Review Sheet for BIOC 460 at UA
Review Sheet for BIOC 460 at UA
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Date Created: 02/06/15
Bioc 460 Dr Miesfeld Spring 2008 Bioenergetics and Metabolism Supplemental Reading Key Concepts Energy Conversion in Biological Systems Review of thermodynamic principles The adenylate system is used for short term energy storage Overview of Metabolic Pathways Metabolic pathways consist of linked enzymatic reactions The six major groups of metabolic pathways in nature KEY CONCEPT QUESTIONS IN BIOENERGETICS AND METABOLISM How iS energy from the sun converted to chemical energy What iS reaction coupling and why iS it important in metabolic pathways Biochemical Applications of Bioenerqetics and Metabolism Under anaerobic conditions many microorganisms can metabolize pyruvate to lactate or to ethanol and C02 The bacterial strain Streptococcus cremoriS is used commercially to make cheese by producing large amounts of lactate from pyruvate whereas the brewers yeast SaccharomyceS cerevisea is used to produce carbonated beer from germinated barley seeds l ENERGY CONVERSION IN BIOLOGICAL SYSTEMS EM Biochemically Speaking an organism at equilibrium with the environment is no longer alive For example the concentration of glucose is much higher inside cells of a saguaro cactus than it is in the surrounding desert figure 1 Similarly the concentration of cellular sodium chloride is lower inside a humpback whale than it is in the surrounding ocean However when an organism dies the intracellular concentration of water essential ions and macromolecules quickly become glucosehnside glucoselinside equilibrated with the surroundings To put off this inevitable mmth WW event as long as possible a living organism must be able to glucoseimside QIUCOSeloutside extract energy from the surroundings to maintain a steady state condition homeostasis that is far from equilibrium To accomplish this task organisms utilize sunlight and materials from the environment to interconvert energy in the forms of work and heat Nacuinside NaCIinside is less than is equal to Natuoutside NaCHOUtside 1 of9 pages Bioc 460 Dr Miesfeld Spring 2008 We can think of this energy conversion or g transduction in terms of 1 chemical work in the form of macromolecular biosynthesis of organic molecules 2 osmotic work to maintain a concentration of intracellular salts and organic molecules that is different than the extracellular milieu and 3 mechanical work Solar L1 7 Photosynthetic cell in the form of agellar rotation or muscle 9399quot x contraction Indeed the cycling of resources and waste between the environment and a Camquot living cell provides the necessary materials for fixation this energy conversion As shown in gure 2 I solar energy ultimately provides the energy 9quot source for life on earth through a three step d390X de process Photosynthesis K Oxygen and r 7 39 Carboh drates Aerobic 4 y respiration i Nonphotosynthetic cell 0 Review of thermodynamic principles Bioenergetics is a term that is used to describe energy conversion in biological systems and it incorporates the idea that cells represent an open system that freely exchange energy and matter with the surroundings To better understand bioenergetics in quantitative terms we need to review three thermodynamic principles 1 First Law of Thermodynamics 2 Second Law of Thermodynamics and 3 Gibbs Free Energy First Law of Thermodynamics The First Law of Thermodynamics states that energy cannot be created or destroyed only converted from one form to another As a demonstration ofthis principle the French scientist Antoine Laurent Lavoisier in 1783 used a small chamber holding a guinea pig to measure the heat production of metabolism by determining how much ice melted as a result of respiration gure 3 The energy potential of a compound can be determined using a quotbombquot calorimeterto measure heat transfer as a result of combustion in pure oxygen 02 For example the combustion of1 gram ofglucose C6H1206 produces carbon dioxide C02 H20 and heat The temperature increase ofthe surrounding water is a measurement ofthe amount of energy stored in the glucose 2 of 9 pages Bioc 460 Dr Miesfeld Spring 2008 We can write this equation as CeHizoe 6 Oz 9 6 C02 6 H20 heat Where heat q AE 375 Ckilogram of water The unit of energy in this example is called a 39m Calorie kcal which was originally defined by 1 gram of glucose the amount of heat energy required to raise 1 kilogram of water from 145 c to 155 c This Emme e 3330quot can also be expressed in the international unit of measurement the Joule J in which 1 I l Calorie 1 kcal 4184 kJ Note that in nutritional sciences calorie with a capital quotCquot L33quot actually refers to a kcal As first demonstrated by Lavoisier and consistent with the First Law of Thermodynamics the total energy potential of this 1 gram of glucose is the same regardless of the metabolic path taken As illustrated in figure A the same amount of energy 157 kJ can be in extracted from 1 gram of glucose independent imam of the path taken In the case of metabolism a portion of the energy content of glucose is captured in the form of ATP and the rest is lost Heat as heat In a steady state condition there is no net gain or loss of ATP so all ofthe energy derived from glucose is eventually lost as heat 157 H of energy It is this metabolic heat that Lavoisier measured in his experiment with the guinea pig Thermometer heat 188 quotC a rHr39J T t 50 DC glucose work Heat Work Second Law of Thermodynamics Figure 5 The Second Law of Thermodynamics states that all natural processes in the Universe 7200c tend towards disorder randomness in the l Ice cube absence of energy input A live cell is highly ordered as compared to the surroundings and thus energy is required to restrain the natural L W my LJrrli tendency toward disorder This concept of I 25 C r 1 r 39 disorder is defined by the term entropy S ce High enmipy Elecmmy melting at room temperature cannot be quot lnpurqfeecrrica energy reversed without the input of energy in the form fjjgggg gzif y w quoteous of electricity to lower the temperature Once the water is frozen the continued input of electricity 39 A J restrains the ice crystals from melting figure 5 Meltedice Similarly the metabolic energy required for sustaining life restrains the natural tendency of the molecules to become disordered Cellular life requires solar energy and conversion of chemical energy into work to restrain entropy 3 of 9 pages Bioc 460 Dr Miesfeld Spring 2008 Gibbs Free Energy The change in free energy AG between a reacting system under standard conditions reactants initially at 10 M the pressure is 1 atmosphere and the temperature is 298 K 25 C and the same system once the reaction reaches equilibrium is defined as the change in standard free energy AG The AGo value is a measure ofthe spontaneity ofa reaction A 69 B as determined empirically by measuring the concentration of reactants at equilibrium using the equation AG RT aneq where Keq Bquot Aa as described in lecture 2 quotaquot and quotbquot are moles A reaction where AGo 0 is reversible and by definition at equilibrium with the surroundings A reaction with AG0 lt 0 is highly favorable and referred to as exergonic or work producing whereas a reaction with a AGo gt 0 is less favorable or endergonic Biochemists use a slightly different term for the change in standard free energy of a reaction as denoted by AG The standard reaction conditions needed to determine AG are the same as those described above for AGo except that the pH of the reaction is 70 H is 10397M and the concentration ofwater is 555 M In metabolism AG values come into play in three important ways 1 Reactions with AG ltlt 0 are a driving force to make unfavorable reactions more favorable through the use of shared intermediates product of reaction 1 is the substrate for reaction 2 lmportantly the AG of a coupled reaction is the sum ofthe AG values for each individual reaction If the conversion ofA to B is unfavorable AG gt 0 but B is quickly converted to C AG ltlt 0 then the conversion ofA to B occurs because the net reaction is favorable as shown below A 69 B AG 4 kJmol B 69 C AG 10 kJmol A 69 C AG 6 kJmol 2 The free energy released from ATP hydrolysis which is relatively large AG 305 kJmol can also be used drive unfavorable reactions In fact the first step in glycolysis is catalyzed by the enzyme hexokinase which utilizes ATP hydrolysis to drive the unfavorable reaction of glucose phosphorylation in a coupled reaction as shown below Glucose Pi 69 glucose 6 phosphate H20 AG 138 kJmol ATP H70 69 ADP Pi AG 305 kJmol Glucose ATP 69 glucose 6 phosphate ADP AG 167 kJmol 3 The actual change in free energy AG ofthe reaction A 69 B is the sum ofthe change in standard free energy AG and the term RT lnBactuaIAactual in which the concentration values of A and B are those present in the cell under steadystate conditions AG AGDH39 RT 39 In Bactual Aactual The ratio ofthe product and reactant concentrations under actual conditions in the cell is called the mass action ratio BactuaAactua and needs to be distinguished from the equilibrium constant Keq BequilibriumAequmbrium which is the ratio of product and substrate concentrations at 4 of 9 pages Bioc 460 Dr Miesfeld Spring 2008 equilibrium Remember you don t want metabolic reactions to reach equilibrium with the surroundings because once they do you are no longer alive The adenylate system is used for short term energy storage Energy obtained from photosynthesis and oxidation of metabolic fuels drives an ATP synthesis reaction that captures redox energy in the form of phosphoanhydride bond energy lmportantly this bond energy can be readily recovered by ATP cleavage and used to drive chemical osmotic and mechanical work The highest energy form is ATP which contains two phosphoanhydride bonds as shown in figure 6 Figure 6 305 kJmol I n 323 kJmol w OCH 0 lIH U NEH 0 L 3 A 39Wquot 5 L W x 39Vquot HO OH H0 0 4 NO ON Adenosine triphosphate Adenosine diphosphate Adenosine monophosphate ATP ADP AMP As shown in figure 7 the breakdown of DEM macromolecules through catabolic pathways yields Carbohydrates ATP whereas anabolic pathways used to synthesize Proteins macromolecules in the cell require ATP hydrolysis to Metabolic Nuc dasdds drive unfavorable reactions 3539 The term adenylate system refers to the j interconversion of low and high energy forms of NAsstPQ IL 1 adenylate between ATP ADP and AMP To see why i i FAD the adenylate system is important considerthat a 70 kg catab quot i AnabOIiC Pathways V A Hex pathwa 5 person requires 100 moles of ATP every day based W ATP y on the energy content of food assuming that 40 of l iI NADHVNADPHEV the potential energy released from metabolism is quotL EADHZ 39 converted to ATP The molecular weight of ATP is 507 1 gmol which means we hydrolyze as much as 50 kg of ATP every day Rather than synthesizing our own C02 Simplesugars weight in ATP on a daily basis it is much more efficient if 2332fo to recycle adenylate forms by reforming ATP from ADP Nucleotide bases Pi This is done in two ways Since ATP is the high energy form ofthe adenylate system then the ratio ofthe concentration of ATP to the concentration of ADP and AMP in the cell at any given time can be used as a measure of the energy state ofthe cell This relationship can be expressed in terms ofthe Energy Charge EC ofthe cell which takes into account the number of phosphoanhydride bonds available for work 5 of 9 pages Bioc 460 Dr Miesfeld Spring 2008 If all forms are present at the same concentrationthen 1 05 1 ATP 05ADP Energy Charge w 2 05 Energy Charge 2 ATP ADP AMP If ATP 2 ADP 1 AMP 05then Energy Charge M 07 2 1 05 Most cells are found to have an EC in the range of 07 to 09 which means that the ATP is higher than ADP or AMP This can be represented schematically by the graph in figure 8 Energy charge is a useful concept when thinking about metabolism As shown in figure 9 when ECltO8 then the activity of phosphorylating systems catabolism increases to replenish ATP levels battery power is low time to recharge Conversely when EC gt 08 then biosynthetic pathways anabolism are more active to take advantage of the high ATP Figure 8 Figure 9 Physiological Physiological Range Range 100 Lox2143531 8 W I 80 u S E g 08 K n O c 39 39 t 60 9 06 o 5 44 m r C Q I g 40 I 04 g3 ADP 2 20 73 0 2 C W 39 39 o v hl has 0 v v 0 0102 03 04 05 06 07 08 09 10 0 0102 0304 05 06 07 08 09 10 Ener Char e Energy Charge gy 9 OVERVIEW OF METABOLISM Metabolic pathways consist of a series of reactions that are coupled together through the metabolism of shared intermediates figure 10 Metabolic pathways can be linked together to form linear pathways cyclic pathways and branched pathways figure 11 Figure 10 Figure 11 A 13 Linear Pathway Enz 6 O Enz 4 E G Enz 1 Enz 2 Enz 3 Reacuon 2 A B 4quot C 439 D Forked Pathway 39 Reaction 1 M Enz 5 am LN ATP ADPPi W I Enz 7 l Reaqion 3 The blue arrows show H the commitmentstep Enz 10 V 1 E02 8 J I Reaction Q G D in each ofthe pathways 4y excreted Cyd c Enz 9 as waste Pathway ATP g Q ADP Pi 6 of 9 pages Bioc 460 Dr Miesfeld Spring 2008 The term metabolic flux refers to the rate at which metabolites are degraded and synthesized by a series of linked reactions For example the metabolic flux through glycolysis is higher than metabolic ux through gluconeogenesis when more glucose is converted to pyruvate glycolysis than pyruvate is converted to glucose gluconeogenesis Three primary mechanisms control metabolic ux 1 the amount of ratelimiting enzyme changes in gene transcription or protein synthesis 2 tha catalytic activity of ratelimiting enzymes covalent modifications or allosteric regulation and 3 bioavailability of substrates nutritional supplies or cell comparmentalization One of the best ways to understand how flux through various catabolic and anabolic pathways changes in response to substrate concentration and enzyme activity levels is to look at glucose metabolism in the liver before and after breakfast as illustrated in figures 12 and 13 Early in the morning before your first meal blood glucose levels begin to decline after a night of fasting which triggers glucagon release from the pancreas Glucagon signaling in liver cells activates both a catabolic pathway glycogen degradation and an anabolic pathway gluconeogenesis while at the same time inhibiting the catabolism of glucose by the glycolytic pathway After breakfast insulin levels increase due to high blood glucose which stimulates glucose uptake glycogen synthesis and glucose catabolism via the glycolytic pathway 9Fi ure 12 59m Liver cell metabolism before breakfast Liver cell metabolism after breakfast Insulin Insulin Glucagon Glycogen clumsich G R Peggraaaqa W p grad iioq S nthesis I ucose Import 55 Clkca G I I Expor glycolysis lGluconepgenesis g Glycolysis Gluconeogenes L lt yank Pyruvate The six major groups of metabolic pathways in nature The breakfast scenario gives the takehome message for the rest of the lectures in this course metabolic pathways are highly interdependent and exquisitely controlled by substrate availability and enzyme activity levels Even though we examine one pathway at a time for pedagogical purposes the key to understanding metabolic integration in terms of nutrition exercise and disease eg diabetes and obesity is learning how metabolic flux between pathways is controlled 7 of 9 pages To try and keep things interesting and organized we will approach the next 16 lectures as a journey through a metabolic forest ie the proverbial don39t lose sight of the forest through the trees As with any extended trip we need three items for ourjourney 1 a good map to figure out where we are 2 an itinerary to keep on schedule and 3 a guidebook to point out the important landmarks Figure 14 shows the metabolic map we will use to keep track of the pathways download a full page copy from the study guide page on the website This metabolic map illustrates the hierarchical nature of metabolism which includes four classes of macromolecules proteins nucleic acids carbohydrates and lipids six primary metabolites amino acids nucleotides fatty acids glucose pyruvate acetyl CoA and six small biomolecules NH4 COz NADH 02 ATP H20 This metabolic map will be used as a template each time a pathway is introduced using the divide and conquer strategy illustrated in figures 15 and 16 Figure 15 Synthesis and Degradation Pathways I Nucleotide Metabolism Amino I I Acid Metabolism I Carbohydrate Metabolism Lipid Metabolism Glycogen Metabolism Fatty Acid Metabolism Gluconeogenesis Nmogen Glycolysis Metabolism Energy Conversion Pathways Citrate Cycle Urea Cycle Carbon Heme Fixation Transport Oxidative System Phosphorylation Photosynthesis Bioc 460 Dr Miesfeld Spring 2008 Figure 14 Nucleic Proteins Acids lCarbohydrates I l Lipids H ii if it 4 monosaccharides triglycerides if H l gt bases NH i l T glycerol v urigagtrj glyceraldehyde 3P 4 Fatty NH4 C02 i k W h oxaloacetate argininosuccinate A ATP urea Figure 16 Acids ATPH b moz lt A citrate Sunhght H20 Synthesis and Degradation Pathways Lect 39 Lectures 35 36 37 Bioc 46 i I Bioc 4i i Lectures 34 9 38 Lecture 33 Lectures 25 26 Energy Conversion Pathways Lecture 39 Lectures 27 28 Lecture 29 Lectulve 3Q Lecture 31 The first group of pathways we will discuss are those involved with the oxidation of monsaccharides through a series of redox reactions culminating in ATP synthesis glycolysis citrate cycle electron transport chain oxidative phosphorylation photosynthesis Lectures 3240 cover three of the groups of pathways shown in blue that together control the synthesis and degradation of 1 carbohydrates carbon fixation pentose phosphate pathway gluconeogenesis glycogen synthesis and degradation 2 lipids fatty acid synthesis and degradation lipid 8 of 9 pages Bioc 460 Dr Miesfeld Spring 2008 transport cholesterol and steroid synthesis and 3 amino acids including nitrogen metabolism Nucleotide metabolism is covered in Bioc 461 or Bioc 411 Finally in lectures 41 and 42 we will tie the various pathways together by looking at how metabolic integration in humans explains normal nutrition and exercise and abnormal diabetes and obesity physiological states We will start off the discussion of each new pathway by answering the following four questions about the pathway 1 What does the pathway accomplish for the cell 2 What is the overall net reaction ofthe pathway 3 What are the key enzymes in the pathway 4 What are examples of this pathway in real life These questions and more importantly the answers function as our guidebook by highlighting the contributions of each pathway to the overall metabolism of the cell Moreover they will help you review your trip through the various pathways in preparation for exams 3 and 4 ANSWERS TO KEY CONCEPT QUESTIONS Life on earth is made possible by the biochemical reactions of photosynthesis carbon xation and aerobic respiration which toqether convert solar enerav into ATP and NADPH which is used to svnthesize carbohvdrates from 007 and H70 Aerobic organisms such as ourselves consume carbohydrates as a chemical source of energy and metabolize them in the presence of 02 to from 002 and H20 All organisms depend directly or indirectly on energy derived from thermonuclear fusion reactions on the sun to prevent for as long as possible reaching equilibrium with the environment a high entropy state called death Reaction coupind permits eneraeticallv unfavorable reactions to be more favorable in the context ofa pathway Coupling ATP hydrolysis to a phosphoryl transfer reaction is one example of reaction coupling that takes place in the same enzyme active site The net AG for an ATP coupled reaction is often highly negative for example the phosphorylation of glucose by the enzyme hexokinase Another type of reaction coupling is when two enzymes in pathway are energetically linked through a shared common intermediate Since the actual change in free energy AG is the sum ofthe change in standard free energy AG and RTlnmass action ratio in which the mass action ratio is productactuallsubstrateactual depletion ofa reaction product by its metabolism as a substrate in the coupled reaction results in a reduction in AG since In ofa mass action ratio lt1 is a negative number Therefore even though the AG for a reaction is a positive number based on the reaction reaching equilibrium in a test tube under ideal conditions the actual AG is a negative number because RTlnmass action ratio is a negative number due to lowerthan quotexpectedquot product in the cell due to its function as a substrate in a linked reaction ofthe pathway 9 of 9 pages
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