Lecture 2.1 - Energy Production (Carbohydrate 1-2) PDF

Carbohydrates - CHO: ◦General formula (CH20)n ◦Contain aldehyde (-CHO) or ketone (-C=O) group ◦Multiple -OH groups ◦Diet: about 80% of human caloric intake ◦Body composition - approximately 1% stored as glycogen or as part of cellular components ◦Most dietary carbs us...

Carbohydrates - CHO: ◦General formula (CH20)n ◦Contain aldehyde (-CHO) or ketone (-C=O) group ◦Multiple -OH groups ◦Diet: about 80% of human caloric intake ◦Body composition - approximately 1% stored as glycogen or as part of cellular components ◦Most dietary carbs used as fuel by tissues and cells Carbohydrates - monosaccharides: ◦Contain 3-9 C-atoms ‣ C3 (trioses): glyceraldehyde ‣ C5 (pentoses): ribose ‣ C6 (hexoses): glucose ◦Except dihydroxyacetone, have asymmetric carbons existing as stereoisomers (mirror-images) D- and L- forms ‣ Enzymes have specificity to one or another enantiomer. Some enantiomers are unable to be digested by the human body. ◦Contain aldose or ketone groups ◦Properties: ‣ Hydrophilic - water soluble, attract water, do not readily cross cell membranes - proteins are needed to facilitate transport of these molecules across the membrane ‣ Partially oxidised - need less oxygen than fatty acids for complete oxidation ◦The major hexose in blood is glucose (~5 mmol/L); also fructose and galactose (important for structures related to cell membranes) ◦Persistently high levels of glucose (greater than or equal to 7 mmol/L) seen in untreated diabetes ‣ Diabetes is characterised by elevated levels of glucose in the blood. Carbohydrates - disaccharides: ◦Condensation of two monosaccharides with the elimination of water and formation of an O-glycosidic bond. ◦Sucrose (glucose and fructose), lactose (glucose and galactose), maltose (glucose and glucose) ◦Can be non-reducing if the aldehyde or ketone groups of the two sugars are both involved in forming the O-glycosidic bond. ◦Sucrose is non-reducing (aldehyde and ketone groups of sugars are forming the O-glycosidic bonds) ◦Maltose and lactose are reducing disaccharides Carbohydrates - polysaccharides: ◦Polymers of monosaccharide units linked by glycosidic bonds ◦Glycogen - the glucose units are joined together in alpha-1,4 and alpha-1,6 glycosidic linkages (10:1) and it has a highly branched structure  (glucose molecules attached to one another, forming chains) ◦Cellulose (plants) - the glucose units are joined by beta-1,4 linkages - humans don’t have enzymes that can break down cellulose. If we ingest cellulose, it will become part of the faeces and is a form of fibre. ◦The human GI tract does not produce enzymes that are able to hydrolyse beta-1,4 linkages and cellulose cannot be digested Stages of catabolism: Stage 1 - overview: ◦Purpose - to convert nutrients to a form that can be taken up into cells ◦Extracellular - (GI tract - enzyme breakdown) ◦Complex molecules —-> building block molecules (which are smaller and so can be absorbed) ◦Building block molecules absorbed from GI tract into circulation. ◦Short metabolic pathways ◦Breakage of C-N and C-O bonds (no C-C broken in stage 1) ◦No energy produced Catabolism of carbohydrates - stage 1: ◦GI tract (extracellular): (1) breakdown and (2) absorption ◦(1) breakdown: hydrolysis of glycosidic bonds to glucose, galactose, fructose ◦GI tract enzymes: glycosidases (amylases) ◦Saliva: amylase (starch, glycogen -> dextrins) ‣ Dextrins -> monosaccharides ◦Pancreas: amylase - major enzyme ◦Small intestine: disaccharides attached to brush border membrane of epithelial cells ‣ Lactase (lactose) - note: lactose intolerance ‣ Sucrose (sucrose) ‣ Pancreatic amylase (alpha 1-4 bonds) ‣ Isomaltase (alpha 1-6 bonds) ◦No significant hydrolysis of cellulose, no enzymes to attack the beta 1-4 linkages 5 ◦(2) Absorption: uptake into cells via facilitated diffusion using GLUT1-GLUT5 transporters - need to have “S’ specific specificity. GLUT1 can affect the concentration of glucose in certain conditions.  ◦Intestinal epithelial cells -> blood -> target tissues Clinical relevance - stage 1 - carbohydrates: ◦Glucose requirements of tissues: ‣ Major sugar in blood ‣ All tissues can metabolise glucose ‣ Blood (glucose) regulated (~5 mM): Hormonal regulation (insulin, glucagon) ‣ Some tissues (RBC, lens of eye) have an absolute requirement on glucose ‣ Uptake by these tissues depends on blood ‣ CNS (brain) prefers glucose and cannot metabolise fatty acids ‣ Some tissues need it for specialised functions (liver, adipose) Stage 2 - overview: ◦Intracellular pathway(primarily cytosolic and mitochondrial) ◦Many pathways (not all in all tissues) ◦Building block molecules -> simpler molecules ◦Oxidative (require coenzymes which are then reduced, e.g. NAD+ —> NADH) ◦Some energy (as ATP) produced ◦C-C bonds broken Catabolism of carbohydrates - stage 2: ◦Intracellular (cytosol): glycolysis/pentose phosphate ◦Intracellular (mitochondria): connecting stage 2-3 ◦Phase 1 (reactions 1-3): energy investment - energy is already in the body (2 moles ATP per 1 mol glucose). Glucose is phosphorylated to glucose-GP ◦Phase 2 (reactions 4-10): energy production (4 moles ATP per 1 mol glucose) ◦Functions: ‣ Yields NADH (reducing power) ‣ ATP produced from ADP (net: 2 moles ATP per mol glucose) ‣ Produces C6 and C3 intermediates (links to other metabolic pathways) ◦Features: ‣ Exergonic (reactions 7 and 10 - generate ATP ) Sees  ‣ C6 (glucose) generate 2 C3 (pyruvate) ‣ Lactate from pyruvate can be generated in the absence of oxygen ◦Lactate dehydrogenase reaction: ◦Reaction occurs in cells with limiting oxygen availability (RBC) and skeletal muscle also brain, skin, GI) ◦Lactate released into blood and metabolised in the liver and heart, and is disposed by the kidneys ◦Regenerates NAD+ needed for glycolysis when NADH is being used up - hence why lactate dehydrogenation is an important process ◦Blood levels < 1mM Clinical relevance - stage 2: ◦Glycolysis needs NAD+ in order to oxidise glucose ◦As total NAD+ and NADH is constant, when all NAD+ is converted to NADH, glycolysis stops ◦NAD+ needs to be regranted by another route ◦Glycolysis intermediates are important for other metabolic routes: ‣ Triglyceride and phospholipid synthesis: Dihydroxyacetone phosphate (DHAP) -> glycerol phosphate (adipose tissue and liver - for the synthesis of triacylglycerol) ‣ Regulator of oxygen affinity to haemoglobin 1,3-Bisphosphoglycerate -> 2,3-Bisphosphoglycerate (in RBC at same concentration as haemoglobin) ◦Lactate dehydrogenase reaction regenerates NAD+ ◦Kidneys work hard to regulate lactate levels. ◦Hyperlactatemia (2-5mM: below renal threshold - no change in pH as kidneys can dispose lactate ◦Lactic acidosis (>5mM): above renal threshold - blood pH lowered Stage 2 - pentose phosphate pathway (hexose monophosphate shunt): ◦Not all of the glucose 6-phosphate produced in cells enters glycolysis, some is metabolised via the pentose phosphate pathway (oxidative but no ATP produced) ‣ Important pathway for the liver, red blood cells and adipose tissue ‣ Functions: Produce NADPH (reducing power for anabolic processes such as lipid synthesis) In red blood cells: maintaining free -SH (thiol ) groups on cysteine residues in certain proteins (important in G6PDH deficiency) Produce the C5-sugar ribose for the synthesis of nucleotides (DNA and RNA)  Catabolism of carbohydrates - other than glucose: Metabolism of galactose: ◦Some galactose is required for the synthesis of glycolipids and glycoproteins, such as blood group antigens (A, B and O) ◦Dietary lactose is hydrolysed by the digestive enzyme lactase to release glucose and galactose that are absorbed into the blood stream (stage 1) ◦Galactose is metabolised largely in the liver (some in the kidney and GI tract) (stage 2) ‣ Lactose = galactose + glucose Clinical relevance - galactosemia: ◦Genetic condition with 2 variants ◦Classical galactosemia - deficiency of enzyme galactose 1-P uridyltransferase ◦Non-classical galactosemia - deficiency of galactokinase ◦Accumulation of galactose lead to accumulation of galactitol which utilises NADPH - depletes NADPH from tissues ‣ Patient safety - galactosemia should be detected in early life so that effective management can be initiated. Treatment = no lactose in diet ◦Effects on health: cataracts -> glaucoma -> damage to liver, brain and kidneys F FISSIITE E ISETTITIS Metabolism of fructose: ◦Dietary sucrose is hydrolysed by the digestive enzyme sucrase to release glucose and fructose (stage 1) ◦Fructose is metabolism largely in the liver by soluble enzymes that catalyse its conversion to glyceraldehyde 3-phosphate an intermediate of glycolysis (stage 2) ‣ Sucrose = fructose + glucose