Carbohydrate Metabolism Module PDF

Metabolism Module SESSION-2, LCETURE-2 CARBOHYDRATE METABOLISM-1 Dr. Aveen Hassan Mustafa MBChB., M.Sc., FKBMS-Chemical pathologist 13th Feb. 2023 Intended learning outcomes 1. Describe the general structures and functions of carbohydrates. 2. Explain why cellulose is not digested in the human ga...

Metabolism Module SESSION-2, LCETURE-2 CARBOHYDRATE METABOLISM-1 Dr. Aveen Hassan Mustafa MBChB., M.Sc., FKBMS-Chemical pathologist 13th Feb. 2023 Intended learning outcomes 1. Describe the general structures and functions of carbohydrates. 2. Explain why cellulose is not digested in the human gastrointestinal tract. 3. Describe how dietary carbohydrates are digested and absorbed. 4. Describe the glucose-dependency of some tissues. 5. Describe the key features of glycolysis. 6. Explain why lactic acid (lactate) production is important in anaerobic glycolysis. 7. Explain how the blood concentration of lactate is controlled. 8. Explain the situations associated with increased lactate production. 9. Explain the biochemical basis of the clinical conditions of lactose intolerance and galactosaemia 2 3 Overview of Catabolism General characteristics of carbohydrates LO-1 Compounds composed of C, H and O. Empirical formula (CH2O)n when n=5 then C5H10O5 Exist as mono, di, and polysaccharides. 4 Monosaccharides (simple sugar molecules) LO-1 The most commonly occurring sugars are ü trioses (C3) e.g. glyceraldehyde, ü pentoses (C5) e.g. ribose ü hexoses (C6) e.g. glucose. They are either Ø aldoses (derived from glyceraldehyde) or Ø ketoses (derived from dihydroxyacetone): 5 Monosaccharides LO-1 Sugars have a number of important physico-chemical properties: - Hydrophilic – water soluble, do not readily cross cell membranes - Partially oxidised – need less oxygen than fatty acids for complete oxidation. 6 Monosaccharides LO-1 The major hexose found in blood is glucose, in addition, fructose and galactose may appear for short periods depending on the dietary intake of fruit and dairy products. Excessive amounts of galactose and fructose in the blood are associated with a number of clinical problems (e.g. Galactosaemia, Fructose intolerance) as are the persistently high levels of glucose seen in untreated diabetes. 7 Disaccharides LO-1 Disaccharides are formed by the condensation of two monosaccharides. They include Ø sucrose (glucose-fructose) and Ø lactose (glucose-galactose). Ø maltose (glucose-glucose) is produced during the digestion of dietary starch. 8 Disaccharides LO-1 Disaccharides are formed by the condensation of two monosaccharides with the elimination of water and formation of an O-glycosidic bond. Disaccharides can be non-reducing if the aldehyde or ketone groups of the two sugars are both involved in the forming the glycosidic bond. 9 Polysaccharides LO-1 Polysaccharides are polymers of monosaccharide units linked by glycosidic bonds. Most are homo-polymers made by the polymerisation of one type of monosaccharide. Glucose Polysaccharides: 1. Glycogen is a polymer of glucose found in animals. The glucose units joined together in α-1,4 and α -1,6 glycosidic linkages (10:1). Glycogen is highly branched. 2. Starch is found in plants. It contains amylose (α -1,4 linkages) and amylopectin (α -1,4 and α -1,6 linkages). Starch can be hydrolysed to release glucose and maltose in the human GI tract. 3. Cellulose is found in plants where it has a structural role. 10 LO-2 Cellulose In the glucose polymer cellulose, glucose monomers are joined together by β -1,4 glycosidic linkages. The human gastrointestinal tract does not produce enzymes that are able to hydrolyze β-1, 4 linkages and cellulose cannot be digested. It thus forms a major component of the dietary fiber that is important for normal gastrointestinal function. 11 For more information please watch this video on YouTube https://www.youtube.com/watch?v=JxK5rZxbyQY 12 LO-3 Stage 1: Metabolism (Digestion and absorption) of dietary carbohydrates Dietary polysaccharides (starch & glycogen) are hydrolysed by glycosidase enzymes. This releases glucose, maltose and leaves smaller polysaccharides (dextrins). This begins in the mouth with salivary amylase and continues in the duodenum with pancreatic amylase. 13 LO-3 Digestion of maltose, dextrins and dietary disaccharides lactose and sucrose occurs in the duodenum and jejunum. The glycosidase enzymes involved are large glycoprotein complexes that are attached to the brush border membrane of the epithelial cells lining these regions. The major enzymes are lactase, glycoamylase and sucrase/isomaltase. They release the monosaccharides glucose, fructose and galactose. Low activity of lactase is associated with a reduced ability to digest the lactose present in milk products and may produce the clinical condition of lactose intolerance. 14 Glucose requirements of tissues LO-4 All tissues can remove glucose, fructose and galactose from the blood. However the liver is the major site of fructose and galactose metabolism. Glucose concentration in the blood is normally held relatively constant. This is because some tissues have an absolute requirement for glucose and the rate of glucose uptake is dependant on its concentration in the blood. 15 LO-4 Glucose requirements of tissues The minimum glucose requirement for a healthy adult is ~180g/day: -~ 40g/day is required for tissues that only use glucose e.g. RBCs, WBCs, kidney medulla and lens of the eye - ~ 140g/day is required by the CNS as this prefers glucose - Variable amounts are required by tissues for specialised functions e.g. synthesis of triacylglycerol in adipose tissue, glucose metabolism provides the glycerol phosphate. 16 Stage 2: Metabolism of glucose in tissues (intracellular) There are a number of pathways that glucose can enter in tissues. These include 1. glycolysis, 2. pentose phosphate pathway, 3. conversion to glycogen for storage and 4. conversion to other sugars such as galactose. The importance of these pathways varies in different tissues. 17 Glycolysis LO-5 Glycolysis is the central pathway in the catabolism of all sugars. It consists of 10 enzyme-catalysed steps that occur in the cell cytoplasm. It is active in all tissues and functions to generate: –ATP for cell function. (Only pathway to generate ATP anaerobically) –NADH from NAD+ –Building block molecules for anabolism –Useful intermediates for specific cell functions (C3) –The starting material, end products and intermediates are C3 or C6. – There is no loss of CO2 –Glucose is oxidised to pyruvate and NAD+ is reduced to NADH –Overall is exergonic with a –ve ΔG value –All intermediates are phosphorylated and some have a high enough phosphoryl group transfer potential to form ATP from ADP (substrate level phosphorylation). –2 moles of ATP are required to activate the process. This is an energy investment to make glucose a little bit unstable in order to carry out reactions on it. 4 moles of ATP are produced to give a net gain of 18 2 moles of ATP. Glycolysis LO-5 https://www.youtube.com/watch?v=gggC9vctvBQ&t=1633s 19 Glycolysis Steps 1, 3 and 10 are irreversible. - Step 1 is catalysed by Hexokinase (in the liver glucokinase) - Step 3 is catalysed by Phosphofructokinase-1 - Step 10 is catalysed by Pyruvate kinase LO-5 20 Anaerobic glycolysis (lactic acid) LO-6 When the oxygen supply is inadequate or in cells without mitochondria, Pyruvate is reduced to lactate by the enzyme lactate dehydrogenase (LDH). 2 Pyruvate + 2 NADH + 2 H+ →2 Lactate + 2 NAD+ Under these conditions the overall equation for the 11 steps of anaerobic glycolysis is: Glucose + 2 Pi + 2 ADP → 2 Lactate + 2 ATP + 2H2O The produced lactate is released into the circulation where it is converted back to Pyruvate and oxidised to CO2 (heart muscle) or converted to glucose (liver). LDH increases NAD+ concentrations under anaerobic conditions for Glycolysis to proceed 21 Anaerobic glycolysis 22 Significance of lactate production LO-7 § Normally the amount of lactate produced equals the amount of lactate utilized. § Plasma lactate < 1mM § This concentration can increase under certain conditions, e.g. strenuous exercise, shock and congestive heart disease. § Increases due to decreased utilization occur in liver disease, thiamine deficiency and during alcohol metabolism. § Only when the concentration reaches > 5mM does this cause a problem, as it exceeds the renal threshold and it begins to affect the buffering capacity of the plasma causing lactic acidosis. 23 Lactose Intolerance LO-8 § Low activity of the enzyme lactase, meaning that one of the main dietary glucose disaccharides, lactose, cannot be digested. § Dietary lactose is hydrolysed by lactase to release glucose and galactose. 24 Galactosaemia LO-8 § Galactose metabolism takes place largely in the liver by soluble enzymes catalysing the following reactions Overall Reaction: Galactose + ATP à Glucose 6-phospate + ADP § Lactose intolerance can affect Galactose metabolism as lactose metabolism releases Glucose and Galactose 25 26 Galactosaemia LO-8 § In Galactosaemia individuals are unable to utilise galactose obtained from the diet because a lack of Galactokinase or Galactose 1-phosphate uridyl transferase. § The absence of the kinase enzyme is relatively rare and is characterised by accumulation of galactose in tissues. § The absence of the transferase is more common and more serious as both galactose and Galactose 1-Phosphate (which is toxic to the liver) accumulate in tissues. 27 Galactosaemia LO-8 Accumulation of galactose in tissues leads to its reduction to Galactitol (aldehyde group reduced to alcohol group) by the activity of the enzyme aldose reductase. This reaction depletes some tissues of NADPH. 28 Galactosaemia LO-8 § In the eye the lens structure is damaged (cross-linking of lens proteins by S-S bond formation causing cataracts. § Un addition there may be non-enzymatic glycosylation of the lens protein because of high galactose concentration. § This may also contribute to cataract formation. § The accumulation of Galactose and Galactitol in the eye may lead to raise intra-ocular pressure (glaucoma) which if untreated may cause blindness. § Accumulation of Galactose 1-phosphate in tissues causes damage to the liver, kidney and brain and may be related to the sequestration of Pi making it unavailable for ATP synthesis. 29