Carbohydrates metabolism.pdf

Biochemistry Carbohydrates Metabolism Glucose Carbohydrates Metabolism Content: Skeletal Muscle ……………………………………………………………………………….. 6 Liver ……………………………………………………………………………….. 18 Carbohydrates Metabolism Carbohydrates Metabolism Glucose: Glucose is the major fuel of most tissues. It is metabolized to pyru...

Biochemistry Carbohydrates Metabolism Glucose Carbohydrates Metabolism Content: Skeletal Muscle ……………………………………………………………………………….. 6 Liver ……………………………………………………………………………….. 18 Carbohydrates Metabolism Carbohydrates Metabolism Glucose: Glucose is the major fuel of most tissues. It is metabolized to pyruvate by the pathway of glycolysis. Aerobic tissues metabolize pyruvate to acetyl-CoA, which can enter the citric acid cycle for complete oxidation to CO2 and H2O, linked to the formation of ATP in the process of oxidative phosphorylation. Glycolysis can also occur anaerobically, the end product is lactate. Carbohydrates Metabolism Metabolic Role of Glucose: Glucose and its metabolites also take part in other processes The synthesis of glycogen and the pentose phosphate pathway. It is a source of reducing equivalents (NADPH) for fatty acid synthesis. Triose phosphate intermediates in glycolysis give rise to the glycerol moiety of triacylglycerols. Pyruvate and intermediates of the citric acid cycle provide the carbon skeletons for the synthesis of nonessential amino acids Acetyl-CoA is the precursor of fatty acids and cholesterol. Carbohydrates Metabolism Skeletal Muscle Carbohydrates Metabolism | Skeletal Muscle Skeletal Muscle: Skeletal muscle utilizes glucose as a fuel, both aerobically, forming CO2, and anaerobically, forming lactate. It stores glycogen as a fuel for use in muscle contraction and synthesizes muscle protein. Muscle accounts for approximately 50% of body mass (store protein that can be drawn upon to supply amino acids for gluconeogenesis in starvation). Carbohydrates Metabolism | Skeletal Muscle Glucose: The excess glucose of immediate requirements is taken up to synthesize glycogen (glycogenesis), or fatty acids (lipogenesis). Between meals, the liver acts to maintain the blood glucose concentration by breaking down glycogen (glycogenolysis), and also, together with the kidney, by converting non-carbohydrate metabolites such as lactate, glycerol, and amino acids to glucose (gluconeogenesis). The maintenance of an adequate blood concentration of glucose is essential for the tissues act as the major fuel (the brain) or the only fuel (erythrocytes). Carbohydrates Metabolism | Skeletal Muscle Glucose: Glycolysis, the pentose phosphate pathway, and fatty acid synthesis all occur in the cytosol. In gluconeogenesis, substrates such as lactate and pyruvate, which are formed in the cytosol, enter the mitochondrion to yield oxaloacetate as a precursor for the synthesis of glucose. Carbohydrates Metabolism | Skeletal Muscle Tissue Requirements: Most tissues have at least some requirement for glucose. There is substantial requirement in the brain, even in prolonged fasting the brain can meet no more than about 20% of its energy needs from ketone bodies. Glycolysis, the major pathway for glucose metabolism, occurs in the cytosol of all cells. It can function either aerobically or anaerobically, depending on the availability of oxygen and the electron transport chain. Carbohydrates Metabolism | Skeletal Muscle Tissue Requirements: Erythrocytes (lack mitochondria), completely reliant on glucose as their metabolic fuel, and metabolize it by anaerobic glycolysis. For glucose oxidation beyond pyruvate (the end product of glycolysis) requires both oxygen and mitochondrial enzyme systems: The pyruvate dehydrogenase complex, the citric acid cycle, and the respiratory chain. Carbohydrates Metabolism | Skeletal Muscle Glycolysis: Cancer cells have elevated levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which may account for the high rate of glycolysis seen in cancer cells. The compound methyl-glyoxal has been shown to inhibit GAPDH in cancer cells but not in normal cells. This observation may lead to the development of rapid screening assays for cancer cells and to the development of drugs for treatment of cancerous tumors. a. What mechanisms might be responsible for the elevated levels of GAPDH in cancer cells? b. Why might methylglyoxal inhibit GAPDH in cancer cells but not in normal cells? Carbohydrates Metabolism | Skeletal Muscle Glycolysis: When glycolysis provide ATP in the absence of oxygen, skeletal muscle perform at very high levels of work output and survive anoxic episodes. Heart muscle adapted for aerobic performance, has relatively low glycolytic activity and poor survival under conditions of ischemia. In fast-growing cancer cells, glycolysis proceeds at a high rate, forming large amount of pyruvate, which is reduced to lactate and exported. Produces an acidic local environment in the tumor. Carbohydrates Metabolism | Skeletal Muscle Glycolysis: Carbohydrates Metabolism | Skeletal Muscle Glycolysis: The lactate is used for gluconeogenesis in the liver, which is responsible for much of the hypermetabolism seen in cancer cachexia. Lactic acidosis results from various causes, including impaired activity of pyruvate dehydrogenase, especially in thiamin (vitamin B1) deficiency. In short supply of oxygen, mitochondrial re-oxidition of NADH formed during glycolysis is impaired, and NADH is re-oxidized by reducing pyruvate to lactate, so permitting glycolysis to continue. Carbohydrates Metabolism | Skeletal Muscle Glycolysis: Glycolysis of glucose to lactate. Glucose + 2 ADP + 2 Pi → 2 Lactate + 2 ATP + 2 𝑯𝟐 𝑶 All of the enzymes of glycolysis are cytosolic. Glucose enters glycolysis by phosphorylation to glucose- 6-phosphate, catalyzed by hexokinase, using ATP as the phosphate donor and required Mg2+. Under physiological conditions, this phosphorylation can be regarded as irreversible. Hexokinase is inhibited allosterically by its product, glucose-6-phosphate. Carbohydrates Metabolism | Skeletal Muscle Glycolysis: In tissues other than the liver and pancreatic β-islet cells, the availability of glucose for glycolysis (or glycogen synthesis in muscle, and lipogenesis in adipose tissue,) is controlled by transport into the cell, which in turn is regulated by insulin. Carbohydrates Metabolism | Skeletal Muscle Carbohydrates Metabolism | Skeletal Muscle Liver Carbohydrates Metabolism | Liver Liver: Hexokinase has a high affinity (low Km) for glucose, and in the liver it is saturated under normal conditions, and so acts at a constant rate to provide glucose-6-phosphate to meet the liver’s needs. Liver cells also contain an isoenzyme of hexokinase, glucokinase, which has a Km very much higher than the normal intracellular concentration of glucose. The function of glucokinase in the liver is to remove glucose from the hepatic portal blood following a meal, so regulating the concentration of glucose available to peripheral tissues. Carbohydrates Metabolism | Liver Glucokinase: This provides more glucose 6-phosphate than is required for glycolysis; it is used for glycogen synthesis and lipogenesis. Also found in pancreatic β-islet cells to detect high concentrations of glucose. As more glucose is phosphorylated by glucokinase, there is increased glycolysis, leading to increased formation of ATP. This leads to closure of an ATP-potassium channel, causing membrane depolarization and opening of a voltage gated calcium channel. The resultant influx of calcium ions leads to fusion of the insulin secretory granules with the cell membrane, and the release of insulin. Carbohydrates Metabolism | Liver Glucose 6-phosphate : Important compound at the junction of several metabolic pathways: Glycolysis, gluconeogenesis, the pentose phosphate pathway, glycogenesis, and glycogenolysis. In glycolysis, it is converted to fructose 6- phosphate by phosphohexose isomerase, which involves an aldose-ketose isomerization. Carbohydrates Metabolism | Liver Glycolysis: Since two molecules of triose phosphate are formed per molecule of glucose undergoing glycolysis, two molecules of ATP are formed in this reaction per molecule of glucose undergoing glycolysis. Most of the reactions of glycolysis are freely reversible. The reactions, catalyzed by hexokinase (and glucokinase), phosphofructokinase, and pyruvate kinase, are the major sites of regulation of glycolysis and are irreversible. Carbohydrates Metabolism | Liver Glycolysis: Fructose enters glycolysis by phosphorylation to fructose 1-phosphate, and bypasses the main regulatory steps, so resulting in formation of more pyruvate and acetyl-CoA than is required for ATP formation. In the liver and adipose tissue, this leads to increased lipogenesis, and a high intake of fructose may be a factor in the development of obesity. The step catalyzed by enolase involves a dehydration, forming phosphoenolpyruvate. Enolase is inhibited by fluoride, and when blood samples are taken for measurement of glucose, glycolysis is inhibited by taking the sample into tubes containing fluoride. Carbohydrates Metabolism | Liver Glycolysis: Enolase is dependent on the presence of either Mg2+ or Mn2+ ions. The phosphate of phosphoenolpyruvate is transferred to ADP in another substrate-level phosphorylation catalyzed by pyruvate kinase to form two molecules of ATP per molecule of glucose. The reaction of pyruvate kinase is irreversible under physiological conditions because: 1. The large free energy change involved. 2. The immediate product of the enzyme catalyzed reaction is enol-pyruvate, which undergoes spontaneous isomerization to pyruvate (the product of the reaction is not available to undergo the reverse reaction). Carbohydrates Metabolism | Liver Glycolysis: Under anaerobic conditions, the NADH cannot be reoxidized through the respiratory chain, and pyruvate is reduced to lactate catalyzed by lactate dehydrogenase. This permits the oxidization of NADH, permitting another molecule of glucose to undergo glycolysis. Under aerobic conditions, pyruvate is transported into mitochondria and undergoes oxidative decarboxylation to acetyl-CoA then oxidation to CO2 in the citric acid cycle. The reducing equivalents from the NADH formed in glycolysis are taken up into mitochondria for oxidation.