Changes in the availability of substrates are responsible for most changes in metabolism either directly or indirectly acting via changes in hormone secretion. Three mechanisms are responsible for regulating the activity of enzymes concerned in carbohydrate metabolism: (1) changes in the rate of enzyme synthesis, (2) covalent modification by reversible phosphorylation, and (3) allosteric effects.

Induction & Repression of Key Enzymes Require Several Hours

The changes in enzyme activity in the liver that occur under various metabolic conditions are listed in Table 1. The enzymes involved catalyze physiologically irreversible non equilibrium reactions. The effects are generally reinforced because the activity of the enzymes catalyzing the reactions in the opposite direction varies reciprocally (see Figure 1). The enzymes involved in the utilization of glucose (ie, those of glycolysis and lipogenesis) become more active when glucose availability is high such as after a meal, and under these conditions the enzymes of gluconeogenesis have relatively low activity. Insulin, secreted in response to increased blood glucose, enhances the synthesis of the key enzymes in glycolysis. It also antagonizes the effect of the glucocorticoids and glucagon stimulated cAMP, which induce synthesis of the key enzymes of gluconeogenesis.

Table1. Regulatory & Adaptive Enzymes Associated With Carbohydrate Metabolism

Fig1. Major pathways and regulation of gluconeogenesis and glycolysis in the liver. Entry points of glucogenic amino acids after transamination are indicated by arrows extended from circles. The key gluconeogenic enzymes are shown in double bordered boxes. The ATP required for gluconeogenesis is supplied by the oxidation of fatty acids. Propionate is important only in ruminants. Arrows with wavy shafts signify allosteric effects; dash-shafted arrows, covalent modification by reversible phosphorylation. High concentrations of alanine act as a “gluconeogenic signal” by inhibiting glycolysis at the pyruvate kinase step.

Covalent Modification by Reversible Phosphorylation Is Rapid

 Glucagon and epinephrine, hormones that are responsive to a decrease in blood glucose, inhibit glycolysis and stimulate gluconeogenesis in the liver by increasing the concentration of cAMP. This in turn activates cAMP-dependent protein kinase, leading to the phosphorylation and inactivation of pyruvate kinase. They also affect the concentration of fructose 2,6-bisphosphate and therefore glycolysis and gluconeogenesis, as described later. In addition, as mentioned glucagon is a potent stimulator of amino acid transport.

Allosteric Modification Is Instantaneous

In gluconeogenesis, pyruvate carboxylase, which catalyzes the synthesis of oxaloacetate from pyruvate, requires acetyl-CoA as an allosteric activator. The addition of acetyl-CoA results in a change in the tertiary structure of the protein, lowering the Km for bicarbonate. This means that as acetyl-CoA is formed from pyruvate, it automatically ensures the provision of oxaloacetate by activating pyruvate carboxylase. The activation of pyruvate carboxylase and the reciprocal inhibition of pyruvate dehydrogenase by acetyl-CoA derived from the oxidation of fatty acids explain the action of fatty acid oxidation in sparing the oxidation of pyruvate (and hence glucose) and stimulating gluconeogenesis. The reciprocal relationship between these two enzymes alters the metabolic fate of pyruvate as the tissue changes from carbohydrate oxidation (glycolysis) to gluconeogenesis during the transition from the fed to fasting state (see Figure 1). A major role of fatty acid oxidation in promoting gluconeogenesis is to supply the ATP that is required for glucose synthesis.

Phosphofructokinase (phosphofructokinase-1) occupies a key position in regulating glycolysis and is also subject to feedback control. It is inhibited by citrate and by normal intra cellular concentrations of ATP and is activated by 5′ AMP. At the normal intracellular [ATP] the enzyme is about 90% inhibited; this inhibition is reversed by 5′AMP (Figure 2).

Fig2. The inhibition of phosphofructokinase-1 by ATP and relief of inhibition by AMP. The yellow bar shows the normal range of the intracellular concentration of ATP

5′ AMP acts as an indicator of the energy status of the cell. The presence of adenylyl kinase in liver and many other tis sues allows rapid equilibration of the reaction

2ADP↔ATP + 5′AMP

Thus, when ATP is used in energy-requiring processes, resulting in the formation of ADP, [AMP] increases. A relatively small decrease in [ATP] causes a several fold increase in [AMP], so that [AMP] acts as a metabolic amplifier of a small change in [ATP], and hence a sensitive signal of the energy state of the cell. The activity of phosphofructokinase-1 is thus regulated in response to the energy status of the cell to control the quantity of carbohydrate undergoing glycolysis prior to its entry into the citric acid cycle. At the same time, AMP activates glycogen phosphorylase, so increasing glycogenolysis. A consequence of the inhibition of phosphofructokinase-1 by ATP is an accumulation of glucose-6-phosphate, which in turn inhibits further uptake of glucose in extrahepatic tissues by inhibition of hexokinase. Remember glucokinase, which is present in the liver, is not inhibited by glucose-6-phosphate thus allowing for high rates of glucose entry and diversion to glycogen deposition at the same time allow for gluconeogenesis-derived carbon to be diverted to glycogen as well.

Fructose 2,6-Bisphosphate Plays a Unique Role in the Regulation of Glycolysis & Gluconeogenesis in Liver

The most potent positive allosteric activator of phosphofructokinase-1 and inhibitor of fructose 1,6-bisphosphatase in liver is fructose 2,6-bisphosphate. It relieves inhibition of phosphofructokinase-1 by ATP and increases the affinity for fructose 6-phosphate. It inhibits fructose 1,6-bisphosphatase by increasing the K_m for fructose 1,6-bisphosphate. Its concentration is under both substrate (allosteric) and hormonal control (covalent modification) (Figure 3).

Fig3. Control of glycolysis and gluconeogenesis in the liver by fructose 2,6-bisphosphate and the bifunctional enzyme PFK-2/F-2,6-Pase (6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase). (F-1,6-Pase, fructose 1,6-bisphosphatase; PFK-1, phosphofructokinase-1 [6-phosphofructo-1-kinase].) Arrows with wavy shafts indicate allosteric effects.

Fructose 2,6-bisphosphate is formed by phosphorylation of fructose-6-phosphate by phosphofructokinase-2. The same enzyme protein is also responsible for its breakdown, since it has fructose 2,6-bisphosphatase activity. This bifunctional enzymeis under the allosteric control of fructose-6-phosphate, which stimulates the kinase and inhibits the phosphatase. Hence, when there is an abundant supply of glucose, the con centration of fructose 2,6-bisphosphate increases, stimulating glycolysis by activating phosphofructokinase-1 and inhibiting fructose 1,6-bisphosphatase. In the fasting state, glucagon stimulates the production of cAMP, activating cAMP-dependent protein kinase, which in turn inactivates phosphofructokinase-2 and activates fructose 2,6-bisphosphatase by phosphorylation. Hence, gluconeogenesis is stimulated by a decrease in the concentration of fructose 2,6-bisphosphate, which inactivates phosphofructokinase-1 and relieves the inhibition of fructose 1,6-bisphosphatase. Xylulose 5-phosphate, an intermediate of the pentose phosphate pathway  activates the protein phosphatase that dephosphorylates the bifunctional enzyme, so increasing the formation of fructose 2,6-bisphosphate and increasing the rate of glycolysis. This leads to increased flux through glycolysis and the pentose phosphate pathway and increased fatty acid synthesis .

Substrate (Futile) Cycles Allow Fine Tuning & Rapid Response

The control points in glycolysis and glycogen metabolism involve a cycle of phosphorylation and dephosphorylation catalyzed by glucokinase and glucose-6-phosphatase; phosphofructokinase-1 and fructose 1,6-bisphosphatase; pyruvate kinase, pyruvate carboxylase, and phosphoenolpyruvate carboxykinase; and glycogen synthase and phosphorylase. It would seem obvious that these opposing enzymes are regulated in such a way that when those involved in glycolysis are active, those involved in gluconeogenesis are relatively inactive, since otherwise there would be cycling between phosphorylated and nonphosphorylated intermediates, with net hydrolysis of ATP. In fact in the liver futile cycling of carbon (1-2%) is present at a low rate. The advantage is by having both pathways the liver is allowed to rapidly transition from the fed, fasted, or exercising state. In muscle both phosphofructokinase and fructose 1,6-bisphosphatase have some activity at all times, so that there is indeed even more wasteful substrate cycling. This permits the very rapid increase in the rate of glycolysis necessary for muscle contraction. At rest the rate of phosphofructokinase activity is some 10-fold higher than that of fructose 1,6-bisphosphatase; in anticipation of muscle contraction, the activity of both enzymes increases, fructose 1,6-bisphosphatase 10 times more than phosphofructokinase, maintaining the same net rate of glycolysis. At the start of muscle contraction, the activity of phosphofructokinase increases further, and that of fructose 1,6-bisphosphatase falls, so increasing the net rate of glycolysis (and hence ATP formation) as much as a 1000-fold.

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مواضيع ذات صلة

Blood Glucose is Derived From the Diet, Gluconeogenesis, & Glycogenolysis

Glucose-1-Phosphate & Glycogen

Thermodynamic Barriers Prevent a Simple Reversal of Glycolysis

Gluconeogenesis & the Control of Blood Glucose: Biomedical Importance

Glycogen Metabolism is Regulated by A Balance in Activities Between Glycogen Synthase & Phosphorylase

cAMP Activates Glycogen Phosphorylase

Cyclic AMP Integrates The Regulation of Glycogenolysis & Glycogenesis

Glycogenolysis is not the Reverse of Glycogenesis, it is A Separate Pathway

Glycogenesis Occurs Mainly in Muscle & Liver

The Oxidation of Pyruvate to Acetyl-COA is The Irreversible Route from Glycolysis to The Citric Acid Cycle

Glycolysis is Regulated at Three Nonequilibrium Reactions

Tissues That Function Under Hypoxic Conditions or have Intrinsically High Rates of Glucose Oxidation Produce Lactate