CARBOHYDRATE METABOLISM Carbohydrates are found as monosaccharides, disaccharides, and polysaccharides or complex carbohydrates. They function in energy storage (starch&glycogen), signaling (glycoproteins and glycolipids, e.g. blood group determinants), fuel the nervous system and muscle (and virtually all cells, although there are distinct cell type specific differences in choice of primary fuel molecule), are parts of nucleic acids (genes, mRNA, tRNA, ribosomes), and as cell surface markers and signaling in glycolipids and glycoproteins, are part of connective tissue (heteropolymers; glycosaminoglycans), cell wall components (cellulose, hemi-cellulose) made of polymers that are enzymatically inert for most mammals to digest (except ruminants that harbor a special digestive tract bacterium with the appropriate cellulase enzyme). The alpha glycosidic bonds found in glycogen and starch is metabolically available to humans. The major source of dietary carbohydrate for humans is starch from consumed plant material. This is supplemented with a small amount of glycogen from animal tissue, disaccharides such as source from products containing refined sugar and lactose in milk. Digestion in the gut converts all carbohydrate to monosaccharides which are transported to the liver and converted to glucose. The liver has central role in the storage anddistribution within the body of all fuels, including glucose. Glucose in the body undergoes one of three metabolic fates. First it is catabolised to produce ATP (Adenosine triphosphate). This occurs in all peripheral tissues, particularly in brain, muscle and kidney. Second it is stored as glycogen. This storage occurs in liver and muscle. Third it is converted to fatty acids; these are stored in adipose tissue as triglycerides.

GLUCOSE CATABOLISM
Glucose will be oxidised by all tisuues to synthesise ATP. The first pathway which begins the complete oxidation of glucose is called glycolysis.

1. GLYCOLYSIS This pathway cleaves the six carbon glucose molecule (C6H12O6) into two molecules of the three carbon compound pyruvate (C3H3O3). This oxidation is coupled to the nett production of two molecules of ATP glucose. One oxidation reaction occurs in the latter part of the pathway. It uses NAD (Nicotinamide adenine dinucleotide) as the electron acceptor. This cofactor is present only in limited amounts and once reduced to NAHD (Nicotinamide adenine hydrodinucleotide), as in this reaction, it must be reoxidised to NAD to permit continuation of the pathway. This re-oxidation occurs by one of two methods: Anaerobic glycolysis: pyruvate is reduced to a compound called lactate. This single reaction occurs in the absence of oxygen (anaerobically) and is ideally suited to utilisation in heavily exercising muscle where oxygen supply is often insufficient to meet the demands of aerobic metabolism. The reduction of pyruvate to lactate is coupled to the oxidation of NADH to NAD. Aerobic metabolism of glucose pyruvate is transported inside mitochondria and oxidised to a compound called acetyl coenzyme A (acetyl CoA). This is an oxidation reaciton and uses NAD as an electron acceptor. By a further series of reactions collectively called the citric acid cycle, acetyl CoA is oxidised ultimately to CO2. These reactions are coupled to a process known as the electron transport chain which has the role of harnessing chemical bond energy from a series of oxidation/reduction reactions to the synthesis of ATP and simultaneously re-oxidising NADH to NAD.
The lactate formed is removed to other tissues and dealt with by one or two mechanisms: it is converted back to pyruvate. The pyruvate then proceeds to be further oxidised by second mechanism described above, finally producing a large amount of ATP. It is converted back to glucose in the liver.

2. GLUCONEOGENESIS The process of conversion of lactate to glucose is called gluconeogesis, uses some of the reactions of glycolysis (but in the reverse direction) and some ractions unique to this pathway to re-synthesise glucose. This pathway requires anenergy input (as ATP) but has the role of maintaining a curculating glucose concentration in the bloodstream (even in the absence of dietary suppy) and also maintaining a glucose supply of fast twitch muscle fibres.

GLYCOGEN AND GLUCOSE INTERCONVERSION Glycogen is a highly branched polymer of glucose. The high degree of branching (about every twelve glocose residues) produces a molecule which is compact and thus can be efficiently stored in the limited space available in liver and muscle tissue. Even though the branching is designed to make the molecule compact, it is still a polar molecule and thus must be stored with associated water. It is stored as aggregates of glycogen molecules within cells (visible microscopically as glycogen granules) with up to 70% of the aggreagate being water. The amount of gylcogen in muscle changes substantially between the fed state and following heavy exercise. The amount of glycogen stored in the liver is more constant and only falls substantially after prolonged sratvation.In both muscle and liver there is interconversion between the monomer glucose and the polymer glycogen. This has the potential to be a futile cycle wasting energy if the interconversion occurred continuously; thus it is controlled to meet the body’s glucose requirements at a particular time.

HORMONAL CONTROL OF GLYCOGEN METABOLISM The control which operates is via different enzymes catalysing the synthesis and breakdown (degradation) of glycogen. The activity of these enzymes is controlled such that only one is active at any one time and thus the pathway can proceed in only one direction – either towards glycogen synthesis OR towards glycogen breakdown and mobilisation of free glucose. The control is exerted by hormones acting to control the activity of the key enzymes. There are some differences in the hormone action in liver and muscle. GLYCOGEN METABOLISM IN LIVER AND MUSCLE The energy yield from the hydrolysis of stored glycogen and the subsequent oxidation of the released glucose is the same in muscle and liver.When glycogen is hydrolysed, the product is glucose 1-phosphate. This is easily converted to glucose 6-phosphate (these are molecules with the phosphate group attached to different carbon atoms on the glucose). Glucose 6-phosphate is the first product in the glycolysis pathway and its formation from glucose requires the expenditure of 1 ATP molucule/glucose.As glucose 6-phosphate if formed directly from glycogen hydrolysis, glucose that is derived from glycogen and enters the glycolsis pathway (rather than starting as monomeric glucose) yields a nett production of 3 ATP/glucose rather than just 2. This is a 50% increase in yield.

ROLE OF GLUCOSE 6-PHOSPHATASE Muscle and liver have different metabolic needs. Liver supplies other organs with glucose so must be able to export glucose released from glycogen hydrolysis. Muscle is a major consumer of glucose and thus does not export glicose. Glucose 6-phosphate formed as described in the previous sections is highly polar and cannot cross the cell’s cytoplasmic membrane. To leave the cell it must be converted to glucose. This reaction is catalysed by enzyme, glucose 6-phosphatase. glucose 6-phosphate glucose + phosphate glucose 6-phosphatase

Liver possesses this enzyme, so glucose released from liver glycogen can be exported to other tissues. It is very important to be aware that muscle does not possess gluco 6-phosphatase so it does not export glucose released from its glycogen stores, but rather uses it as a fuel to power muscle contraction.

CONVERSION OF EXCESS GLUCOSE TO FAT Sustained high glucose intake in the diet leads to increased fat synthesis. If glucose intake continues after muscle and liver glycogen stores are saturated, the glocose is not excreted or wasted. It is converted to a fuel storage from which has an unlimited capacity i.e triglycerides stored in adipose tissue.Glucose is converted to pyruvate by glycolysis. The pyruvate is converted to acetyl CoA, which is the starting material for the synthesis of fatty acids. This synthesis occurs in the liver followed by conversion of the fatty acids to trigcerrides (also in the liver) and than trasnport to adipose tissue for storage. Triglycerdes (fat) form the major energy store in the body. The mechanism of fatty acid synthesis will be discussed under the heading of fat metabolism.

PATHWAY OF CARBOHYDRATE METABOLISM

What happens to the carbohydrates that we eat? What our body does to carbohydrates is a series of mechanical and chemical breakdown known as carbohydrate metabolism. Carbohydrates made up of carbon, hydrogen, and oxygen atoms are classified as mono-, di-, and polysaccharides, depending on the number of sugar units they contain. The monosaccharides— glucose, galactose, and fructose—obtained from the digestion of food are transported from the intestinal mucosa via the portal vein to the liver. They may be utilized directly for energy by all tissues; temporarily stored as glycogen in the liver or in muscle; or converted to fat, amino acids, and other biological compounds. Carbohydrate metabolism begins with glycolysis, which releases energy from glucose or glycogen to form two molecules of pyruvate, which enter the Krebs cycle (or citric acid cycle), an oxygen-requiring process, through which they are completely oxidized. Before the Krebs cycle can begin, pyruvate loses a carbon dioxide group to form acetyl coenzyme A (acetyl-CoA). This reaction is irreversible and has important metabolic consequences. The conversion of pyruvate to acetyl-CoA requires the B vitamins. The hydrogen in carbohydrate is carried to the electron transport chain, where the energy is conserved in ATP molecules. Metabolism of one molecule of glucose yields thirty-one molecules of ATP. The energy released from ATP through hydrolysis (a chemical reaction with water) can then be used for biological work. Only a few cells, such as liver and kidney cells can produce their own glucose from amino acids, and only liver and muscle cells store glucose in the form of glycogen. Other body cells must obtain glucose from the bloodstream. Under anaerobic conditions, lactate is formed from pyruvate. This reaction is important in the muscle when energy demands exceed oxygen supply. Glycolysis occurs in the cytosol (fluid portion) of a cell and has a dual role. It degrades monosaccharides to generate energy, and it provides glycerol for triglyceride synthesis. The Krebs cycle and the electron transport chain occur in the mitochondria. Most of the energy derived from carbohydrate, protein, and fat is produced via the Krebs cycle and the electron transport system. Glycogenesis is the conversion of excess glucose to glycogen. Glycogenolysis is the conversion of glycogen to glucose (which could occur several hours after a meal or overnight) in the liver or, in the absence of glucose-6-phosphate in the muscle, to lactate. Gluconeogenesis is the formation of glucose from noncarbohydrate sources, such as certain amino acids and the glycerol fraction of fats when carbohydrate intake is limited. Liver is the main site for gluconeogenesis, except during starvation, when the kidney becomes important in the process. Disorders of carbohydrate metabolism include diabetes mellitus, lactose intolerance, and galactosemia.

CARBOHYDRATE METABOLISM IN THE MOUTH The metabolism of carbohydrates begins in our mouth. The first step is mastication - chewing. When we chew, food is mechanically divided into smaller pieces and is mixed with an enzyme in our saliva (salivary amylase) that chemically breaks down carbohydrates into its simpler components. A carbohydrate may be compared to a chain with many links. Each link is a monosaccharide (literally one carbohydrate or one sugar). A series of links forming a chain is a polysaccharide (several carbohydrate or sugar). Chewing mechanically cuts the chains (polysaccharides) into more manageable chunks while salivary amylase cleaves one link from the divided chunks, releasing a monosaccharide.

CARBOHYDRATE METABOLISM IN THE STOMACH Once we swallow our food, it passes through our chest via the esophagus into the stomach. In the stomach, the mechanical breakdown of carbohydrates continues. It takes about four hours before a meal we eat completely passes out of the stomach. During that time, food is ground by repetitive and forceful contraction of the stomach and transformed into a semi-liquid substance called chyme. Chyme, to continue our analogy, is made up of very short chunks of chain composed of one to five links each. The very short chunks facilitate the further chemical breakdown of carbohydrates in the small intestine.

CARBOHYDRATE METABOLISM IN THE INTESTINES Chyme is slowly released from the stomach into the small intestines. Here the chemical breakdown of carbohydrates, which started in the mouth, is completed. Enzymes from the pancreas flow into the small intestine together with chyme. The enzyme breaks the very small chunks of carbohydrate into individual links. The long chain of carbohydrate which was mechanically broken down into smaller chunks in the mouth and stomach are now broken down into separate links (monosaccharides). Monosaccharides, of which glucose is well known, are taken up by the cells of the intestines and go into the bloodstream.

CARBOHYDRATE METABOLISM IN THE BLOOD Once in the blood, glucose (and other monosaccharides) is used by the cells of the body as a source of energy. A molecule of glucose may be taken up by the cell, broken down further into its components and, by a series of chemical reactions, transformed into ATP (adenosine triphosphate), the primary energy currency of cells. The formation of ATP marks the end of the catabolic metabolism (breakdown) of carbohydrates. Cells of the pancreas, liver, and fats use glucose in unique ways.

CARBOHYDRATE METABOLISM IN THE PANCREAS After a meal, the glucose level in the blood goes up. This high level of glucose causes the pancreas to release insulin, a hormone that affects the metabolism of glucose in the liver and fat tissues.

CARBOHYDRATE METABOLISM IN THE LIVER Insulin promotes the uptake of glucose by liver cells. In addition to using glucose as a source of energy, liver cells store the excess glucose as glycogen. Glycogen is converted back to glucose when the sugar level goes down between meals.

CARBOHYDRATE METABOLISM IN FAT CELLS Fat cells take up glucose from the blood and convert it to ATP. When there is an excess of ATP, as when caloric intake exceeds caloric requirement, fat cells convert ATP to fat. This is the reason why any excess in our caloric intake, be it protein, carbohydrates or fat, increases our body fat and, consequently, our body weight.

REFERENCES 1. Bland, S. & Schiltz, B. et al (1999). Clinical Nutrition: A Functional Approach. Gig Harbor, WA: Institute of Functional Medicine. 2. Linder, M. (1991). Nutritional Biochemistry and Metabolism, with Clinical Applications, 2nd edition. New York: Elsevier. 3. Newsholme E. A. & Leech, A. R. (1994). Biochemistry for the Medical Sciences. New York: Wiley. 4. Salway, J. G. (1999). Metabolism at a Glance, 2nd edition. Malden, MA: Blackwell Science.
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