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Dr.H.MOHAMMAD HANAFI, MBBS (Syd).MS. MEDICAL FACULTY UNAIR Blog : http//mhanafi123.wordpress.com INTRODUCTION Carbohydrate is a staple food of Indonesian, as many others, specially of Asian and African countries. In general, the source of carbohydrate in food derived from rice, but some are derived from corn, sago, cassava, potatoes, sweet potatoes, and bananas. In rice amylum is the major component. Others are minerals, vitamins, and fibers Amylum : amylopectin and amylose Classification of Carbohydrate • Hetero polysaccharides • Homo polysaccharides • Oligosaccharides • Disaccharides • Monosaccharide's Digestion and absorption • Amylase pancreas (alfa amylase) • Endopolysaccharidase : break up alfa link ( 1 4 ), except on the tip of polymers, and near the branch points. • Result of digestion : glucose, maltose, maltotriose, iso maltose, and oligosaccharides (limit dextrins) • Intestinal enzymes : maltase, lactase, sucrase, limit dextrase etc. • Active absorption : glucose and galactose Blood & guts: Putting it together for glucose transport… glucose Fig. 11-44 Transfer of Glucose and Other Sugars Through The Lipid Bilayer • Because the lipid bilayer of the eucaryotic plasma membrane is impermeable for hydrophilic molecules, glucose is transported across the plasma membrane by membrane associated carrier proteins, glucose transporters. There are 2 different types of transporter proteins, which mediate the transfer of glucose and other sugars through the lipid bilayer: + • Na -coupled carrier system (SGLT) • The facilitative glucose transporters (GLUT) PATH WAYS IN CARBOHYDRATE METABOLISM Glycolysis Glycogenesis Glycogenolysis Pyruvate oxidation TCA Cycle (final common pathway) Hexose Mono-phosphate Shunt or Pentose Phosphate Pathway Gluconeogenesis Uronic Acid pathway Fructose and Galactose metabolism Hexosamine GLYCOLYSIS • Change : glucose pyruvate glucose lactic acid • Function : produce ATP • Site : cytoplasm • Aerobic glycolysis forms 7 ATP • Anaerobic glycolysis forms 2 ATP Pyruvate Lactate G G 6P HEXOKINASE Found in all cells except pancreas Inhibited by ( G 6P ) Km for glucose low Catalyze the reaction Fructose (F) F 6P GLUCOKINASE • Found in liver and pancreas • G 6P has no effect • Km for glucose high • The only enzyme for G G 6P G 6P F 6P Phosphofructokinase 6 CH OPO 2 2 3 O H 5 H 4 OH 6 CH OPO 2 2 3 1CH2OH O ATP ADP HO 2 3 OH H fructose-6-phosphate 5 Mg2+ 1CH2OPO32 H H 4 OH HO 2 3 OH H fructose-1,6-bisphosphate Regulator enzyme PFK-1 F 6P F 1,6 BP One way reaction PHOSPHO FRUCTO KINASE 1 ( PFK 1 ) Activators : • ADP • AMP • Pi • NH3 • F 2,6 BP ( fructose 2,6 Bis Phosphate ) • F6P Inhibitors ATP Citric acid 2,3 BP Glycerate ( in erythrocytes) Free Fatty Acid Acetyl-CoA Ketone bodies Ketone bodies : Acetoacetate Betahydroxy Butyrate Acetone O || CCCCOOH OH | CCCCOOH O || CCC UNIQUE ROLE OF 2,6 BP In the liver The most potent positive allosteric activator for enzyme Phosphofructokinase-1 (PFK-1), and It relieves inhibition of PFK-1 by ATP, and ↑ affinity for F 6 P Inhibit Fructose 1,6-bisphosphatase ( ↑ Km for F 1,6 BP ) F 6P F2,6 BP PFK-2 cAMP Dependent Protein Kinase Protein Protein P ( few proteins ) Phosphofructokinase-2 (PFK-2) is also a phosphatase (bifunctional enzyme) Bifunctional enzyme has two activities: • 6-phosphofructo-2-kinase activity, decreased by phosphorylation • Fructose-2,6-bisphosphatase activity, increased by phosphorylation kinase ATP ADP fructose-2,6-bisphosphate fructose-6-phosphate Pi phosphatase 2 CH OPO 1 2 3 2C O HO 3C H 4C H H 5 C H Aldolase 2 CH OPO 2 3 3 OH 2C OH 1CH2OH 2 CH OPO 2 3 6 fructose-1,6bisphosphate O + O 1C H 2C OH 2 CH OPO 3 2 3 dihydroxyacetone glyceraldehyde-3phosphate phosphate Triosephosphate Isomerase F 1,6 BP Gld 3P + DHAP Triosephosphate Isomerase H H C OH C O + H H CH2OPO32 dihydroxyacetone phosphate + H OH H H C C + + H OH CH2OPO32 enediol intermediate O C H C OH CH2OPO32 glyceraldehyde3-phosphate In Glycolysis DHAP is converted into glyceraldehyde -3P Glyceraldehyde-3-phosphate Dehydrogenase H O NAD 1C H 2 C OH + Pi 2 CH OPO 2 3 3 glyceraldehyde3-phosphate + OPO32 + H+ O NADH 1C H C 2 OH 2 CH OPO 2 3 3 1,3-bisphosphoglycerate 6. Glyceraldehyde-3-phosphate Dehydrogenase catalyzes: glyceraldehyde-3-P + NAD+ + Pi 1,3-bisphosphoglycerate + NADH + H+ If oxygen available Respiratory Chain in function, by mean of Malate shuttle system oxidizes NADH in the resp. syst ; 2.5 ATP released NAD+ recovered, catalyzed by malate dehydrogenase Enzyme glyceraldehyde 3P dehydrogenase required NAD+ in function If R. C. not in function, NADH will reduces Pyruvate into Lactate Exergonic oxidation of the aldehyde in glyceraldehyde-3-phosphate, to a carboxylic acid, drives formation of an acyl phosphate, a "high energy" bond (~P). This is the only step in Glycolysis in which NAD+ is reduced to NADH. Phosphoglycerate Kinase O OPO32 ADP ATP O O 1C H 2C OH 2 CH OPO 2 3 3 1,3-bisphosphoglycerate C 1 Mg2+ H 2C OH 2 CH OPO 2 3 3 3-phosphoglycerate This phosphate transfer is reversible (low ∆G), since one ~P bond is cleaved & another synthesized. The enzyme undergoes substrate-induced conformational change similar to that of Hexokinase. Phosphoglycerate Mutase O O C 1 C 1 H 2C OH 3 CH2OPO3 O O H 2C OPO3 2 3-phosphoglycerate 2 3 CH2OH 2-phosphoglycerate Phosphate is shifted from the OH on C3 to the OH on C2. Fluoride (-) Enolase O O C 1 H 2 C OPO32 3 CH2OH H O O C C OH O O 1 OPO32 CH2OH C 2C OPO32 3 CH2 2-phosphoglycerate enolate intermediate phosphoenolpyruvate Fluoride in tooth paste inhibits oral bacterial growth F is also used in glucose determination Pyruvate Kinase O O ADP ATP C 1 C 2 O O C C 1 OPO32 3 CH2 phosphoenolpyruvate C 2 O O 1 OH C 2 3 CH2 enolpyruvate O 3 CH3 pyruvate This phosphate transfer from PEP to ADP is spontaneous. PEP has a larger ∆G of phosphate hydrolysis than ATP. Removal of Pi from PEP yields an unstable enol, which spontaneously converts to the keto form of pyruvate. Required inorganic cations K+ and Mg++ bind to anionic residues at the active site of Pyruvate Kinase. Pyruvate Kinase activity Activators : F 1,6 BP In the liver F 1,6 BP able to abolish inhibition of ATP and Alanine Inhibitors : • ATP • Free Fatty Acid • Acetyl CoA • Ketone bodies • Alanine (in liver only) Protein Kinase (P.K.) controls in Glycogen. • cAMP dependent Protein Kinase activated by cAMP. • cAMP synthesized from ATP • enzyme adenylyl cyclase • Glucagon activates adenylyl cyclase (through G protein) cAMP Dependent Protein Kinase inhibits Glycolysis in two sites 1. PFK-1, with decreasing F2,6 BP. PFK-2-P catalyzes F2,6 BP F6P + Pi. Active cAMP Dependent P.K. converts PFK-2 PFK-2-P ( ATP ADP ) 2.Inactive Pyruvate Kinase PEP P Pyruvate Kinase PK-P Pyruvate Kinase is phosphorylated by cAMP Dependent P.K. Pyruvate Kinase phosphate (PK-P) is inactive If oxygen available for respiratory chain activity, Pyruvate is the end product of Glycolysis with 7 ATP as high energy phosphate. ( older textbook still counting as 8 ATP). In unaerobic Glycolysis of certain type of muscle for sprinters, lack of oxygen cause inactive respiratory chain. NADH will reduces Pyruvate, and Lactate is the final product of Glycolysis. NAD+ is ready as coenzyme for Glyceraldehyde 3P dehydrogenase Lactate Dehydrogenase O O C C NADH + H+ NAD+ O CH3 pyruvate O O C HC OH CH3 lactate NAD+ is the target product. Lactate is the by product. Lactate is one of the substrate of gluconeogenesis, will be taken up by the liver and changed into glucose. Glycolysis in Erythrocyte No mitochondria No Respiratory enzymes NADH reduces Pyruvate into Lactate 2,3 BP Glycerate drives oxygen dissociation of Oxy hemoglobin to release Oxygen inhibits PFK-1 In the tissue where oxygen required but not ATP, 1,3 BP Glycerate is converted into 2,3 BP Glycerate Lactate release . Tissues that normally derive much of their energy from glycolysis and produce lactate include brain, gastrointestinal tract, renal medulla, retina, and skin. Lactate production is also increased in septic shock, and many cancers also produce lactate.