Class Note for BIOC 460 at UA 5
Class Note for BIOC 460 at UA 5
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Date Created: 02/06/15
Biochemistry 460 Dr Tischler METABOLIC CONCEPTS Related Reading Chapter 15 410420 428429 Chapter 27 770774 in Stryer 639h edition OBJECTIVES 1 Identify the three major forms in which energy is stored and the four primary circulating fuels 2 Distinguish between the terms AG and AGquot 3 Explain the relationship between mass action effect and AG 4 De ne high energy phosphate transfer potential and explain its signi cance in terms of the formation of ATP via substratelevel phosphorylation 5 De ne the absorptive well fed postabsorptive fasting starvation gluconeogenic and prolonged starvation nutritional states and identify the primary sources of glucose in each of these PHYSIOLOGICAL PREMISE In attempting to do minimal exercise a 7year old experiences muscle cramps which severely limit his exercise tolerance The parents note that the child has never been very active Phosphorus NMR nuclear magnetic resonance analysis of his forearm is performed before during and after high intensity lifting of weights His duration for doing such exercise is very short The muscle amounts of ATP and phosphocreatine are low even prior to exercise During exercise these compounds are depleted very rapidly with ATP falling even further below normal Normally ATP levels would decline only slightly Recovery of the concentrations of ATP and phosphocreatine to initial levels is very slow The child s stored glycogen is abnormally high initially and only decreases slightly during attempted exercise Glycogen returns to its original high concentration after exercise Normally glycogen stores would decline during such an exercise regimen Additionally in this child glucose is not processed signi cantly by the muscle under any conditions How does this premise tie into this lecture You will learn in this lecture Why ATP and phosphocreatine are called highenergy phosphate compounds In an earlier lecture you learned of the role of ATP in muscle contraction and so should recognize that ATP depletion would prevent one from sustaining muscle use This lecture will also identify the pathways which store and use glycogen and utilize glucose ENERGY OVERVIEW Introduction Pathways that produce energy from fuels are termed catabolic Those pathways that produce and store fuels are anabolic Energy in mammalian cells is produced in most cells primarily via oxidative metabolism The notable exceptions are anaerobic metabolism in mature red blood cells erythrocytes which have no mitochondria and in skeletal muscle undergoing high intensity exercise In plants energy is derived from photosynthesis To produce energy mammals must take in an appropriate balance of nutrients An imbalance of nutrients leads to malnutrition disorders Complete lack of dietary intake induces the events associated with starvation which will be discussed near the end of the course ATP the most common direct energy source may be used for motion signal ampli cation biosynthetic processes and active transport and in mammals is derived mostly from the oxidation of fuels such as glucose and fatty acids Metabolic Concepts l Stored Energy and Circulating Fuels OVERVIEW OF METABOLIC PATHWAYS AND SYSTEMS OF ENERGY METABOLISM GLYCOGEN NucleicAcids PROTEIN TRIACYLGLYCEROLS Riboset5P c d l f g UREA i111 a e gt AMIN h 4 G39 se395quot ACIDS REE FATTY b ACIDS b a 41 I H Pyruvate Acet COA 392 Legend h ureogenesis a glyCOIVSiS i esterification quot b gluconeogenesis j lipolysis glycogenesis c k lipogenesis cl glycogenolysis betaoxidation e pentose pathway m ketogenesis ATP f1 Pr tein SYHIheSIS n ketone oxidation 91 Pr0tein degradation 0 citric acid cycleloxidative phosphorylation p pyruvate dehydrogenase Boldfaced pathways will be discussed in the metabolism section Figure 1 Energy systems rectangle biomolecular forms of energy storage oval substances that can serve as a fuel circulating in the blood boldfaced substances key metabolic intermediates Below are links to the lecture for each pathway listed in bold faced type a glycolysis b gluconeogenesis cd glycogenesis c glycogenolysis d e pentose pathway h ureogenesis ik esteri cation i lipogenesis k jlmn lipolysis j betaoxidation l ketogenesis m ketone oxidation 11 op citric acid cycle 0 pyruvate dehydrogenase p and oxidative phosphorylation 0 Figure 1 provides an overview of the metabolic pathways that pertain to carbohydrate amino acid and fatty acid metabolism to be discussed during the remainder of course The names of the pathways are identi ed in the legend This diagram will prove useful as a reference as we proceed through the discussion of metabolic pathways and the student is urged to refer to them to help develop the quotbig picturequot Energy is stored as glycogen carbohydrates protein amino acids or triacylglycerol fatty acids Under most circumstances the most important circulating fuel is glucose Lactate free fatty acids and ketone bodies also serve as circulating fuels in response to speci c physiological conditions Lactate usually is recycled back to glucose but may provide energy for heart function Fatty acids are an important fuel in muscle during sustained aerobic exercise and for a variety Metabolic Concepts 2 of tissues as one progresses through starvation The brain can NEVER use fatty acids as a fuel because it lacks the necessary pathway for their oxidation Besides it would be detrimental for the brain to use fatty acids because their higher oxygen requirement could not be met by the brain that normally consumes oxygen at a maximal rate to sustain the oxidation of glucose Some key metabolic intermediates include glucose6phosphate pyruvate and acetyl CoA These compounds serve as quotcrossroadsquot in metabolism that is they occupy key positions at junctures of pathways Most energy in the body is produced by complete oxidation of acetyl CoA leading to ATP production Notable exceptions are the red blood cell erythrocyte which lacks mitochondria and therefore the ability to carry out oxidative metabolism and anaerobic skeletal muscle Free Energy of Reactions In chapter 8 you learned that the direction a reaction will take depends on the relative energies of the products and reactants and their relative amounts The inherent energy of a compound is G and the difference in energy between two products and reactants is AG Under physiological conditions reactants and products rarely start out at the same concentration Under these conditions the spontaneous direction of a reaction is signi cantly affected by the relative concentrations of the reactants and products It is this ability of the cell to regulate the concentrations of products and reactants that can permit an endergonic thermodynamically unfavorable reaction to occur in the cell The spontaneous direction of a reaction is set by the actual energy difference AG note absence of superscript which is described by the equation AG AG 23 log productsreactants Physiological free energy When considering a metabolic pathway the AG term is the most important as AG standard free energy change is simply a point of reference It is useful to think of AG as the physiological free energy difference since that is what occurs in the cell A decrease in product concentration or an increase in reactant concentration lowers AG so that the reaction proceeds to the right LeChatelier Principle mass action effect For an enzyme reaction in the cell to proceed the free energy term AG must be negative If the calculated AG is positive the reaction will not proceed in that direction but rather in the reverse direction Remember that only the sign positive or negative changes for AG when the reaction is reversed not the absolute magnitude If a reaction is favored in one direction it will be unfavorable in the opposite direction Recall that the log of a number less than one is negative Therefore a small ratio of productreactant can make the overall AG negative so that the reaction can proceed In a pathway this situation can be achieved if the product from one reaction is constantly removed by the subsequent reaction Thus unfavorable reactions can be driven by highly favorable ones A reaction that is very favorable makes the overall AG negative for the unfavorable reaction because of a small productreactant ratio Note that the AG for a metabolic pathway is the sum of the AG values for each enzyme reaction in that pathway For a pathway to proceed from the initial substrate to the nal product the overall AG st be negative High Energy Phosphate Compounds Energy in ATP is stored in phosphoanhydride bonds between the y 3 and Boc phosphates Fig 2 Removing the on phosphate does not release energy so that AMP is a low energy compound The energy from hydrolysis of the ATP phosphoanhydride bonds drives energyrequiring reactions of biological processes Thus this represents energy coupling Release of these phosphates from ATP and other highenergy phosphate compounds constitutes the high energy phosphate transfer potential Other important highenergy compounds include phosphocreatine creatine phosphate 13 bisphosphoglycerate and phosphoenolpyruvate that are hydrolyzed to provide energy for ATP formation Fig 2 Metabolic Concepts 3 O O 0 ATP PHOSPHOCREATINE 0 NH OFgtO3O H2 Adenine II o39 39 O O FNC ll CH2 COO B O O U h a 039 CH3 OHOH 403 Kcal 148 401 0 H2 El El pH I II O39P oc CH CHg O IiD O39 039 C0039 039 O 13bisPHOSPHOGLYCERATE PHOSPHOENOLPYRUVATE Y 13 66 Kcal TWO HIGH ENERGY INTERMEDIATES OF THE GLYCOLYTIC PATHWAY Figure 2 Structures of important compounds having high energy bonds Hydrolysis of the end phosphate bond of ATP yields 73 kcalmol of energy The bond energy between the Boc phosphates is somewhat smaller The bond linking the xphosphate to the ribose ring is very low energy ADP adenosine diphosphate has just one high energy bond whereas AMP adenosine monophosphate has no high energy phosphate bond Phosphocreatine transfers energy to make ATP in muscle l3bisphosphoglycerate and phosphoenolpyruvate are intermediates in the glycolytic pathway glucose to pryuvate metabolism that transfer their energy to form ATP SubstrateLevel Phaspharylatian Versus Oxidulive Phaspharylatian Oxidation of fuels provides energy for phosphorylation of ADP to ATP oxidative phosphorylation However compounds having higher energy phosphate bonds than in ATP can also phosphorylate ADP without consumption of oxygen substrate level phosphorylation such as those identi ed in Figure 2 Hydrolysis of creatine phosphate yields 103 kcalmole which is sufficient energy to phosphorylate ADP to ATP requires 73 kcalmol during the rst few seconds of acute intense exercise This reaction is catalyzed by creatine phosphokinase and is represented by phosphocreatine ADP gt creatine ATP In muscle creatine phosphate is rapidly depleted even if creatine supplements are taken Most muscle energy for short duration performance gtseveral seconds is derived from stored glycogen that is degraded to provide energy via the glycolytic pathway Consequently any defect of an enzyme in the metabolism of glucose see Physiological Premise makes maintenance of ATP during exercise impossible Metabolic Concepts 4 CARBOHYDRATE OVERVIEW Pathways 0f Carbohydrate Metabolism Figure 3 Summarizes the pathways of glucose metabolism The general functions of these pathways are Glycolysis splits glucose to pyruvate which can be converted to lactate or the pyruvate can be processed in the mitochondrion to produce energy or be converted to fat Gluconeogenesis converts pyruvate to glucose via glucose6phosphate G6P this is a key pathway for generating glucose with food deprivation Glycogenesis is the synthesis of glycogen the carbohydrate fuel storage form Glycogenolysis is the breakdown of glycogen to G6P in muscle this G6P is used to produce energy whereas in liver it is used to produce glucose during fasting Pentose Phosphate Pathway PPP produces NADPH for cell biosynthesis reactions and for maintaining glutathione in its reduced state ribose5phosphate as a precursor for the biosynthesis of nucleic acids SUMMARY OF CARBOHYDRATE PATHWAYS GLYCOGEN Glycogenolysis Glycogenesis NADPH formation I GlucoseSP gt ppp Nucleic acid synthesis GIYCOIYSiS Gluconeogenesis Acetyl CoA Pyruvate aerobic Citric Acid anaerobic I Cycle metabolism r etabOllsm co 2 PPP pentose phosphate pathway Figure 3 Summary of carbohydrate pathways Pyruvate metabolism to acetyl CoA and carbon dioxide is irreversible Metabolic Concepts 5 Sources And Fates 0f Glucose In Di rerent Nutritional States The various nutritional states are de ned in Table 1 related to the time period from the last meal Table 1 Summary of Nutritional States Nutritional State Description Abso ve period within no more than 4 hours after the last meal commenced during which food is rp digested and absorbed also called wellfed state Postabso ve period after food is completely digested and absorbed up until 18 to 24 hours afterwards rp also referred to as a fasting state Starvation period of time from about 24 hours after the last meal and onwards until refeeding or death early starvation is approximately the rst 5 days Z iigff period of time one week and longer after food deprivation Maintenance of blood glucose levels is de ned as blood glucose homeostasis The brain s dependence on glucose under normal conditions requires a complex series of events to ensure that the glucose supply does not diminish appreciably Control of glucose homeostasis is so well regulated that a very obese individual can fast for months with less than a 25 reduction in blood glucose levels However glucose homeostasis is lost if insulin levels are not well regulated such as in diabetes or in a patient with an insulinoma insulinsecreting tumor In the latter instance excess circulating insulin will cause hypoglycemia below normal blood glucose which the body compensates for by emitting hunger signals to increase food intake Sources of blood glucose include the diet exogenous in the absorptive phase liver glycogenolysis endogenous in the postabsorptive phase 420 h after the last food intake and liver gluconeogenesis from lactate and amino acids in early starvation gluconeogenic phase but only from lactate in prolonged starvation Table 2 Later we will discuss in depth the pathways associated with these processes Utilization of glucose primarily includes its catabolism replenishment of storage pools and synthesis of fats In the fed state liver and adipose tissue use glucose to produce fat as another means of storing fuel The use of glucose in the body diminishes as food deprivation progresses Reduced use is rst apparent in liver muscle and adipose tissue followed later by diminished metabolism in the brain during prolonged starvation Table 2 Since red blood cells contain no mitochondria they metabolize glucose anaerobically under all states The only condition in which the brain does not use glucose generally is in prolonged starvation Ketone bodies a derivative of stored fats are produced in abundance in prolonged starvation and the brain switches to this fuel to help spare blood glucose Only red blood cells continue to use blood glucose because having no mitochondria they do not burn the carbons of glucose to carbon dioxide Instead the carbons are recycled The brain however would oxidize the carbons to carbon dioxide which is then lost from the system thus preventing the maintenance of the body s pool of glucose for survival Metabolic Concepts 6 Table 2 Primary sources and fates of glucose and the major fuel for the brain in each phase ofthe Brain Nutritional Absorptive Postabsorptive Prolonged status Wellfed Fasting Early Stananon Starvation Sources of Liver glycogen Liver D1et Blood Glucose gluconeogenes1s gluconeogenes1s Tissues Using All Primarily brain and Brain and red Red blood cells Glucose fates red blood cells blood cells anary Fuel Glucose Glucose Glucose Ketone bodies Metabolic Concepts 7
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