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• Glycolysis • Gluconeogenesis • Glycogen Synthesis

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• Glycolysis • Gluconeogenesis • Glycogen Synthesis Carbohydrate Metabolism! Wichit Suthammarak – Department of Biochemistry, Faculty of Medicine Siriraj Hospital – Aug 1st and 4th, 2014! • Glycolysis • Gluconeogenesis • Glycogen synthesis • Glycogenolysis • Pentose phosphate pathway • Metabolism of other hexoses Carbohydrate Digestion! Digestive enzymes! Polysaccharides/complex carbohydrates Salivary glands Amylase Pancreas Oligosaccharides/dextrins Dextrinase Membrane-bound Microvilli Brush border Maltose Sucrose Lactose Maltase Sucrase Lactase ‘Disaccharidase’ 2 glucose 1 glucose 1 glucose 1 fructose 1 galactose Lactose Intolerance! Cause & Pathophysiology! Normal lactose digestion Lactose intolerance Lactose Lactose Lactose Glucose Small Intestine Lactase lactase X Galactose Bacteria 1 glucose Large Fermentation 1 galactose Intestine gases, organic acid, Normal stools osmotically Lactase deficiency! active molecules • Primary lactase deficiency: อาการ! genetic defect, การสราง lactase ลด ลงเมออายมากขน, พบมากทสด! ปวดทอง, ถายเหลว, คลนไสอาเจยนภาย • Secondary lactase deficiency: หลงจากรบประทานอาหารทม lactose acquired/transient เชน small bowel เปนปรมาณมาก เชนนม! injury, gastroenteritis, inflammatory bowel disease! Absorption of Hexoses! Site: duodenum! Intestinal lumen Enterocytes Membrane Transporter! Blood SGLT1: sodium-glucose transporter Na+" Na+" •! Presents at the apical membrane ! of enterocytes! SGLT1 Glucose" Glucose" •! Co-transports Na+ and glucose/! Galactose" Galactose" galactose! GLUT2 Fructose" Fructose" GLUT5 GLUT5 •! Transports fructose from the ! intestinal lumen into enterocytes! GLUT2 •! At the basal membrane: ! Glucose! GLUT2 Glucose" transports glucose, galactose! and fructose from enterocytes ! Galactose! Galactose" into bloodstream! Fructose! Fructose" GLUT2 •! Presents at the apical membrane during high luminal [hexoses]! GLUT2 •! Transports glucose, galactose, and fructose! The liver is the first stop for the most nutrients absorbed from ! the digestive tract! Glucose Uptake at the Peripheral Tissues! Glucose transporter- GLUT! Glucose Glucose transporter (GLUT) Outside plasma membrane Cytosol Glucose Transport via glucose transporter (GLUT) • GLUT: transmembrane glycoprotein on the plasma membrane! • Facilitated passive transport (no ATP required, downhill, protein carrier)! • Conformational change! Glucose Transporter! Transporter Tissue(s) Role GLUT1 Ubiquitous Basal glucose uptake (every cell) Endothelial cells of the Transport glucose from blood-brain barrier blood to CSF GLUT2 Liver, pancreas, intesHne Remove of excess glucose from blood GLUT3 Neuron Basal glucose uptake (neurons) GLUT4 Muscle, fat, heart AcHvity increased by insulin GLUT5 IntesHne, tesHs, kidney, Primarily fructose sperm transport GLUT6 - GLUT12 Others Currently being studied GLUT4! Insulin-responsive glucose transporter! GLUT4 • Myocytes, skeletal muscle, adipocytes! • Insulin-responsive GLUT! o Increases glucose ! uptake up to 15X! • Some SCL2A4 mutations have been found to be associated with diabetes mellitus (DM)! Regulation of glucose transport by insulin-responsive GLUT4 (Lehninger Principle of Biochemistry, 4th edition) Kinetics of Glucose Uptake via GLUT! Characteristic of GLUT1 vs GLUT2! Vmax Normal plasma ! ½ Vmax [glucose]! 0 = 80 - 110 mg/dl! (4.5 - 6 mM)! entry, V (uM/min) entry, Initial velocity of glucose Kt Extracellular [glucose] (mM) GLUT1 GLUT2 • Every tissue! • Enterocyte, hepatocyte, pancreatic islet! • Kt of glucose " 1.5 mM! • Kt of glucose " 66 mM! • Basal glucose uptake! • Control plasma glucose! Major Pathways of Glucose Utilizations! Extracellular matrix and cell wall polysaccharides Glycogen, starch synthesis of ! storage;! structural polymer! ‘Glycogen synthesis’! GLUCOSE! oxidation via ! oxidation via ! ‘Pentose phosphate pathway’! ‘Glycolysis’! Ribose 5-phosphate Pyruvate Glycolysiszc! Glycolysis: glykys (Greek); sweet + lysis; splitting Breakdown of glucose! A series of enzyme-catalyzed reactions (10 reactions)- glycolytic pathway! Glucose 2ADP + 2Pi 2NAD+ 2ATP + 2H2 O 2NADH 2Pyruvate Final product: 2 molecules of 3-carbon compound; pyruvate! Glycolysis provides the largest flux of carbon in most cells! Glycolysis! Embden-Meyerhof-Parnas pathway! Preparatory Phase Glucose Glyceraldehyde-3-phosphate (x2) Glucose 2Pi ATP hexokinase/ G3P 2NAD 2ATP 4ADP + glucokinase dehydrogenase + 2Pi 2NAD ADP 2NADH + H Glucose-6-phosphate 1,3-Bisphosphoglycerate (x2) 4ATP 2ADP 2NADH Phosphohexose Phosphoglycerate isomerase kinase 2ATP 2Pyruvate Fructose-6-phosphate 3-Phosphoglycerate (x2) Phospho- ATP Phosphoglycerate Net: 2ATP, 2NADH" fructokinase-1 mutase ADP Fructose-1,6-phosphate Triosephosphate isomerase Triosephosphate 2-Phosphoglycerate (x2) Rate-determining Reaction! Aldolase Enolase •! Hexokinase/ H2 O Glyceraldehyde-3-phosphate glucokinase! Phosphoenolpyruvate (x2) + •! Phosphofructokinase! Dihydroxyacetone phosphate Pyruvate 2ADP kinase •! Pyruvate kinase! 2ATP Pyruvate (x2) Glycolysis! Flux through a metabolic pathway can be regulated in several ways! 1. Availability of substrate! •! GLUT1 (Kt 1.5 mM) vs GLUT2 (Kt 66 mM)! •! Insulin-responsive GLUT4! 2. Concentration of enzymes responsible for rate-limiting steps! Insulin stimulates the transcription of the genes that encode ! •! Hexokinase! •! Pyruvate kinase! •! Phosphofructokinase-1! •! PFK-2/FBPase-2! 3. Allosteric regulation of enzymes! •! Allosteric activator/inhibitor! 4. Covalent modification of enzymes! •! Phosphorylation! Glycolysis! Rate-determining reactions: hexokinase vs glucokinase! •! Every tissue! Hexokinase •! Km " 0.1 mM! •! G6P is an allosteric inhibitor! normal plasma Glucokinase [glucose] (Vo/Vmax) •! Hepatocyte, #-cell! •! Km " 10 mM! Relative enzymatic activity •! G6P does not inhibit glucokinase! 0 5 10 15 20 [Glucose] mM Glycolysis! Rate-determining reactions: phosphofructokinase-1 (PFK-1)! ATP ADP, AMP Fructose-6" Fructose-1,6" +" ATP" +" ADP" phosphate" PFK-1 bisphosphate" citrate F26P Allosteric inhibitor: ATP, citrate! ATP เปน product ของกระบวนการ glycolysis! Citrate เปนสารตงตนใน Krebs cycle! Allosteric activators: ADP, AMP, fructose-2,6-bisphosphate (F26P)! ADP, AMP ไดจากปฏกรยา ATP hydrolysis! F26P เปลยนมาจาก F6P ซงเปน glycolytic intermediate! Glycolysis! Formation of fructose-2,6-bisphosphate (F26P)! Fructose-6-phosphate ATP Pi (glycolytic intermediate) insulin PFK-2 FBPase-2 glucagon ADP Fructose-2,6-bisphosphate H2 O Insulin กระตน phosphofructokinase-2 Glucagon กระตน fructose bisphosphatase-2 ! (PFK-2) เปนผลให F26P มปรมาณเพมขน (FBPase-2) เปนผลให F26P มปรมาณลดลง ! ทให glycolysis ถกกระตน ! ทให glycolysis ถกยบยง (ผานการทงานของ (ผานการทงานของ PFK-1)! PFK-1)! Glycolysis! Rate-determining reactions: pyruvate kinase! Covalent modification Allosteric control (liver only) (all glycolytic tissues) glucagon F16BP F16BP ADP ATP PKA PEP PEP P ADP ATP acetyl-CoA Pyruvate long-chain fatty acids ATP carboxylase Pyruvate Pyruvate Pyruvate Pyruvate kinase (L) PP kinase transamination (inactive) H2 O Pi (L/M) Alanine PKA- protein kinase A! PP- phosphoprotein phosphatase! During fasting, glycolysis is inhibited in the liver (glucagon signal) but unaffected in the muscle ! Hormone: glucagon (êF26P)! Hormone: insulin (éF26P)! High energy index: ATP Low energy index: ADP, AMP ! acetyl-CoA, citrate, LCFA! Intermediate: F16P! Intermediate: G6P! Glucose + - 2Pyruvate 2ATP, 2NADH Glycolysis! Other clinical significance- formation of 2,3BPG in RBC! Bisphosphoglycerate mutase 1,3-Bisphosphoglycerate (x2) 2ADP Phosphoglycerate 2,3-Bisphosphoglycerate (x2) kinase 2ATP 2Pi 3-Phosphoglycerate (x2) 2,3-Bisphosphoglycerate phosphatase 2,3-bisphophoglycerate (2,3-BPG) 2,3-BPG มผลตอการจบกบ O2 ของ hemoglobin (O2 affinity): มมาก จบนอย ปลอยงาย! [2,3-BPG] in normal RBC " 5 mM! [2,3-BPG] > 5 mM (eg. pyruvate kinase deficiency)- O2 delivery ไปยง peripheral tissue ! [2,3-BPG] < 5 mM (eg. hexokinase deficiency)- O2 delivery ไปยง peripheral tissue! Glycolysis! Other clinical significance- fluoride can inhibit enolase! O Glyceraldehyde-3-phosphate (x2) P O CH2 CH C Dental carries (ฟนผ)! 2Pi OH H G3P 2NAD dehydrogenase + Common pathogen: Streptococcus mutans! 2NADH + H O 1,3-Bisphosphoglycerate (x2) P O CH2 CH C O 2ADP OH P Fluoride ion (F-)! Phosphoglycerate kinase 2ATP Magnesium ion (Mg2+) (cofactor ของเอนไซม)! O 3-Phosphoglycerate (x2) P O CH CH C 2 Inorganic phosphate (Pi) ! OH O Phosphoglycerate mutase O Enolase Mg2 F2 Pi- inhibitory complex! 2-Phosphoglycerate (x2) HO CH2 CH C O O ทให 2PG เขาถง active site ไมได! Enolase P H O 2 O Phosphoenolpyruvate (x2) CH2 C C O Pyruvate 2ADP O kinase P 2ATP O Pyruvate (x2) CH3 C C O O Metabolic Fate of Pyruvate! NADH must be reoxidized! Glucose NAD+ NAD+ 2 Ethanol + 2CO2 2 Lactate NADH NADH Anaerobic condition Anaerobic condition Yeast 2 Pyruvate Vigoriously contracting muscle RBC NADH 4CO2 NAD+ 2 Acetyl-CoA Krebs cycle 4CO2 + 4H2 O ETC Aerobic condition Anaerobic Glycolysis! Lactic and ethanol fermentation! Skeletal muscle, RBC! O O O O NADH + H+ NAD+ C C C O HO C H lactate CH 3 dehydrogenase (LDH) CH 3 Pyruvate Lactate Baker yeast! + CO2 NADH NAD O O O OH CH C C CH C CH C H 3 pyruvate 3 alcohol 3 O decarboxylase H dehydrogenase H Pyruvate Acetaldehyde Ethanol Anaerobic Glycolysis! Energy harvesting efficiency! Lactic Fermentation Ethanol Fermentation + + 2NAD+ 2NADH 2NADH 2NAD+ 2NAD 2NADH 2NADH 2NAD Glucose 2Pyruvate 2Lactate Glucose 2Pyruvate 2EtOH + 2CO2 2ADP 2ATP 2ADP 2ATP $G’° = -196 kJ/mol of glucose ! $G’° = -235 kJ/mol of glucose ! 2ATP! 2ATP! Efficiency! =! Efficiency! =! 196 kJ/mol! 235 kJ/mol! =! 2(30.5 kJ/mol)! =! 2(30.5 kJ/mol)! 196 kJ/mol! 235 kJ/mol! =! 32%! =! 26%!
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