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1 BI25M1 ENERGY TRANSFORMATIONS LECTURE 1 AIMS: To review: the nature of energy; the ways in which living organisms transform energy from one form to another. [Lehninger (Edition 4) pp.21-27 and Chapter 13 Lehninger (Edition 5) pp.19-26 and Chapter 13 Instant Notes Section C2] 2 1 ENERGY IS THE CAPACITY TO DO WORK. Kinetic energy is to do with movement. Some examples: Type of energy What moves Example of work done heat molecules steam engine light photons photosynthesis electrical energy electrons household appliance mechanical energy any moving object bicycle pedal Potential energy is energy stored in matter because of its location or structure. Some examples: water in dam energy stored because of its altitude complex molecule energy stored in arrangement of atoms 3 2 ENERGY MAY BE TRANSFORMED FROM ONE FORM TO ANOTHER. Some examples: potential energy of water in dam to electrical energy sunlight to potential energy of complex molecules in photosynthesising plant 3 ENERGY TRANSFORMATIONS ARE SUBJECT TO TWO LAWS OF THERMODYNAMICS. 1 Energy, although transformable from one form to another, cannot be created or destroyed. 2 All energy transformations ultimately increase the entropy (disorder/ randomness) of the universe. 4 4 LIVING ORGANISMS ORIGINATED, EVOLVED AND EXIST BECAUSE OF ENERGY TRANSFORMATIONS. Life must have originated like this: simple abiotic molecules taken into ‘organism’ simpler molecules chemical conversion (‘food molecules’) (‘excretory products’) some potential energy zero potential energy energy released some energy ‘saved’ and used by the organism some energy ‘lost’ and returned to environment as heat to allow energy-requiring biosynthesis to allow energy-requiring activity e.g. locomotion, reproduction, etc simple molecules zero or low potential energy complex molecules of which the organism is built high potential energy 5 5 DURING EVOLUTION, THE RANGE OF HIGH POTENTIAL ENERGY ‘FOOD MOLECULES’ WIDENED. Some present-day micro-organisms still use very simple, inorganic ‘food molecules’, which are converted into lower potential energy forms as just described. Examples are bacteria that live in hot sulphur springs. They carry out this reaction: FeS + H2S FeS2 + H2 energy released Other organisms evolved the capacity to synthesise complex molecules from very simple precursors (‘photosynthesis’): sunlight (light energy) CO2 H2O complex molecules used to as form the structure of the organism zero potential energy high potential energy 6 Still other organisms evolved the capacity to use such biologically-synthesised complex molecules themselves as ‘food molecules’: complex biomolecules excretory products high potential energy zero potential energy To summarise: for most present-day organisms, sunlight is the ultimate ‘source’ of energy. It, through many transformations, enables organisms to be constructed, and to be biologically active. 7 6 ALTHOUGH LIFE INVOLVES CONSTRUCTING LOW ENTROPY SYSTEMS, THIS OCCURS WITHIN A LARGER SYSTEM, IN WHICH ENTROPY INCREASES. Life involves complexity and organisation at a number of levels: whole body organs and tissues cells subcellular compartments/organelles molecules all of which are highly ordered. This contrasts with the generally simpler, less organised arrangements in inanimate matter: rock, soil, air, water. Thus, building and maintenance of the structure of living organisms involves a decrease in entropy (disorder/randomness). 8 A closer look at the energy flow through the organism, however, shows how life occurs with an increase in entropy of a larger system, consisting of the organism within its surrounding environment. complex ‘food molecules’ simple molecules simple molecules used for biosynthesis very simple excretory molecules used for biosynthesis energy ‘lost’ as heat ‘saved’ ‘saved’ used in various activities energy energy ‘lost’ as heat simpler molecules ‘saved’ used in various activities energy ‘lost’ as heat complex molecules used in various activities ‘lost’ as heat complex molecules The overall process may be summarised thus: complex molecules of high potential energy taken from the environment simple molecules of zero potential energy returned to the environment more order (low entropy) less order (high entropy) potential energy of the complex molecules heat energy 9 To summarise: building and maintaining the structure of an organism involves constructing a highly complex, organised, low entropy system. Viewed in isolation, this seems to go against the second Law of Thermodynamics (Section 3). However, as we have seen, the process is possible because it does not occur in isolation. When organism and surroundings are considered together, the process is seen to occur with an increase in the entropy of the larger (organism/surroundings) combination. Put another way, life, (like all other processes occurring in the universe), ultimately involves making the universe more random. 10 7 HEAT IS THE LOWEST ‘GRADE’ OF ENERGY. When energy flows through an organism, some is ‘saved’, and used for biosynthesis and activity of the organism (Sections 4, 6). However, in any energy-transforming machine, not all the energy transformed can be turned into useful energy. Some becomes less useful energy and is ‘lost’. Living organisms are no exception. At each stage of the flow of energy through them, some energy is ‘lost’ back to the environment, generally as heat (Sections 4, 6). Eventually, as we have seen, (Section 6) all the energy, originally potential energy of ‘food molecules’, returns to the surroundings, largely as heat. 11 Why is heat a ‘lower grade’, ‘less useful’ form of energy? All forms of energy ‘do work’ (Section 1), but heat energy only does this when it flows from a place with a high temperature to one with a low temperature. Many systems are not like this, and organisms/cells certainly aren’t. So heat in general is not a useful form of energy for living organisms. It may warm a body up, but it can’t readily be transformed into other energy forms. To summarise: an abbreviated version of energy flow into, through and out of the biosphere is: light energy (of sun) chemical potentia energy (of biomolecules) heat energy 12 8 ‘HIGHER GRADE’ ENERGY (THAT CAN BE USED BY ORGANISMS) IS CALLED (GIBBS) FREE ENERGY. Section 7 suggests that it is possible to consider ‘useful’ and ‘non-useful’ energy, if we define the former as that which can be transformed into other forms of energy, and the latter as that which cannot. total energy = useful energy + non-useful energy Physical scientists translate this into: H enthalpy = G free energy + T x S absolute temperature entropy (T x S) is equivalent to non-useful energy, because it’s proportional to the rate at which molecules move about randomly – energy expended in making them do this can’t be easily transformed into other forms of energy. 13 9 THE CHANGE IN FREE ENERGY DURING A PROCESS INDICATES WHETHER THE PROCESS IS SPONTANEOUS (THAT IS, WHETHER IT OCCURS UNAIDED). In a spontaneous process, a system: (a) gives up energy e.g. water runs downhill spontaneously, giving up its potential energy; and/or (b) becomes more random (that is, increases in entropy) e.g. complex structures decay spontaneously, giving up their potential energy. 14 So, according to the ‘translation’ outlined in Section 8, a spontaneous process involves (a) a decrease in H; and/or (b) an increase in S. And, because H = G + TxS (Section 8) this means that any process leading to a decrease in G (i.e. occurring with a -G) is spontaneous. This makes sense: throughout the universe, ‘useful’ energy is gradually (and spontaneously) being transformed into less ‘useful’ heat (as occurs during the flow of energy through organisms) (Section 6). 15 10 THE CHANGE IN FREE ENERGY DURING A REACTION IS RELATED TO THE CONCENTRATIONS OF THE REACTANTS RELATIVE TO THEIR CONCENTRATIONS AT EQUILIBRIUM. A reaction A B reaches equilibrium when the rate at which A is being converted to B equals the rate at which B is being converted into A. Spontaneous reactions proceed towards (but do not necessarily reach) equilibrium. Suppose, for the reaction above, equilibrium occurs when there is 1 molecule of A for every 10 molecules of B. 16 What happens if the A to B ratio isn’t 1 to 10? We can imagine various scenarios: Molecular ratio of A to B Status of A B conversion Status of B A conversion 5 to 10 spontaneous -G non-spontaneous +G 1 to 100 non-spontaneous +G spontaneous -G 1 to 10 reaction at equilibrium G = 0 To summarise: the sign of G indicates on which side of the equilibrium the reactant concentrations lie at any particular time. The size of G is an indication of how far from the equilibrium the reaction is. 17 11 IN LIFE, SPONTANEOUS REACTIONS ARE NOT ALLOWED TO REACH EQUILIBRIUM. For a system at equilibrium, G = 0, (Section 10) and no net energy flow occurs from one process to another, so no work can be done. Such a situation is incompatible with life. Life involves continuous energy flow from the environment, through the organism, and back to the environment (Sections 4, 6). For the flow to continue, the components of the flow system must be stopped from reaching equilibrium. How is this achieved? The energy flow occurs through pathways of reactions (Section 14): food molecule excretory product 18 As the product of a reaction is formed, it is removed by the following reaction, and so the system is prevented from reaching equilibrium. So, as long as food is supplied and excretory products are removed, a steady, continuous flow occurs. This system is said to be in a ‘dynamic steady state’. While the flow continues, the organism ‘saves’ free energy released during the flow, to use in building its structure and in its various activities (Sections 4, 6). When the flow stops, the organism decays to a non-organised collection of simple molecules. At that stage, it has reached equilibrium with its environment. 19 BI25M1 ENERGY TRANSFORMATIONS LECTURE 2 AIMS: To review: life as a process depending upon maintenance of dynamic steady states; metabolism as a continuous flow of energy through an organism; roles of ATP-ADP inter-conversions in metabolism. [Lehninger (Edition 4) Lehninger (Edition 5) Instant Notes pp.21-27 and Chapter 13 pp.19-26 and Chapter 13 Section C2] 20 12 A RECAP: LIFE MAINTENANCE OF STEADY STATES. INVOLVES DYNAMIC Life involves systems of reactions held in dynamic steady states and prevented from reaching equilibrium (Section 11). With the simple system food molecule intermediate molecule a excretory molecule b (where a and b are the rates of the processes shown), when a = b, the system is in a dynamic steady state, and the intermediate molecule, although it is continuously being made and degraded, does not change in concentration. 21 In general, compositions of cells and organisms as a whole stay fairly constant over long periods, because of the maintenance of dynamic steady states. Thus, haemoglobin molecules in red blood cells; skin cells; the body structure of mature organisms and so on are all maintained in relatively constant compositions over long periods. All are in dynamic steady states: none are ‘at equilibrium’. Biologists refer to this state of affairs as ‘homeostasis’, and biochemists refer to the balanced synthesis and degradation of molecules as their ‘turn-over’. 22 Flow rates (a and b) may be very different in different parts of the flow system, i.e. different molecules and cells may ‘turn-over’ at very different rates. Flow rates may change in a controlled way in response to changes in the environment of the organism. Thus, a system may change from one dynamic steady state to another (with faster, or slower flow through the system). Such changes are discussed Metabolic Regulation lectures. in the 23 13 ‘Metabolism’ is the continuous flow of energy through the organism. Another definition: Metabolism is ‘the sum of all the chemical transformations taking place in a cell or organism’ (Lehninger Edition 4 p.482; Edition 5 p.486). During the flow of energy through organisms (Section 6) two types of process occur: complex ‘food molecules’ simple molecules used for biosynthesis simple molecules used for biosynthesis very simple excretory molecules energy ‘lost’ as heat ‘saved’ energy used in various activities ‘saved’ used in energy various activities ‘lost’ as heat simpler molecules ‘saved’ used in energy various activities ‘lost’ as heat complex molecules ‘lost’ as heat complex molecules 24 The processes are either degradative; occur with a -G (i.e. free energy flows from an ‘exergonic’ process); are spontaneous; and are referred to as catabolic processes; or synthetic; occur (in isolation) with a +G (i.e. in order to occur, free energy must flow to an ‘endergonic’ process); are (in isolation) non-spontaneous; and are referred to as anabolic processes. The diagram shows that the latter processes do not, in fact, occur in isolation: free energy flows from the former processes to the latter processes allowing them to occur. How energy flows from catabolic to anabolic processes is discussed in Sections 19 and 21. 25 14 METABOLISM OCCURS THROUGH PATHWAYS OF REACTIONS. A particular part of the metabolic system can be used to illustrate this statement. Glucose, a molecule of high potential energy, is used as a food material by many organisms. In the laboratory, it can be degraded by heating it in air. The potential energy of the glucose is released as heat: glucose + 6O2 6CO2 + 6 H2O high potential energy low potential energy heat In cells, the same (overall) reaction occurs, but through a series of small, cumulative, chemical changes (an example of the metabolic pathways referred to in Section 11). We see later (Section 18) why such an arrangement is advantageous to cells. 26 15 EACH STEP IN A METABOLIC PATHWAY IS CATALYSED BY AN ENZYME. Spontaneous reactions move towards (but, in organisms, do not reach) equilibrium (Section 10). ‘Spontaneous’ does not mean ‘instantaneous’. If it did, organisms, with their complex structures of high potential energy, would instantly decay to simpler structures with zero potential energy. In time, of course, this decay DOES occur, but it is not instantaneous. The key function of enzymes is to increase selectively the rate of particular spontaneous reactions, allowing the flow through particular metabolic pathways at the rate required. In the Enzymes lectures, we see what it is that ‘holds back’ spontaneous reactions, and how enzymes overcome this barrier. 27 16 CATABOLISM INVOLVES MOLECULAR CONVERGENCE; ANABOLISM INVOLVES MOLECULAR DIVERGENCE. CATABOLISM ANABOLISM proteins 20 amino acids carbohydrates a few sugars a few, simple intermediary metabolites a few fatty acids lipids 8 nucleotides nucleic acids large number of complex molecules large number of complex molecules 28 17 METABOLISM PIVOTS AROUND INTERMEDIARY METABOLITES. ‘Metabolites’ are reactants of reactions involved in metabolic flow. ‘Intermediary metabolites’ is the name given to a small number of relatively simple molecules, common to many organisms, through which much of the flow is channelled. Thus another version of the flow through the organism can be represented thus: food molecules intermediary metabolites excretory molecules complex molecules An intermediary metabolite, then, tends to be a component of several metabolic pathways. Examples are: glucose 6-phosphate pyruvate acetyl coenzyme A (acetyl CoA). 29 18 ORGANISATION OF METABOLISM INTO PATHWAYS ALLOWS FREE ENERGY FLOW BETWEEN CATABOLIC AND ANABOLIC PROCESSES. In the laboratory, glucose can be degraded by heating it in air. Its potential energy is transformed into heat. (Section 14) glucose + 6O2 6CO2 + 6 H20 high potential energy zero potential energy heat In the cell, the same (overall) reaction occurs, but through a series of small, cumulative chemical changes – a catabolic pathway. This allows some of the potential energy of the glucose to be saved at particular point(s) along the pathway. 30 Similarly, organisation of anabolic processes as pathways allows free energy to be ‘fed’ in at particular point(s) along the pathways. Free energy flowing from catabolic processes enables the various activities of the organism. Some of it flows to anabolic processes. CATABOLISM complex molecule (like glucose) simple molecules (like CO2 + H2O) free energy some heat lost throughout the pathway various activities (e.g. locomotion) complex molecule simple molecules ANABOLISM This allows ‘coupling’ of exergonic catabolism to endergonic anabolism. (Section 13) 31 19 MUCH FREE ENERGY FLOW BETWEEN PATHWAYS INVOLVES ATP-ADP INTER-CONVERSION. The structure of ATP (adenosine 5’-triphosphate) is in Lehninger Editions 4, 5 p.23 and Instant Notes p.94. 32 ATP and ADP are inter-converted by hydrolysis and condensation. hydrolysis ATP + H2O ADP condensation + Pi (inorganic phosphate) Because ATP has a higher potential energy than ADP/Pi, hydrolysis occurs with a decrease in free energy (i.e. is exergonic): G = - 7.3 kcal/mol (or - 30.5 kJ/mol) under ‘standard’ laboratory conditions (pH 7; molar concentrations of ATP, ADP, Pi). The condensation reaction requires a corresponding input of free energy (i.e. is endergonic): G = + 7.3 kcal/mol (or + 30.5 kJ/mol) (under ‘standard’ conditions). 33 ATP hydrolysis to ADP + Pi is exergonic because: (1) hydrolysis relieves electrostatic repulsion between the four negative charges that occur in ATP in water at neutral pH ; (2) more resonance is possible for ADP + Pi than for ATP; (3) more H-bonding with water is possible for ADP + Pi than for ATP; (4) ADP, when formed from ATP, releases H+ into a medium of low [H+]. This combination of factors means that, at the equilibrium of the inter-conversion, [ADP and Pi] is high and [ATP] low. In cells, [ADP] is lower, and [ATP] higher than at equilibrium, so movement towards equilibrium occurs in the direction of hydrolysis, which is therefore spontaneous, occurring with a -G. 34 All of this is relevant to metabolism, because free energy flowing from an exergonic, catabolic pathway can be ‘saved’ by endergonic conversion of ADP to ATP at particular reaction(s) of the pathway. And free energy flowing to an endergonic, anabolic pathway can be ‘supplied’ by exergonic conversion of ATP to ADP at particular reaction(s) of the pathway. So, modifying the Section 18 diagram: complex molecule simple molecules ADP ATP some heat lost throughout the pathway ATP conversion to ADP may then be used to drive various free energy-requiring activities of the organism. Among them are endergonic anabolic processes: ADP complex molecule ATP simple molecules 35 BI25M1 ENERGY TRANSFORMATIONS LECTURE 3 AIMS: To review: examples of ATP-ADP inter-conversion in free energy transfer during metabolism roles of redox reactions in free energy transfer during metabolism; the difference between substrate-level and oxidative phosphorylations. [Lehninger (Edition 4) Lehninger (Edition 5) Instant Notes pp.21-27 and Chapter 13 pp.19-26 and Chapter 13 Section C2] 36 20 ATP-ADP INTER-CONVERSION IN METABOLISM OCCURS BY PHOSPHATE TRANSFER, NOT BY HYDROLYSIS/CONDENSATION. To illustrate this, we can return to the catabolic pathway by which the food molecule glucose releases its potential energy when degraded (Section 14). One of the pathway steps involves conversion of one metabolite, phosphoenolpyruvate (PEP), to another, pyruvate. And, at this step, some of the glucose potential energy is ‘saved’ as ATP is made from ADP. glucose PEP ADP pyruvate ATP 37 How does converting PEP to pyruvate allow endergonic conversion of ADP to ATP? In the laboratory, PEP can be hydrolysed to pyruvate and inorganic phosphate (Pi). PEP + H2O pyruvate + Pi The reaction is exergonic, with a G of -61.9 kJ/mol under ‘standard’ conditions. We know (Section 19) that ADP + Pi ATP + H2O is endergonic, with a G of +30.5 kJ/mol under ‘standard’ conditions. In the cell, remember, the reaction that actually occurs is PEP + ADP pyruvate + ATP 38 This is equivalent to the sum of the two laboratory reactions PEP ADP + + H2O Pi pyruvate + ATP + Pi H2O PEP + ADP pyruvate + ATP Because free energy changes are additive, the reaction occurring in the cell has a G = to the sum of the Gs of the two, separate, laboratory reactions = (-61.9 +30.5) = -31.4 kJ/mol (under ‘standard’ conditions). So, some potential energy of PEP, (originally part of the potential energy of glucose), is ‘released’ as it is converted to pyruvate, and ‘saved’ as the potential energy of ATP. Notice that ATP synthesis did not involve the actual condensation of ADP and Pi, but the transfer of a phosphate group from PEP to ADP. 39 A second illustration of phosphate group transfer in metabolic energy flow is the synthesis of an amino acid, glutamine, from another amino acid, glutamate. The process is endergonic, and ATP conversion to ADP ‘supplies’ the necessary free energy. How does converting ATP to ADP allow endergonic synthesis of glutamine? In the cell, glutamine is made like this: glutamate + ATP glutamyl phosphate + ADP NH4+ glutamine + Pi glutamine + ADP + Pi + glutamyl phosphate The net effect is glutamate + ATP + NH4+ 40 In the laboratory, glutamine synthesis like this glutamate + NH4+ glutamine + H2O is endergonic, with a G of +14.2 kJ/mol under ‘standard’ conditions. And we know (Section 19) that ATP + H 2O ADP + Pi is exergonic, with a G of -30.5 kJ/mol under ‘standard’ conditions. In the cell, remember, the net effect of the reaction that actually occurs is glutamate + ATP + NH4+ glutamine + ADP + Pi This is equivalent to the sum of the two laboratory reactions glutamate + NH4+ glutamine + H2O ATP ADP + H 2O glutamate + ATP + NH4 + glutamine + Pi + ADP + Pi 41 Because free energy changes are additive, the reaction occurring in the cell has a G = to the sum of the Gs of the two, separate, laboratory reactions = (+14.2 -30.5) = -16.3 kJ/mol (under ‘standard’ conditions), So, potential energy of ATP, ‘released’ as it is converted to ADP, is ‘supplied’ to the process of glutamine synthesis. Notice that this use of ATP did not involve its actual hydrolysis to ADP and Pi, but the transfer of a phosphate group from ATP to glutamate. Energy flow between many metabolic pathways involves similar ATP-ADP interconversions through phosphate group transfers. Because of its role in transferring energy between cellular processes, ATP is often called the ‘energy currency’ of the cell. 42 21 FREE ENERGY FLOW BETWEEN PATHWAYS ALSO INVOLVES REDUCTION-OXIDATION (REDOX) REACTIONS. Much of the potential energy of food molecules arises because they contain large numbers of H atoms. Examples are glucose C6H12O6 and fatty acids, like palmitate CH3(CH2)14COO- The latter, in particular, resemble longchain hydrocarbons of petroleum, that are also, in a different context, fuels. Why should having H atoms give such molecules potential energy, and how is this relevant to energy transfer in metabolism? 43 H atoms may be said to have ‘high-energy electrons’. They are so-called electropositive. because H is Electrons of electropositive atoms are attracted to electronegative atoms. When they associate with an electronegative atom, a more stable state is reached, and energy is released. O atoms are very electronegative. If the electrons of the food molecule H atoms are made to combine with O to produce water, much energy is released. (Just as petroleum hydrocarbons, burned in air, release energy.) To summarise: we ‘burn’ food molecules using oxygen we breathe in, and ‘save’ some of energy released. using inspired oxygen. 44 How does this work in practise? In certain reactions of catabolic pathways, H atoms are stripped, two at a time, from what was originally a food molecule. They are accepted by one of a small set of co-reactants (represented as ‘X’), in a redox reaction (making ‘XH2’). reduced food molecule oxidised product X XH2 ‘XH2’ passes the H atoms, with their ‘highenergy’ electrons, through various redox reactants, until eventually they reach electronegative oxygen. When they do, much energy is released. Some is used to make ATP from ADP, and so ‘saved’ by the organism. 45 What has this got to do with ‘free energy flow between pathways’? In some cases, XH2, instead of passing its H’s towards O2, links the catabolic pathway in which it was produced to a particular reaction of an anabolic pathway: catabolic pathway reduced food molecule oxidised product X XH2 reduced product oxidised starting material anabolic pathway To summarise again: free energy flow between exergonic catabolism and endergonic anabolism occurs not just through ADP/ATP interconversion (Section 19), but also by inter-conversion of redox co-reactants (‘X’/‘XH2’). 46 22 THE MAJOR REDOX CO-REACTANTS (‘X’/XH2’) OF METABOLIC PATHWAYS ARE NAD, NADP and FAD. . All are dinucleotides containing adenine and ribose, with structures similar in part to that of ATP. (Section 19) 47 [NAD, NADP, FAD structures are also in Lehninger Edition 4 pp.513,516; Edition 5 pp.517,520; Instant Notes p.89.] To summarise: 2 hydrogen atoms (i.e. 2 protons, 2 electrons) X XH2 NAD+ NADP+ FAD NADH + H+ NADPH + H+ FADH2 Passing H’s towards O2 (Section 21) mainly involves NAD and FAD, while NADP is mainly involved in energy flow between catabolism and anabolism. (Section 21) 48 23 ATP SYNTHESIS FROM ADP OCCURS BY SUBSTRATE-LEVEL OR OXIDATIVE PHOSPHORYLATION. Substrate-level phosphorylation is ATP synthesis that occurs without direct intervention of redox reactions. Oxidative phosphorylation is ATP synthesis that occurs as a consequence of oxidation of a co-reactant (‘XH2’). To illustrate this, we can return to the catabolic pathway by which the food molecule glucose releases its potential energy when degraded (Sections 14,18,20). Partial breakdown of glucose, to lactate or ethanol, releases a little of its potential energy, and some is saved by making ATP (Sections 19,20). glucose lactate or ethanol ADP ATP 49 No redox reactions are (directly) involved. This is substrate-level phosphorylation. Complete breakdown of glucose to CO2 and H2O involves production of reduced co-reactants (XH2), which eventually pass on ‘high energy electrons’ to O2 (Section 22). All the potential energy of glucose is released, and much more ATP is made. This is oxidative phosphorylation. glucose CO2 ADP ATP X XH2 substrate-level phosphorylation YH2 Y ADP ATP oxidative phosphorylation 1 /2O2 H2O The X-XH2/YH2-Y redox reaction represents a series of such reactions, through which H atoms with their electrons pass before eventually reaching O2. This series is called ‘the terminal respiratory system’. 50 Only hexoses, like glucose, generate ATP by substrate-level phosphorylation. Other foods, like fatty acids (Section 21), can only generate ATP by oxidative phosphorylation. Although it produces small amounts of ATP, substrate-level phosphorylation is not trival: it provides ATP for human cells lacking oxygen (e.g. in vigorously exercising skeletal muscle) and/or lacking mitochondria (which is where oxidative phosphorylation occurs) (e.g. RBCs). Because of this, glucose is a major food for most organisms, many of which can also make it (gluconeogenesis) from non-carbohydrate sources. 51 The coming course deals with: the following fundamental catabolism-associated processes: glycolysis: the partial catabolism of hexoses to 3-carbon pyruvate, with the conservation of a little of the potential energy of the hexose in ATP formation (substrate-level phosphorylation); the pyruvate dehydrogenase-catalysed reaction: in which further catabolism of the 3-carbon pyruvate to 2-carbon acetyl CoA occurs; the partial catabolism of fatty acids: this is ‘ oxidation’ and again generates 2-carbon acetyl CoA; the citric acid cycle: in which further catabolism of the 2-carbon acetyl CoA to CO2 occurs; the terminal respiratory system: in which electrons, originally part of food molecules and subsequently passed during their catabolism to redox co-reactants, are then passed through a series of redox reactions to oxygen to form water, much of the potential energy of the food molecule being conserved in ATP formation (oxidative phosphorylation); the pentose phosphate pathway: in which an alternative catabolism of hexoses is used to produce other sugars and a particular form of ‘XH2’ (NADPH + H+); 52 and the following processes which centre on anabolism: glycogen synthesis: the storage of hexose residues in polymeric form which may be mobilised later (glycogen breakdown); gluconeogenesis: in which glucose is synthesised from noncarbohydrate sources; fatty acid synthesis: in which 2-carbon acetyl CoA molecules are precursors of long hydrocarbon chains; triacylglycerol and phospholipid synthesis: in which fatty acids are used in the synthesis of molecules with important structural, storage and other roles; photosynthesis: in which sugars are synthesised from very simple precursors, using sunlight to drive the process. We will also consider: nitrogen metabolism: the inter-conversions of nitrogen-containing molecules, including their entry to and exit from the biosphere; enzymes: the properties of the catalysts of the reaction steps of metabolic pathways; metabolic regulation: the ways in which flow rates through pathways can be changed in the face of changing requirements of the cell/organism. 53 We will concentrate on function rather than (just for the sake of them) names and structures of the chemical intermediates, although a coherent discussion of function requires some knowledge of names and structures. And, in a metabolic retrospective, we will deliberately pause to consolidate understanding of how the pathways interact and connect. The various pathways can seem daunting when first encountered. In fact, there are relatively few major ones, and they are common to very many organisms. When you encounter a pathway for the first time, don’t start by trying to remember every last detail of the pathway. Begin by following the advice in Lehninger (Editions 4,5 p.488): Ask yourself ‘What does this chemical transformation do for the organism?’ ‘How does this pathway interconnect with the other pathways … to produce the energy and products required for cell maintenance and growth?’ If you reach an understanding of why evolution has made the pathway the way it is, you will be able more easily to remember its various features.