PowerPoint PresentationSlide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Carbohydrate and energy metabolismYue [email protected] Lineberger Cancer CenterCarbohydrate and Energy MetabolismLecture 1: Overview of carbohydrate and energy metabolismLecture 2: Glycolysis and gluconeogenesisLecture 3: TCA and oxidative phosphorylationLecture 4: Glycogen metabolismLecture 5: Pentose phosphate pathway and integration of energy metabolismCarbohydrate metabolism: why do you need to study it? Altered carbohydrate metabolisms contribute to multiple major diseases: diabetes, obesity, heart diseases, and cancer  Linked to multiple topics of this courses: Amino acid metabolism, lipid metabolism, nucleotide metabolism  Rich history of scientific discoveries: At least 19 Nobel prizes awarded to the discoveries linked tothe studies of carbohydrate metabolism Basis for your future studies: Ph.D., M.D., DNP, Pham D …..Altered carbohydrate metabolism contributes to multiple human diseasesHeart diseases: kills ~600,000 (25% of total death). Costs: $108.9 billion3 Diabetes: 29.1 million, 9.3% of population, kills 69,071 and linked to 234,051 deaths. Costs: $245 billion1Obesity: affects ~ 35% US population. Costs: 147 billion2Cancer: 1.67 million new cases and 585,720 deaths (1 in 4). Costs: $216 billion41. http://www.diabetes.org/diabetes-basics/statistics/2. http://www.cdc.gov/obesity/data/adult.html3. http://www.cdc.gov/heartdisease/facts.htm4. http://www.cancer.org/indexAltered metabolism: the first tumor phenotypeThe Nobel Prize in Physiology or Medicine 1931"for his discovery of the nature and mode of action of the respiratory enzyme"Otto Warburg(1883 – 1970)“I discovered the quantum chemistry of photosynthesis and finally, in the field of medicine, the primary cause of cancer.” “In a few words, the primary cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar”Altered metabolism: the first tumor phenotypeShown are fused coronal images of Positron emission tomography–computed tomography (PET/CT) of a patient with a gastrointestinal stromal tumor before and after therapy (with sunitinib). The tumor (T) is readily visualized by FDG-PET/CT before therapy (left), but not after 4 weeks of therapy (right), Excess FDG is excreted in the urine, and therefore the kidneys (K) and bladder (B) are also visualized as labeled. M. G. Vander Heiden (2009) Science 324:1029Cancer Metabolism: the Emerging Hallmarks of CancerDouglas Hanahan and Robert A. Weinberg (2011 ） Cell. 144 (PMID: 21376230) 2000 2011Douglas Hanahan and Robert A. Weinberg (2000 ） Cell. 100 (PMID: 10647931)Carbohydrate metabolism: what we will learn:5 pathways: GlycolysisKrebs cycle (TCA)GluconeogenesisPentose phosphate pathway (PPP)Glycogen metabolism4 organs: Liver (and kidney)Muscle (and heart)Brain (and red blood cells)Adipose3 hormones: Insulin, glucagon, and epinephrine2 states: Fed, fasting/excisingMany enzymes:6 metabolites: Glucose, G6P, F2,6-BP, pyruvate, Ac-CoA, and NADPH 1 concept: Metabolism is composed of many coupled, interconnecting reactions that are coordinately regulated by different physiological conditions.Energy cycle in living things: from the Sun to sugar to ATPMolecules 6 CO2 + 6H2O + energy C6H12O6 + 6 O2Photosynthesis: energy inC6H12O6 + O2CO2 + H2OC6H12O6 + 6 O2 6 CO2 + 6H2O + energyAerobic respiration: energy outAnnual photosynthesis on Earth4.2 x 1017 kJ orAssimilation of 1010 tons of carbon into carbohydrate orA heap of sugar canes 2 miles high over 43 square miles Photosynthetic catastropheAll higher forms of life would be extinct in 25 years without photosynthesis. Could this ever happen? A large asteroid struck the Yucatan Peninsula of Mexico 65 million years ago, generating dust into the atmosphere that greatly diminished photosynthetic capacity and causing the disappearance of dinosaursFree energy is used for three purposes Mechanical work: cellular movements and muscle contraction Molecular transport: molecules and ions are actively transported inside cell Biosynthesis: macro-biomolecules are synthesized from simple precursors and the synthesis requires energyFree energy:Refers to the energy in a system that is free to do work i.e. the internal energy minus any energy that is unavailable to perform work. Internal Energy accounts for the total energy of the systemLife without currency is inconvenient An energy-rich nucleoside triphosphate used in cells as a co-enzyme during energy transfer reactions.  Under typical cellular concentration of ions, the actual G for ATP to ADP and ATP to AMP hydrolysis are -30.5 kJ/mol (-7.3 kcal/mol) and -45.6 kJ/mol (-10.9 kcal/mol), respectively. ATP is the universal currency of free energy in biological system ATP undergoes dynamic turnover: A body contains ~ 10 g ATP and uses 40 kg / 24 hours at resting or 0.5 kg / min during excise First Law: the total energy of a system and its surroundings is constant ATP drives thermodynamically unfavorable reaction Second Law: the total entropy of a system plus that of its surroundings always increases: Hence, the free-energy change must be negative for a process (e.g. a biochemical reaction) to occur spontaneously Entropy:A measure of the number of specific ways in which a thermodynamic system may be arranged, commonly understood as a measure of disorder How can a thermodynamic unfavorable reaction occur?Glucose + Pi + 3.0 kcal/mol  Glucose-6-phosphate + H2OATP + H2O  ADP + Pi + 7 kcal / molATP + Glucose  Glucose-6-phosphate + ADP + 4 kcal / molIndividual enzymes catalyze specific chemical reactionsA series of linked reactions comprises a metabolic pathwayHexokinase / GlucokinaseDifferent metabolic pathways are coupled and interconnected, making up the metabolismMetabolic pathways can be classified into two major types:Catabolism (breakdown) and anabolism (synthesis)Catabolism can be divided into three major stagesGlycolysis breaks down glucose to produce ATP and pyruvateGlucose metabolism can generate the ATP to power muscle contraction and cell proliferation. During exercise or rapid tumor growth when the ATP needs outpace oxygen delivery, glucose is metabolized to lactate (A).