme amount result from an alteration in the rate of enzyme synthesis or degradation or both. [Note: Hormonal control of the glucoregulatory system is presented in Chapter 23.]
This peptide hormone from pancreatic islet α cells (see p. 313) stimulates gluconeogenesis by three mechanisms.
1.
Changes in allosteric effectors: Glucagon lowers hepatic fructose 2,6bisphosphate, resulting in fructose 1,6-bisphosphatase activation and PFK-1 inhibition, thereby favoring gluconeogenesis over glycolysis (see Fig. 10.5). [Note: See pp. 99–100 for the role of fructose 2,6bisphosphate in glycolysis regulation.] 2.
Covalent modification of enzyme activity: Glucagon binds its G protein– coupled receptor (see p. 95) and, via an elevation in cyclic AMP (cAMP) level and cAMP-dependent protein kinase A activity, stimulates the conversion of hepatic PK to its inactive (phosphorylated) form. This decreases PEP conversion to pyruvate, which has the effect of diverting PEP to gluconeogenesis (Fig. 10.8).
the enzyme. [Note: Only the hepatic isozyme is subject to covalent regulation.]
AMP.