The following points highlight the top four stages for reregulation of carbohydrate metabolism. The stages are: 1. Regulation of Carbohydrate Metabolism at the Cellular and Enzymatic Level 2. Regulation of Glycolysis, Gluconeo-Genesis and Hexose Monophosphate Shunt 3. Regulation of Glycogen Metabolism 4. Regulation of the Citric Acid Cycle.
Stages for Regulation of Carbohydrate Metabolism:
- Regulation of Carbohydrate Metabolism at the Cellular and Enzymatic Level
- Regulation of Glycolysis, Gluconeo-Genesis and Hexose Monophosphate Shunt
- Regulation of Glycogen Metabolism
- Regulation of the Citric Acid Cycle
Regulation of Carbohydrate Metabolism at the Cellular and Enzymatic Level:
a. The changes in the metabolism fully depend on the changes in the availability of substrates. The concentration of glucose, fatty acids and amino acids in blood influences their rate and pattern of metabolism in many tissues.
b. Alterations in the concentrations of glucose, fatty acids and amino acids in the blood owing to the changes in the dietary availability may alter the rate of secretion of hormones that influence the pattern of metabolism in metabolic pathways.
c. Three types of mechanisms are responsible for regulating the activity of enzymes concerned in carbohydrate metabolism:
(i) Changes in the rate of enzyme synthesis.
(ii) Conversion of an inactive to an active enzyme.
(iii) Allosteric effects.
Regulation of Glycolysis, Gluconeo-Genesis and Hexose Monophosphate Shunt:
a. Glucokinase catalyzes the conversion of glucose to glucose-6-phosphate. In the same extra mitochondrial region glucose- 6-phosphatase is also found which catalyses the same inter-conversion in the reverse direction on the supply of sufficient carbohydrate, glucokinase activity is increased whereas glucose-6-phosphatase activity is decreased.
In starvation, glucokinase activity falls as compared to glucose-6-phosphatase activity.
b. Under the availability of glucose the enzymes utilizing glucose are all activated but the enzymes producing glucose by gluconeogenesis are all depressed. The secretion of insulin controls the activity of the enzymes responsible for glycolysis as well as gluconeogenesis.
c. Both dehydrogenases of the HMP shunt are adaptive enzymes since their activity is increased in the well-fed animal as well as when insulin is given to a diabetic animal. Their activity is low in diabetes or fasting. Similar behaviour has been found in “Malic enzyme” and ATP-dtrate lyase. This indicates that these two enzymes are involved in lipogenesis rather than gluconeogenesis.
d. The activity of pyruvate dehydrogenase is decreased since it is regulated by phosphorylation involving an ATP-specific kinase and its activity is increased by de-phosphorylation by a phosphatase. Thus, pyruvate dehydrogenase is inhibited during fatty acid oxidation. Its activity is increased after administration of insulin and decreased in starvation.
e. The allosteric control of the activity of an enzyme is also available in carbohydrate metabolism. In gluconeogenesis, the synthesis of oxaloacetate from pyruvate by the enzyme pyruvate carboxylase requires the presence of acetyl-CoA as an allosteric activator.
The activation of pyruvate carboxylase and the inhibition of pyruvate dehydrogenase by acetyl-CoA formed from the oxidation of fatty acids helps to explain the sparing action of fatty acid oxidation.
On the oxidation of pyruvate and the stimulation of gluconeogenesis in the liver (Fig. 19.1), the main role of fatty acid oxidation in promoting gluconeogenesis is to supply ATP required in the pyruvate carboxylase and phosphoenolpyruvate carboxykinase reactions.
f. Glucagon accelerates gluconeogenesis in the liver, probably by increasing cAMP concentrations that stimulate the substrate concentration through the phosphoenol- pyruvate carboxykinase reaction and inhibit pyruvate kinase. Glucagon also stimulates triphosphatase in order to promote glycerol metabolism.
g. Phosphofructokinase, the occupier of key position in regulating glycolysis, is inhibited by citrate and ATP and is activated by AMP. The glycolysis is increased with the increase in the concentration of AMP during anoxia.
The inhibition of phosphofructokinase by citrate and ATP is another explanation of the sparing action of fatty acid oxidation and glucose oxidation. The consequence of the inhibition of phosphofructokinase is an accumulation of glucose-6-phosphate which, in turn, inhibits further uptake of glucose by allosteric inhibition of hexokinase.
Regulation of Glycogen Metabolism:
a. Glycogen metabolism regulation is affected by the balance in activation between the enzymes of glycogen synthesis and those of glycogen breakdown as well as the hormonal control.
b. Cyclic AMP-dependent protein kinase activates phosphorylase b kinase and inactivates glycogen synthetase. Thus, inhibition of glycogenoiysis promotes glycogenosis and inhibition of glycogenesis enhances glycogenoiysis.
c. Glycogen metabolism in the liver is controlled by the concentration of phosphorylase a. This enzyme not only controls the rate-limiting step in glycogenoiysis but also inhibits the activity of synthetase, phosphatase and thereby controls glycogen synthesis.
d. Inactivation of phosphorylase is caused by glucose and activation is caused by 5′- AMP.
e. It has been suggested that catecholamine’s, including epinephrine, stimulate glycogenoiysis by an addition mechanism not involving cAMP. These mechanisms probably involve direct stimulation of phosphorylase kinase by Ca++. Cyclic AMP-independent glycogenoiysis is also caused by vasopressin, oxytocin and angiotensin II.
f. Phosphorylase is immediately activated followed by the activation of glycogen synthetase on the administration of insulin. The presence of glucose is essential on the effects of insulin.
Regulation of the Citric Acid Cycle:
a. The activity of the enzymes of Citric acid cycle is immediately dependent on the supply of oxidized dehydrogenase cofactors (e.g., NAD) which, in turn, is dependent on the availability of ADP and ultimately on the rate of utilization of ATP.
b. Control of the citric acid cycle occurs at the pyruvate dehydrogenase step. Control may be experienced by allosteric inhibition of citrate synthase by ATP or long chain fatty acyl-CoA.
c. Oxaloacetate inhibits succinate dehydrogenase and the availability of oxaloacetate, as controlled by malate dehydrogenase, depends on the ratios of the concentrations of NADH and NAD+.
d. The increase in the ratio of the concentration of ATP and ADP is considered to raise the ratio of the concentration of GTP and GDP at the succinate thiokinase step, thereby increasing the concentration of succinyl-CoA.