Harpers

GLUCONEOGENESIS & CONTROL OF THE BLOOD GLUCOSE / 157enzymes in glycolysis. Likewise, it antagonizes the effectof the glucocorticoids and glucagon-stimulated cAMP,which induce synthesis of the key enzymes responsiblefor gluconeogenesis.Both dehydrogenases of the pentose phosphatepathway can be classified as adaptive enzymes, sincethey increase in activity in the well-fed animal andwhen insulin is given to a diabetic animal. Activity islow in diabetes or starvation. “Malic enzyme” andATP-citrate lyase behave similarly, indicating that thesetwo enzymes are involved in lipogenesis rather thangluconeogenesis (Chapter 21).Covalent Modification by ReversiblePhosphorylation Is RapidGlucagon, and to a lesser extent epinephrine, hormonesthat are responsive to decreases in blood glucose,inhibit glycolysis and stimulate gluconeogenesis in theliver by increasing the concentration of cAMP. This inturn activates cAMP-dependent protein kinase, leadingto the phosphorylation and inactivation of pyruvatekinase. They also affect the concentration of fructose2,6-bisphosphate and therefore glycolysis and gluconeogenesis,as explained below.Allosteric Modification Is InstantaneousIn gluconeogenesis, pyruvate carboxylase, which catalyzesthe synthesis of oxaloacetate from pyruvate, requiresacetyl-CoA as an allosteric activator. The presenceof acetyl-CoA results in a change in the tertiarystructure of the protein, lowering the K m value for bicarbonate.This means that as acetyl-CoA is formedfrom pyruvate, it automatically ensures the provision ofoxaloacetate and, therefore, its further oxidation in thecitric acid cycle. The activation of pyruvate carboxylaseand the reciprocal inhibition of pyruvate dehydrogenaseby acetyl-CoA derived from the oxidation of fattyacids explains the action of fatty acid oxidation in sparingthe oxidation of pyruvate and in stimulating gluconeogenesis.The reciprocal relationship between thesetwo enzymes in both liver and kidney alters the metabolicfate of pyruvate as the tissue changes from carbohydrateoxidation, via glycolysis, to gluconeogenesisduring transition from a fed to a starved state (Figure19–1). A major role of fatty acid oxidation in promotinggluconeogenesis is to supply the requirement forATP. Phosphofructokinase (phosphofructokinase-1)occupies a key position in regulating glycolysis and isalso subject to feedback control. It is inhibited by citrateand by ATP and is activated by 5′-AMP. 5′-AMPacts as an indicator of the energy status of the cell. Thepresence of adenylyl kinase in liver and many othertissues allows rapid equilibration of the reaction:ATP + AMP ↔2ADPThus, when ATP is used in energy-requiring processesresulting in formation of ADP, [AMP] increases. As[ATP] may be 50 times [AMP] at equilibrium, a smallfractional decrease in [ATP] will cause a severalfold increasein [AMP]. Thus, a large change in [AMP] acts asa metabolic amplifier of a small change in [ATP]. Thismechanism allows the activity of phosphofructokinase-1to be highly sensitive to even small changes in energystatus of the cell and to control the quantity of carbohydrateundergoing glycolysis prior to its entry into thecitric acid cycle. The increase in [AMP] can also explainwhy glycolysis is increased during hypoxia when [ATP]decreases. Simultaneously, AMP activates phosphorylase,increasing glycogenolysis. The inhibition of phosphofructokinase-1by citrate and ATP is another explanationof the sparing action of fatty acid oxidation onglucose oxidation and also of the Pasteur effect,whereby aerobic oxidation (via the citric acid cycle) inhibitsthe anaerobic degradation of glucose. A consequenceof the inhibition of phosphofructokinase-1 is anaccumulation of glucose 6-phosphate that, in turn, inhibitsfurther uptake of glucose in extrahepatic tissuesby allosteric inhibition of hexokinase.Fructose 2,6-Bisphosphate Plays a UniqueRole in the Regulation of Glycolysis &Gluconeogenesis in LiverThe most potent positive allosteric effector of phosphofructokinase-1and inhibitor of fructose-1,6-bisphosphatasein liver is fructose 2,6-bisphosphate. It relievesinhibition of phosphofructokinase-1 by ATP andincreases affinity for fructose 6-phosphate. It inhibitsfructose-1,6-bisphosphatase by increasing the K m forfructose 1,6-bisphosphate. Its concentration is underboth substrate (allosteric) and hormonal control (covalentmodification) (Figure 19–3).Fructose 2,6-bisphosphate is formed by phosphorylationof fructose 6-phosphate by phosphofructokinase-2.The same enzyme protein is also responsible forits breakdown, since it has fructose-2,6-bisphosphataseactivity. This bifunctional enzyme is underthe allosteric control of fructose 6-phosphate, whichstimulates the kinase and inhibits the phosphatase.Hence, when glucose is abundant, the concentration offructose 2,6-bisphosphate increases, stimulating glycolysisby activating phosphofructokinase-1 and inhibiting