Carbohydrate metabolism

By Asad vaisi-Raygani

Associate Professor

In Clinical Biochemistry

Carbohydrate metabolism

• Starch, maltose, sucrose, lactose, cellulose

• Salivary α amylase• Digestion begins in the mouth, where salivary α-

amylase hydrolyzes the internal glycosidic linkages of starch, producing short polysaccharide fragments or oligosaccharides.

Cleavage α 1 4 linkage at Starch

• a second form of a-amylase, secreted by the pancreas into the small intestine, continues the breakdown process.

• Pancreatic a-amylase yields mainly maltose and maltotriose (the di- and trisaccharides of α(1->4) glucose) and oligosaccharides called limit dextrins, fragments of amylopectin containing α (1->6) branch points.

• Maltose, Glc, Isomaltase Glc α(1 6) and dextrins are degraded by enzymes of the intestinal brush border (the fingerlike microvilli of intestinal epithelial cells, which greatly increase the area of the intestinal surface).

dextrinase

maltase

trehalase

sucrase

lactase

• Lactose intolerance, common among adult's of most human populations except those originate in Northern Europe and some parts of Africa, is due to

• the disappearance after childhood of most or all of the lactase activity of the intestinal cells.

• Lactose cannot be completely digested and absorbed in the small intestine and passes into the large intestine, where bacteria convert it to toxic products that cause abdominal cramps and diarrhea.

• The problem is further complicated because undigested lactose and its metabolites increase the osmolarity of the intestinal contents, favoring the retention of water in the intestine.

• In most parts of the world where lactose intolerance is prevalent, milk is not used as a food by adults,

• although milk products predigested with lactase are commercially available in some countries.

• In certain human disorders, several or all of the intestinal disaccharidases are missing.

• In these cases, the digestive disturbances triggered by dietary disaccharides can sometimes be minimized by a controlled diet.

• Glycolysise• Gluconeogenesis• Cori cycle and alanin cycle, Rapopor-

Laoburing cycle, fructose and galactose metabolism

• Crobs cycle, pentose phosphate shunt, propionate metabolism

• Glycogenolysis, glycogenosis, glucronic pathway

Glycolysis & the Oxidationof Pyruvate

• BIOMEDICAL IMPORTANCE• Most tissues have at least some

requirement for glucose.• In brain, the requirement is substantial.

Glycolysis, the major pathway for glucose metabolism, occurs in the cytosol of all cells.

• It is unique in that it can function either aerobically or anaerobically

• Erythrocytes, which lack mitochondria, are completely reliant on glucose as their metabolic fuel and metabolize it by anaerobic glycolysis.

• Glycolysis is both the principal route for glucose metabolism and the main pathway for the metabolism of fructose, galactose, and other carbohydrates derived from the diet.

• The ability of glycolysis to provide ATP in the absence of oxygen is especially important because it allows skeletal muscle to perform at very high levels when oxygen supply is insufficient and because it allows tissues to survive anoxic episodes.

• However, heart muscle, which is adapted for aerobic performance, has relatively

• low glycolytic activity and poor survival under conditions of ischemia.

• Diseases in which enzymes of glycolysis (eg, pyruvate kinase) are deficient are mainly seen as hemolytic anemias or,

• if the defect affects skeletal muscle (eg, phosphofructokinase), as fatigue.

• In fast-growing cancer cells, glycolysis proceeds at a higher rate than is required by the citric acid cycle,

• forming large amounts of pyruvate, which is reduced to lactate and exported.

• This produces a relatively acidic local environment in the tumor which may have implications for cancer therapy.

• The lactate is used for gluconeogenesis in the liver, an energy-expensive process responsible for much of the hypermetabolism seen in cancer cachexia

• Lactic acidosis results from several causes, including impaired activity of

pyruvate dehydrogenase

glycolysis

• In glycolysis (from the Greek glykys, meaning "sweet,“ and lysis, meaning "splitting"), a molecule of glucose is degraded in a series of enzyme-catalyzed reactions to yield two molecules of the three-carbon compound pyruvate.

• During the sequential reactions of glycolysis, some of the free energy released from glucose is conserved in the form of ATP and NADH.

• Glycolysis was the first metabolic pathway to be elucidated and is probably the best understood.

• From Eduard Buchner's discovery in 1897 of fermentation in broken extracts of yeast cells until the elucidation of the whole pathway in yeast (by Otto Warburg and Hans von Euler-Chelpin) and in muscle (by Gustav Embden and Otto Meyerhof) in the 1930s

Glucokinase

•At normal systemic-blood glucose concentrations (4.5–5.5 mmol/L), the liver is a net producer of glucose.

0.05mmol/l

10 mmol/l

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glycolysis0

glycolysis1

phosphohexose isomerase (phosphoglucose isomerase

Phosphofructokinase I

Glyceraldehyde 3-phosphate and dihydroxyacetone phosphate Are interconverted by the enzyme phosphotriose isomerase

phosphotriose isomerase

Glyceraldehyde 3-phosphate dehydrogease

iodoacetate

phosphoglycerate kinase

substrate-level phosphorylation

toxicity of arsenic

• The toxicity of arsenic is due to competition of arsenate with inorganic phosphate (Pi) in the above reactions to give 1-arseno-3-phosphoglycerate, which hydrolyzes

• spontaneously to give 3-phosphoglycerate plus heat, without generating ATP.

phosphoglycerate mutase

enolase

Enolase is inhibited by fluoride. To prevent glycolysis in the estimation of glucose, blood is collected in tubes containing fluoride

pyruvate kinase

Rapoport-Leoburing cycle

Pyruvate dehydrogenase

L

Pyruvate dehydrogenase

Gluconeogenesis & Controlof the Blood Glucose

• Gluconeogenesis is the term used to include all pathways responsible for converting noncarbohydrate precursors to glucose or glycogen.

• The major substrates are the glucogenic amino acids and lactate, glycerol, and propionate.

• Liver and kidney are the major gluconeogenic tissues.

• Gluconeogenesis meets the needs of the body for glucose when carbohydrate is not available in sufficient amounts from the diet or from glycogen reserves.

• A supply of glucose is necessary especially for the nervous system and erythrocytes.

• Failure of gluconeogenesis is usually fatal. Hypoglycemia causes brain dysfunction, which can lead to coma and death.

• Glucose is also important in maintaining the level of intermediates of the citric acid cycle even when fatty acids are the main source of acetyl-CoA in the tissues.

• In addition, gluconeogenesis clears lactate produced by muscle and erythrocytes and glycerol produced by adipose tissue.

• Propionate, the principal glucogenic fatty acid produced in the digestion of carbohydrates by ruminants, is a major substrate for gluconeogenesis in these species.

• Three nonequilibrium reactions catalyzed by hexokinase, phosphofructokinase, and pyruvate kinase prevent simple reversal of glycolysis for glucose synthesis (Chapter 17). They are circumvented as follows:

Mitochondria

or ITP

Gluconeogenesis Is Energetically Expensive,but Essential

• The main source of GTP for phosphoenolpyruvate carboxykinase inside the mitochondrion is the reaction

• of succinyl-CoA synthetase (Chapter 16).

• This provides a link and limit between citric acid cycle activity and the extent of withdrawal of oxaloacetate for gluconeogenesis.

Fructose 2,6-Bisphosphate Plays a UniqueRole in the Regulation of Glycolysis &

Gluconeogenesis in Liver

• The most potent positive allosteric effector 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 affinity for fructose 6-phosphate.

• It inhibits fructose-1,6-bisphosphatase by increasing the Km for fructose 1,6-bisphosphate.

Glucagon

Protein kinase

Insulin active diesterase andphosphatase

• Of the amino acids transported from muscle to the liver during starvation, alanine predominates.

• The glucose-alanine cycle (Figure 19–4) transports glucose from liver to muscle with formation of pyruvate, followed

• by transamination to alanine, then transports alanine to the liver, followed by gluconeogenesis back to glucose.

• A net transfer of amino nitrogen from muscle to liver and of free energy from liver to muscle is effected.

• The energy required for the hepatic synthesis of glucose from pyruvate is derived from the oxidation of fatty acids.