Glucose metabolism Glycolysis Biological meaning 2 or 3 phases Compartmentation Energetic balance Regulation Aerobic and anaerobic Substrates other than glucose Figures Pratt and Cornely Essential Biochemistry Moran Principles of Biochemistry 4th 5th edition Tymoczko Biochemistry A Short Course Recommended animation http www youtube com watch v O5eMW4b29rg 1 Carbohydrate digestion I Poly and disaccharide hydrolysis to monosaccharides Main carbohydrates in food Starch 1 amilases of saliva and pancreas cleave at random places produce di and trisaccharides matose maltotriose isomaltose 2 maltase isomaltase cleave maltose and isomaltose respectively to produce glucose Lactose lactase glucose galactose Sucrose sucrase glucose fructose II Monosaccharide absorption in the intestine 2 Monosaccharide absorption I Active transport Sodium glucose transporter 1 SGLT1 Secondary active transport of glucose and galactose symport with Na II Passive transport Glucose transporters Glut2 and Glut5 Passive transport of glucose galactose and fructose GLUT2 5 Glucose fructose galactose 3 Glycolysis Embden Meyerhof Parnas pathway a major catabolic pathway Can be used for anaerobic production of energy 2ATP glucose could exist before raise of atmospheric 02 Under aerobic conditions glycolysis supplies fuel for mitochondrial ATP production Shares reversible reactions with gluconeo genesis anabolic pathway of glucose synthesis Carbohydrate Metabolism Overview 5 NADPH and ribose production for anabolic reactions 8 Energy Storage Glycogen 5 2 NAD regeneration for anaerobic glycolysis 6 8 Glucose Pentose NADH NAD 1 Pyruvate 2 4 Lactate 7 7 de novo glucose production 10 ATP 10 ATP production Acetyl CoA 9 TCA Cycle Structural signaling functions Other sugars 2ADP 2NAD 2ATP 2NADH H Energy production EtOH CO2 3 NAD regeneration for anaerobic glycolysis in yeast 9 1 NADH FADH2 production for e transport chain 2 metabolite supply for anabolism 5 5 Carbohydrate Metabolism Overview Glycogen 5 Glucose Pentose Other sugars 6 8 2ADP 2NAD 1 2ATP 2NADH H Pyruvate 2 3 Lactate 4 7 Acetyl CoA 9 10 ATP Energy production TCA Cycle EtOH CO2 1 Glycolysis 1 2 Anaerobic glycolysis 1 3 Alcoholic fermentation 1 4 9 10 Aerobic glycolysis 5 Pentosephosphate shunt 6 Glycogenolysis 7 Gluconeogenesis 8 Glycogenesis 9 TCA Cycle 10 Electron Transport 6 Oxidative Phosphorylation Glycolysis Overview Glycolysis occurs in 10 steps Steps 1 5 energy investment Steps 6 10 energy payoff Glucose a six carbon molecule is broken down into two 3 carbon molecules Electron carriers 2NAD are reduced 2 ATP are invested 4 ATP molecules are produced Net Yield is 2 molecules of ATP and 2 NADH 2014 John Wiley Sons Inc All rights reserved Three phases of glycolysis Energy investment phase per glucose molecule Phase I 2 ATP Phase II 4ATP 2NADH Net 2 ATP 2NADH 8 Turbo design of glycolysis Turbo engine Glycolysis Engine Part of the produced energy is invested to rotate a turbine that facilitates fresh air intake 2ATP Fructose1 6 BP 4ATP Pyruvate Reinvestment of produced energy Reinvestment of produced energy Glucose Glycolysis Part of the produced energy 2ATP is invested to activate glucose for efficient release of energy during the second step 9 First 5 Steps of Glycolysis per glucose molecule 2014 John Wiley Sons Inc All rights reserved Phase I 2 ATP Phase II 4ATP 2NADH Net 2 ATP 2NADH Last 5 Steps of Glycolysis per glucose molecule Phase I 2 ATP Phase II 4ATP 2NADH Net 2 ATP 2NADH 2014 John Wiley Sons Inc All rights reserved NADH can be used for ATP production in mitochondria but only under aerobic conditions Gibbs energy changes in glycolysis I II III Regulated steps are irreversible under cellular conditions These steps define the direction of metabolic reactions 12 Glycolysis step 1 Hexokinase Hexokinase I IV Irreversible large negative G a regulated step Inhibited by the product Glucose 6 Phosphate Why Phosphorylation 1 Phosphorylated glucose is charged and therefore cannot cross the membrane 2 Phosphorylated glucose is not recognized by the transporters retained in the cell 3 Required for glycolysis AND glycogenesis and pentose phosphate pathways 4 Renders hydroxyl more reactive 6 phospha 13 Glucose Glucose6Phosphate G6P is not committed to glycolysis 1 Locks Glucose inside the cell maintains glucose gradient across the membrane 2 Glycogen synthesis storage 3 Pentose phosphate shunt ribose Pi for DNA RNA and NADPH for fatty acids and redox maintenance 14 Step 2 Glucose 6 phosphate isomerase Near equilibrium reaction This isomerization makes OH 1 accessible for phosphorylation G 0 Step 3 Phosphofructokinase 1 PFK1 G 0 The first committed step of glycolysis This Phosphorylation traps the sugar as the fructose isomer REGULATION Large negative G an important regulatory step Regulated by AMP or ATP or Citrate a downstream product in TCA cycle or 16 Step 4 Aldolase Reaction G 0 The aldolase reaction is the reverse of an aldol condensation F1 6BP is cleaved between carbons 3 4 to form two threecarbon phospho trioses interconverted to one another on the 17 next step Step 5 Triose Phosphate Isomerase G 0 96 4 Converts DHAP to GAP and vice versa Result 2 GAP s proceed through remainder of glycolysis Even though Go 0 reaction proceeds forward because GAP is quickly consumed 18 Step 6 Glyceraldehyde 3 Phosphate Dehydrogenase G 0 x2 Large negative Go of aldehyde group oxidation is trapped by i Addition of a phosphoryl group not from ATP ii Formation of NADH reducing agent equivalent to 2 5 ATP molecules upon oxidative phosphorylation in mitochondria Go of the entire reaction is slightly positive while G is maintained at near equilibrium level Reaction is inhibited by AsO43 which competes with PO42 for binding the enzyme 19 This is an example of a coupled reaction G 0 Aldehyde oxidation Go 0 50kJ mole Phosphoryl group transfer Go 0 50kJ mole Energy profile for I hypothetical separate II Actual coupled reaction Reaction proceeds via formation of high energy thioester intermediate DGo 0 DGo 0 20 GAP Dehydrogenase Mechanism Step 7 Phosphoglycerate kinase G 0 X2 The first substrate level phosphorylation in glycolysis 2ATP are produced per each glucose entered the glycolysis ATP energy spent in the preparatory phase is fully compensated at this step Step 8 Phosphoglycerate mutase 23 x2 Phosphate gets moved from C3 to C 2 23 Step 8 Phosphoglycerate mutase Mechanism Histidine Phosphate at the active site participates as a transient donor of a phosphoryl group 24 Step 9