Carbohydrates are major constituents of physiological systems. The organic compounds composed of carbon, hydrogen and oxygen [CxH2O)y]n, which along with lipids and proteins, provide energy and contribute to the structure of organisms. Complex carbohydrates are digested into simple sugars, principally glucose, which is used primarily as an energy source and stored as glycogen. The most important dietary hexoses (6 carbon-containing carbohydrates) are D-glucose, D-galactose and D-fructose but the principal sugar circulating in the bloodstream is glucose. Lactose (glucose and galactose) and sucrose(glucose and fructose) are important disaccharides. Carbohydrates are needed for specific cellular functions (such as ribose in nucleic acids) and can modify proteins and their functions by glycosylation.
Glycolysis is an anaerobic degradation of glucose to lactate which occurs in all human cells. This process is capable of yielding 2 mol of ATP from 1 mol glucose in the absence of molecular oxygen. Provided cells contain mitochondria, the end product of glycolysis in the presence of oxygen is pyruvate rather than lactate. Pyruvate is then oxidized to CO2 and H2O by enzymes in the mitochondria.
Glucose is metabolized differently in various cells. In red blood cells, after penetrating the plasma membrane, glucose is metabolized mainly by glycolysis. Since red blood cells lack mitochondria, the lactic acid is released into the blood. Glucose used by pentose phosphate pathway in red blood cells provides NADPH to keep glutathione in the reduced state, which has important role in the destruction of organic peroxides. Peroxides cause irreversible damage to membranes, DNA and other cellular component.
The brain tissue has an absolute need for glucose and processes it via glycolysis. Pyruvate produced is then oxidized to CO2 and H2O in the mitochondria. The pentose phosphate pathway in these cells generating part of NADPH needed for reductive synthesis and the maintenance of glutathione in the reduced state.
Muscle and heart cells readily utilize glucose. Insulin stimulates transport of glucose into these cells by way of glucose transport protein. In these cells, glucose can be utilized by glycolysis to give pyruvate, which is used by the pyruvate dehydrogenase complex and the TCA cycle to provide ATP. Muscle and heart cells are capable of synthesizing glycogen.
Adipose tissues also transport glucose by glucose transport protein in an insulin dependent mechanism. Pyruvate is generated by glycolysis and oxidized by the pyruvate dehydrogenase complex to give acetyl CoA, which is used primarily for de novo fatty acid synthesis.
Liver has the greatest number of ways to utilize glucose. Uptake of glucose by the liver occurs independent of insulin by means of a low affinity, high-capacity glucose transport protein. Glucose is used by the pentose phosphate pathway for the production of NADPH, which is needed for reductive synthesis, maintenance of reduced glutathione and reactions catalyzed by endoplasmic reticulum enzyme systems. Pentose phosphate pathway provides ribose phosphate which required for the synthesis of nucleotides such as ATP, DNA and RNA. Glucose is also used for glycogen synthesis. In glucuronic acid pathway, glucose can also be used in drug and bilirubin detoxification. In the liver, glycolysis occurs and the pyruvate produced being used as a source of acetyl CoA for complete oxidation by the TCA cycle and the synthesis of fat by the process of de novo fatty acid synthesis.The liver has the capacity to convert three carbon precursors, such as lactate, pyruvate, glycerol and alanine, into glucose by the process of gluconeogenesis, to meet the need of glucose of other cells.
Glycolysis occurs in three stages. Priming stage involves input of two molecules ATP and catalyzed by hexokinase to convert glucose into a molecule of fructose 1,6-biphosphate. The splitting stage involves fructose 1,6-biphosphate aldolase which catalyzed fructose-1,6-biphosphate into two molecules of glyceraldehydes 3-phosphate. In the oxidoreduction-phosphorylation stage, two molecules glyceraldehydes 3-phosphate are converted into two molecules of lactate with the production of four molecules of ATP. The overall process of glycolysis generates two molecules of lactate and two molecules of ATP.
Net synthesis or formation of glucose from various substrates is termed gluconeogenesis. This includes use of various amino acids, lactate, pyruvate, propionate and glycerol. Glucose is also synthesized from galactose and fructose. Two important cycles in tissues that involves gluconeogenesis are Cori Cycle and the alanine cycle. The cycles are only functional in liver and tissues that do not completely oxidize glucose to CO2 and H2O. Peripheral tissues must release either alanine or lactate as the end product of glucose metabolism. The type of recycled three-carbon intermediate is the difference between the Cori cycle and the alanine cycle. In the liver, carbon returns to lactate in Cori cycle but in alanine cycle, it returns to alanine.
Only two molecules of ATP per molecule of glucose are produced by Cori Cycle and six molecules of ATP are needed in liver to provide the energy for glucose synthesis. Oxygen and mitochondria are required in peripheral tissue for participation in the alanine cycle. Alanine cycle transfers the energy from liver to peripheral tissues because of the six to eight molecules of ATP produced per molecule glucose. Participation of alanine in the cycle presents liver with amino nitrogen, which is then disposed of as urea.
Glucose in synthesized from the carbon chains of amino acids except leucine and lysine. All other amino acids are classified as glucogenic or both glucogenic and ketogenic give rise to net synthesis of either pyruvate or oxaloacetate. Oxaloacetate is an intermediate in gluconeogenesis.
Glucose can also be synthesized from odd-chain fatty acids such as phytanic acid. Catabolism of such compounds yield propionate, a precursor for gluconeogenesis generating oxaloacetate. Triacylglycerols, which are composed of three O-acyl groups combined with one glycerol molecule. Hydrolysis of a triacylglyserol yield three fatty acids and glycerol, the substrate for gluconeogenesis.
Glucose is synthesized from other sugars such as fructose, galactose, and mannose. In the liver,fructose phosphorylated by a special ATP-linked kinase yielding fructose 1-phosphate which is then cleaved by enzyme fructose 1-phosphate to yield one molecule of dihydroxyacetone phosphate and one glyceraldehydes. Dihydroxyacetone phosphate can be converted to glucose or into pyruvate or lactate.
Milk sugar or lactose is an important source of galactose in the human diet. UDP-glucose serves as a recycling intermediate in the overall process of converting galactose into glucose.
Glycogenolysis and Glycogenesis
Glycogenolysis refers to breakdown of glycogen to glucose or glucose 6-phosphate. Muscle and liver glycogen stores serve different roles. Glycogen serves as fuel reserve for the synthesis of ATP within muscle, whereas liver glycogen functions as a glucose reserve for the maintenance of blood glucose concentrations.
Glycogenesis refers to synthesis of glycogen. The first reaction is being catalyzed by glucokinase in hepatic tissues and hexokinase in peripheral tissue. Liver glycogenesis contributes to the lowering of glucose in the blood.
The most important hormone controlling plasma glucose concentrations is insulin. Insulin binds to specific cell-surface receptor on adipose tissue and muscle, enhances the rate of glucose entry into these cells. The intracellular glucose concentration is kept low by insulin-induced activation of enzymes which stimulate its incorporation into glycogenesis in liver and muscle. Insulin also inhibits gluconeogenesis from fats and amino acids. Glucagon secretion stimulated by hypoglycaemia, enhances hepatic glycogenolysis and gluconeogenesis.
Disorders Of Carbohydrates Metabolism
Fructose Intolerance is a hereditary disease which caused by deficiency of liver aldolase responsible for splitting fructose 1-phosphate into dihydroxyacetone phosphate and glyceraldehydes.
Diabetes Mellitus is the most common set of disorders of carbohydrate metabolism. It comprises a heterogeneous group of metabolic diseases that are characterized by chronic hyperglycaemia and disturbances in carbohydrate, lipid and protein metabolism resulting from defects in insulin secretion and/or insulin action. Fasting (chronic) and postprandial hyperglycemia are mainly responsible for the acute, short term and late complications, which affect all body organs and systems. In the diabetic, both the release of insulin (type I diabetics) and the cellular response to insulin (insulin resistance in Type 2 diabetics) are decreased. The decreased insulin control causes the diabetic to be in semi starvation state, with an increased dependence on triglycerides as an energy source and protein as a source of glucose.
This disease is characterized by elevated blood lactate levels (more than 5 mmol/L), along with decreased blood pH and bicarbonate concentration. All tissues of the body have the capacity to produce lactate by anaerobic glycolysis but in small quantities because much more ATP can be gained by complete oxidation of pyruvate. All tissues respond with an increase in lactate generation when oxygenation is inadequate such as during convulsions and diseases involving circulatory and pulmonary failure. A decreased in ATP resulting from reduced oxidative phosphorylation allows the activity of 6-phosphofructo-1-kinase to increase. These tissues have to rely on anaerobic glycolysis for ATP production and results in excessive lactic acid production.
Hypoglycemia and premature infants
Premature and small-for-gestational age infants are believed to be susceptible to hypoglycemia than normal infants because the smaller store of glycogen. Fasting depletes their glycogen stores more rapidly, making these neonates more dependent on gluconeogenesis.
Glycogen storage diseases
The most common glycogen storage disease is Type I or von Gierke’s disease which is a genetic abnormality caused by a deficiency of liver, intestinal mucosa, and kidney glucose 6-phosphatase.
Glucose 6-phosphate dehydrogenase deficiency
Glucose 6-phosphate dehydrogenase catalyzed the oxidation of Glucose 6-Phosphate to 6-phosphogluconate and the reduction of NADP+. Cells lacking Glucose 6-Phosphate dehydrogenase do not reduce enough NADP to maintain glutathione in its reduced state. Reduced glutathione is necessary for the integrity of the erythrocyte membrane.
Galactosemia is hereditary disorder caused by deficiency of galactokinase or galactose 1-phosphate uridylyl transferase which makes the individual unable to metabolize galactose derived from lactose to glucose metabolites.
- Thomas M. Devlin. (1997). Carbohydrates Metabolism, Textbook of Biochemistry with clinical correlations. 4th edition. Wiley-Liss.
- Philip D. Mayne . (1994). Carbohydrates Metabolism . Clinical Chemistry in diagnosis and treatment, 6th edition (196-222), Arnold, London.
- Halimah Abdullah Sani (1989) Metabolisme Karbohidrat . Biokimia klinik, Gangguan Metabolisme Karbohidrat (1-10). Dewan Bahasa dan Pustaka, Kuala Lumpur
|Last Reviewed||:||5 December 2013|
|Writer||:||Noriha bt. Sanusi|
|Accreditor||:||Liew Chuan Hee|