BCH Graduate Survey of Biochemistry

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1 BCH 5045 Graduate Survey of Biochemistry Instructor: Charles Guy Producer: Ron Thomas Director: Glen Graham Lecture 45 Slide sets available at: Images from the Text are protected by Copyright (c) 2008 by W. H. Freeman and Company, and by the licensors

2 David L. Nelson and Michael M. Cox LEHNINGER PRINCIPLES OF BIOCHEMISTRY Fifth Edition CHAPTER 14 Glycolysis, Gluconeogenesis, and the Pentose Phosphate Pathway 2008 W. H. Freeman and Company Images from the Text are protected by Copyright (c) 2008 by W. H. Freeman and Company, and by the licensors

3 Seven of the ten reactions of glycolysis are physiologically reversible and three are not under physiological conditions. What controls which direction a reaction will go? What about reactions 1, 3 and 10, can they be reversed? Images from the Text are protected by Copyright (c) 2008 by W. H. Freeman and Company, and by the licensors

4 Glycolytic Intermediate Rat Liver nmol/mg DNA Mouse Muscle mmol/kg d. m. ATP ADP AMP UDP-Glucose Glucose-1-P Glucose-6-P Fructose-6-P Fructose-1,6-BP Dihydroxyacetone Phosphate Glyceraldehyde-3-P Glycerol-1-P Phosphoglycerate Phosphosglycerate Phosphoenolpyruvate Pyruvate Lactate Human Blood nmol/ml 1 From Faupel, Seitz and Tarnowski, (1972) Arch. Biochem. Biosphys. 148, ; 2 Harris, Hultman and Nordesio (1974) Scand. J. clin. Lab. Invest. 33, ; 3 Minakami, Suzuki, Saito and Yoshikawa (1965) J. Biochem. 58, Images from the Text are protected by Copyright (c) 2008 by W. H. Freeman and Company, and by the licensors

5 This slide is not in the lecture video Glucose in the brain is used to produce energy, perhaps its most critical function, but is also needed for regulatory, protective (against ROS) and anabolic (protein and lipid synthesis) processes. In the brain, surprisingly glucose metabolism can deliver energy quickly and efficiently for cell functions independent or without the operation of oxidative phosphorylation. Energy production from glucose in an aerobic environment is termed aerobic glycolysis. Recent studies suggest there is regional variation in the rate of aerobic glycolysis within a resting brain, and possibly high rates of aerobic glycolysis may be linked to the formation of amyloid-β plaques. High rates of aerobic glycolysis have been observed in the prefrontal and lateral parietal cortex, and posterior cingulate cortex just to list a few regions that make up the default mode network that is active when one is awake but not performing a task. Images from the Text are protected by Copyright (c) 2008 by W. H. Freeman and Company, and by the licensors

6 In contrast, the cerebellum and inferior temporal gyrus, including the hippocampus, have low aerobic glycolysis rates. Amyloid-β plaques are often found in the default mode network regions in the early stages of Alzheimer's disease. In a study of patients with Alzheimer's disease and people with elevated levels of the amyloid-β protein that were cognitively normal, PET was used to assess amyloid-β deposition and mapped against the spatial distribution aerobic glycolysis levels. There was a high spatial correlation between levels of amyloid-β deposition and aerobic glycolysis, and the correlation was higher in people with Alzheimer's than in cognitive normal people with elevated amyloid-β. Please keep in mind that correlation does not prove cause and effect. Vaishnavi, S. N. et al. (2010) Regional aerobic glycolysis in the human brain. Proc. Natl Acad. Sci. Vlassenko, A. G. et al. Spatial correlation between brain aerobic glycolysis and amyloid-β deposition. Proc. Natl Acad. Sci. Images from the Text are protected by Copyright (c) 2008 by W. H. Freeman and Company, and by the licensors

11 The Pentose Phosphate Pathway or the Reductive Pentose Pathway has two major functions: the production of reducing potential in the form of NADPH, and the synthesis of five carbon sugars, notably D- ribose. Thus there are two ways of viewing this metabolic pathway, that part which generates NADPH and the portion that leads to the production of 4, 5 and 7 carbon sugars. The first step of the pathway begins when G-6-P is oxidized to 6- phospho-gluconolactone producing NADPH. The lactone is hydrated to form 6-phospho-gluconate which is then oxidized and decarboxylated to form a second molecule of NADPH and D-ribulose-5-phosphate. The Ru-5-P is isomerized to D-ribose-5-P. If five carbon sugars are not needed, then they are recycled back into hexose phosphates. This part of the pathway is a recapitulation of part of the Calvin Cycle, the cycle important in photosynthesis. I will have more to say about that when we discuss photosynthesis. Images from the Text are protected by Copyright (c) 2008 by W. H. Freeman and Company, and by the licensors

12 The second part of the pathway produces the 4, 5, and 7 carbon sugars by combining the activities of four enzymes, isomerase, epimerase, transketolase and a transaldolase. Like glycolysis all of the sugars of the PPP are sugar phosphates. Images from the Text are protected by Copyright (c) 2008 by W. H. Freeman and Company, and by the licensors

19 This slide is not in the lecture video It can be said that for many organisms, there are two primary routes for glucose metabolism, glycolysis and the Pentose Phosphate Pathway (PPP). While glucose-6-phosphate can be the initial substrate for the the direct entry into the PPP, glycolytic metabolites fructose-6- phosphate (F6P) and glyceraldehyde-3-phosphate (G3P) derived from glucose can also serve as the building blocks for the sugar phosphate intermediates of the second phase of the PPP. Based on thermodynamic considerations the non-oxidative second phase of the PPP would be presumably fully reversible meaning inputs of F6P and G3P may just as easily enter as exit the PPP. However, sedoheptulose- 1,7-bisphosphatase (SBPase) appears to catalyze the committed reaction that allows metabolite flow from glycolysis into the PPP which is often directed into ribose-5-phosphate production, a process known as ribogenesis. Images from the Text are protected by Copyright (c) 2008 by W. H. Freeman and Company, and by the licensors

20 This slide is not in the lecture video Clasquin et al. has concluded that the riboneogenic pathway in yeast based on their findings has striking similarity to the Calvin Cycle of photosynthesis. A sedoheptulose-1,7-bisphosphatase (SBPase) catalyzes the dephosphorylation sedoheptulose-1,7-bisphosphate to form sedoheptulose-7-phosphate, that is then converted to ribulose- 1,5-bisphosphate, which is the primary the substrate for fixation of carbon dioxide in photosynthesis. Clasquin et al (2011) Ribogenesis in yeast. Cell 145, This and the previous slide is on exam III. Images from the Text are protected by Copyright (c) 2008 by W. H. Freeman and Company, and by the licensors

THE PENTOSE PHOSPHATE PATHWAY. Dr. Gamal Gabr, College of Pharmacy

THE PENTOSE PHOSPHATE PATHWAY. Dr. Gamal Gabr, College of Pharmacy THE PENTOSE PHOSPHATE PATHWAY Dr. Gamal Gabr, College of Pharmacy METABOLISM OF OTHER IMPORTANT SUGARS THE PENTOSE PHOSPHATE PATHWAY The pentose phosphate pathway is an alternative metabolic pathway for