Glycolysis and the Cori Cycle Lecture Notes

Glycolysis and the Cori cycle Bronwen Dalziel Ack.... Yikes.... Blarg... Bleh.... Images: wikimedia commons Cellular metabolism The conversion of food to ATP to power our cells Glycolysis is the first step of converting glucose to energy The Cori cycle looks at maximising the energy potential of glu...

Glycolysis and the Cori cycle Bronwen Dalziel Ack.... Yikes.... Blarg... Bleh.... Images: wikimedia commons Cellular metabolism The conversion of food to ATP to power our cells Glycolysis is the first step of converting glucose to energy The Cori cycle looks at maximising the energy potential of glucose when we are operating under anaerobic conditions Glycogenesis and glycogenolysis describe the storage and release of glucose in the body The Krebs cycle (citric acid cycle or TCA cycle) and electron transport chain continue the conversion of glucose into energy (my next lecture) glycolysis Understanding Pathophysiology, ANZ Edition, Chapter 3, 32-57 Vocab H + - In biological systems: – Oxidised = energy removed from molecule OIL (oxidation is “losing” electron in form of H) – Reduced = energy carrying molecule RIG (reduction is “gaining” an electron in form of H) H bonds with C, P, O and N electron hogs See tute – www.youtube.com/user/khanacademy#p/c/7A9646BC5110CF64/22/_KyyVhlUDNU H -O - H Some key molecules Glucose (c-c-c-c-c-c) ATP ßà ADP NADH ß à NAD+ FADH2 ßà FAD + Energy storage Electron transport Glucose image: Wikimedia commons Glut 4 Investment stage C-C-C-C-C-C Glucose ATP Regulation point: hexokinase (traps glucose in cell via phosphorylation) ADP C-C-C-C-C-C- ATP ADP P -C-C-C C-C-C- P Glycolysis P Glc-6-P Regulation point: phosphofructokinase-1 Activated by AMP Inhibited by ATP 2 phosphorylated, 3 carbon molecules The entry of glucose into the cell is regulated by insulin Glucose image: By NEUROtiker (Own work) via Wikimedia Commons Summary of previous slide In tissues other than the liver (and pancreatic β-islet cells), the availability of glucose for glycolysis is controlled by transport into the cell, which in turn is regulated by insulin. Hexokinase has a high affinity for glucose and so acts at a constant rate to provide glucose-6-phosphate to trap glucose in the cell. Glucose-6-phosphate is then converted into two triose phosphates through a series of reactions. The regulation point is the phosphofructokinase reaction which is irreversible under physiological conditions. Phosphofructokinase is both inducible and subject to allosteric regulation. This means that AMP can increase the rate of glycolysis and ATP can reduce the rate of glycolysis via phosphofructokinase The net result of the investment stage in glycolysis is the use of 2 ATP molecules This happens with each c-c-c- P group Yield stage (payoff) C-C-C- P P NADH NAD+ P -C-C-C- P ADP ATP ADP ATP C-C-C pyruvate Glycolysis The poison arsenic interferes with glycolysis at this point by binding inorganic phosphate in the cell C-C-C- P NADH Regulation point: Pyruvate Kinase (this reaction is irreversible) -C-C-C- P ADP ATP ADP ATP Summary of previous slide Inorganic phosphate is added to the triose phosphate (C-C-C-P) and at the same time NAD+ is reduced to NADH (it gains an electron by gaining an H atom) to form P-C-C-C-P The two phosphate groups are in turn transferred onto ADP, forming 2 ATPs. Since two molecules of triose phosphate are formed per molecule of glucose metabolized, 4 ATP are formed in this reaction per molecule of glucose undergoing glycolysis. Clinical insight: The toxicity of arsenic is the result of competition of arsenate with inorganic phosphate (Pi) and hence disrupts glycolysis at this stage. The reaction of pyruvate kinase is essentially irreversible under physiological conditions, partly because the immediate product undergoes spontaneous isomerization to pyruvate, so that the product of the reaction is not available to undergo the reverse reaction. The net result of the yield stage in glycolysis is the creation of 4 ATP molecules and 2 NADH molecules (remembering that you subtract 2 ATP molecules from the investment phase) Summary of Glycolysis Glucose C-C-C-C-C-C Investment is 2 ATP P -C-C-C C-C-C- P Payoff is 4 ATP and 2 NADH C-C-C C-C-C 2 Pyruvate Total 2 ATP 2 NADH Fructose enters glycolysis by phosphorylation to fructose-1-phosphate, and bypasses the main regulatory steps (hexokinase and phosphofructokinase enzymes), so resulting in formation of more pyruvate and acetyl-CoA than is required for ATP formation. Clinical insight: In the liver and adipose tissue, this leads to increased lipogenesis, and a high intake of fructose may be a factor in the development of obesity. Red Blood Cells (Erythrocytes) and Glycolysis: Red blood cells are unique in the human body in that they lose their nuclei and organelles, including mitochondria, early in their development. As a result, red blood cells are unable to utilize the krebs cycle or oxidative phosphorylation and are solely reliant on ATP production from glycolysis. When pyruvate is transformed into lactate, the NADH is converted back to NAD+ This makes it available for further ATP production in glycolysis. The resulting lactate is transported from the red blood cells and then taken into and used by tissues such as heart and liver. Fermentation No oxygen ahead C-C-C pyruvate NADH NAD+ C-C-C Oxygen starved cell: Exercising muscle Red Blood Cell Phagocytes in pus Cancer cells lactate Lactate dehydrogenase anaerobic conditions Cori cycle: gluconeogenesis Intense exercise in Muscle pyruvate lactate blood O2 absent NAD+ needed LIVER Liver image adapted from Wikimedia commons Cori cycle: gluconeogenesis Pyruvate Lactate Pyruvate carboxylase Oxaloacetate - 6 ATP provided by fatty acid oxidation --> Krebs cycle Phospho-enol pyruvate Triose-phosphates Glucose 6-P Glucose-6-phosphatase Glucose Final step: Glucose created from removal of phosphate group from glucose-6-phosphate LIVER can be released back into the blood stream Image: Wikimedia commons Image: Wikimedia commons Cori Cycle summary The Cori cycle describes the metabolic pathway in which lactate produced by anaerobic glycolysis in muscles, is transported to the liver and converted to glucose, which then returns to the muscles and can be used in glycolysis again. Lactate is made so that the muscle cell has access to NAD+ and glycolysis can continue to provide ATP to the muscle. Gluconeogenesis (of lactate to glucose) in the liver ensures that the ATP rich glucose skeleton is not lost as a waste product (lactate can be excreted by the kidneys) but can be recycled to be used by the muscle in aerobic metabolism at a future time. The Cori Cycle shows a net loss of 8 ATP (but there is a net gain once the carbon chain leaves the Cori Cycle and enters into regular aerobic metabolism) Clinical insight: The drug metformin (used regularly for Type 2 diabetes) can cause lactic acidosis in patients with renal failure because metformin inhibits the hepatic gluconeogenesis of the Cori cycle. Normally the excess lactate would be cleared by the kidneys, but this doesn’t happen successfully in patients with renal failure. Quiz question Glycolysis is performed: A. B. C. D. E. Only in the absence of oxygen Only in the presence of oxygen Exclusively in the red blood cell Either in the absence or presence of oxygen As a way to recycle NADH in the cell Quiz question The cell turns pyruvate into lactate to: A. B. C. D. E. Create ATP To regenerate NAD+ To prepare it for the Krebs cycle As a low O2 signal (muscle burn) To prepare it for glycogenesis Quiz question Which cells can turn glucose into lactate? A. B. C. D. E. Red blood cells Muscle cells Liver cells Adipocytes All cells Quiz question How many ATP are created/used in the process of turning lactate into glucose? A. B. C. D. E. 6ATP are used 6ATP are created 2ATP are created 2ATP are used 4ATP are created Regulation of glycolysis ATP is only made in small quantities Glucose is stored as glycogen Fatty acids are stored as triglycerides Amino acids make proteins the body needs High [glucose] reacts with protein so it needs to be stored safely Glycogenesis “genesis” = creation Storing glucose by creating glycogen Glycogenesis is activated: – during rest (after the Cori cycle) – when insulin signals there is excess glucose Occurs in muscle cells and liver A core protein of glycogenin is surrounded by branches of glucose units. The entire globular granule may contain approximately 30,000 glucose units. Image: Wikimedia commons Glycogenesis P Glucose-1-phosphate P UTP UDP-glucose Glucose-6-phosphate Glycogen synthase Glycogen branching enzyme glycogen glycogenin UTP = uracil triphosphate G G G G G G G G Glycogen synthase Glycogenesis Branching allows multiple points of access to the glucose molecules, which wouldn’t happen in a linear chain. Glycogen branching enzyme G glycogenin G G G G G G G Glycogen synthase A–B. Glycogen Synthesis. A. The synthesis of glycogen begins with the conversion of glucose to glucose-1-phosphate and subsequent bonding to uridine triphosphate (UTP) to form uridine diphosphate–glucose (UDP glucose) and two phosphate groups. B. UDP glucose serves as the source for the addition of new glucose molecules to an existing glycogen molecule either via a 1,4-bond or a 1,6-bond with a resulting uridine monophosphate (UMP) molecule. Enzymes are shown in blue-shaded boxes. [Adapted with permission from Naik P: Biochemistry, 3rd edition, Jaypee Brothers Medical Publishers (P) Ltd., 2009.] Citation: CARBOHYDRATE METABOLISM, Janson LW, Tischler ME. The Big Picture: Medical Biochemistry; 2018. Available at: https://accessmedicine.mhmedical.com/content.aspx?sectionid=185844537&bookid=2355&jumpsectionid=185844574&Resultclick=2 Accessed: April 07, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Glycogenesis/Glycogenolysis Activated (glycogenesis): – during rest (after the Cori cycle) – when insulin signals there is excess glucose Stops: – As glucose levels fall and insulin levels fall Reverses (glycogenolysis): – Low insulin levels and high glucagon levels – Adrenalin Glycogenolysis glycogenin G G G G G G P P Glycogen phosphorylase c-c-c-c-c-c Glc1-P Krebs cycle c-c-c-c-c-c glycolysis P Glc6-P Cori cycle P Glucose (liver only can remove phosphate group so that glucose can go enter the blood stream again) G glycogenin G G G G G G G G Glycogen phosphorylase G G G G G Glucan transferase G glycogenin G G G G G G G G G G G G Glycogen phosphorylase Glycogen debranching enzyme G Glycogen Breakdown. The breakdown of glycogen proceeds by glycogen phosphorylase cleavage of the α 1,4-bonds until four residues remain before the α 1,6-bond. Glucan transferase then moves three residues to the other chain. Finally, the remaining α 1,6-bound glucose is released as free glucose by a debranching enzyme. Resulting glucose-1-phosphate molecules are subsequently converted to glucose-6-phosphate for reentry into glycolysis (not shown). [Adapted with permission from Naik P: Biochemistry, 3rd edition, Jaypee Brothers Medical Publishers (P) Ltd., 2009.] Citation: CARBOHYDRATE METABOLISM, Janson LW, Tischler ME. The Big Picture: Medical Biochemistry; 2018. Available at: https://accessmedicine.mhmedical.com/content.aspx?sectionid=185844537&bookid=2355&jumpsectionid=185844574&Resultclick=2 Accessed: April 07, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Glycogenesis/Glycogenolysis – Glycogen in the liver Storage of dietary glucose (up to 8% of liver weight after a meal) Can be released for use by whole body Can be source of glucose for 8-12 hours – Glycogen in the muscle Immediate glucose reserve for muscle only (glucose can’t get out again because of lack of necessary enzyme) “hitting the wall” is when an athlete runs out of glycogen – endurance sports. Hopefully this happens just as they cross the finish line. Cellular respiration (quick version) cytoplasm c-c-c-c-c-c glucose 2 ATP NADH Glycolysis c-c-c + c-c-c 2 pyruvate NAD+ c-c-c 2 lactate b to d loo r e v i /l Cori cycle mitochondria NADH CO2 c-c-CoA acetylCoA 3 NADH FADH2 Oxidative phosphorylation ATP ATP Krebs cycle 2 CO2 GTP x2 Learning objectives Know that ATP is used is a way to store instant energy in our cells Describe how glycolysis converts glucose to pyruvate and: Ø produces 2 ATP net and 2 NADH Ø has 2 phases, investment and payoff Outline how the Cori Cycle allows muscle to produce lactate as an end product during exercise and recover the carbon as glucose, through gluconeogenesis in the liver and: Ø Uses up 6ATP (a net 4ATP loss if you include 2ATP made in glycolysis) Ø The conversion of pyruvate to lactate is needed to regenerate NAD+ in anaerobic conditions Explain how glucose is: Ø Stored as glycogen during glycogenesis. Ø Can be rapidly broken down into glucose when needed by muscles or for release into the blood stream for the whole body by the liver