Pyramid Science

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Friday, December 26, 2008


The currency of all energy requirements involves the chemical adenosine triphosphate (ATP) and is one compound made up of a nitrogen base (adenosine) linked to three phosphate groups. The cleavage of one phosphate-adenosine chemical bond releases a large quantity of energy forming adenosine diphosphate (ADP). It is ATP -> ADP that produces the driving force to make muscle contract. All chemical reactions in the body require energy be they the formation of structural proteins or enzymes (proteins) through peptide bond formation between amino acids or breakdown of foodstuffs in digestion. All require energy. The combustion of fat, carbohydrate or protein will provide this energy to restore the ADP -> ATP. It is basically as simple as that. The complicated part is how this energy is provided, but still it remains a matter of breaking one adenosine-phosphate bond to energise other chemical reactions and reforming the bond to resynthesise ATP. Essentially, the ATP -> ADP + energy is the trigger for other processes.

There is a limited amount of ATP in the body so once ATP -> ADP has occurred, the ADP must be converted back into ATP to replenish these limited stores. Several mechanisms occur depending on the speed at which the energy is required. The complete and efficient combustion of fat, carbohydrate and protein is a relatively slow process. For aerobic (using oxygen) and anaerobic (without oxygen) activity a different series of chemical reactions occurs. Creatine phosphate is a stop gap chemical high-energy provider, but for a very short term period (30-60 secs). The restoration of all phosphate linkages to other chemicals requires energy and this must be provided from the large storage reserves of mostly fat and carbohydrate. Protein can also be destroyed to provide energy.

ATP is not synthesised in any one particular tissue and then transported around the body, but rather every cell has the capacity to synthesise and use ATP within itself. It is very important to appreciate that the processes which use ATP are closely matched with those that produce energy so that the greater the demand for energy the faster the energy must be produced. Otherwise a mismatch between ATP demand and supply will lead to an energy crisis and the cell couldn't function.

Before fat can be mobilised from the subcutaneous fat cells under the skin, the muscle must still be able to work. If cells did not contain there own store of energy then disaster would result. The substance creatine phosphate (CP) does this. Once the main source of energy is supplied to the working muscle the CP stores can then be repleted, its job over. Fat and carbohydrate are the two main foodstuffs which are oxidised. To a lesser extent, unless through prolonged endurance work or where carbohydrate and/or fat is in limited supply, protein will be utilised and this defines starvation conditions. The rate of energy requirement will determine the source of energy given that there are normal levels within the body. This energy is then trapped by ATP (from ADP) with carbon dioxide and water as the byproducts.

The mitochondria within cells are the engines which actually burn the fuel to produce the energy. These are highly specialised structures and are the powerhouses of all cellular activity and account for most of the oxygen used by the body. The chemical pathway by which energy is produced is called the Krebs cycle (after Sir Hans Krebs), sometimes referred to as the citric acid cycle, which describes the chemical fate (metabolism) of fat, carbohydrate and protein. In other words how nutrients provide ATP from ADP.

High rates of energy requirement must come from carbohydrate. They are capable of rapid release of energy where the slower oxidative processes cannot match the need. Glycogen stored within the liver can provide glucose which can be transported to glycogen starved muscle. Muscle glycogen cannot be mobilised in the same way to supply other muscles.

During high energy demanding activity the rate at which energy is required outstrips the rate at which normal oxidative processes work: carbohydrate combustion. Glycogen is broken down into a smaller chemical entity called pyruvate which can then enter the Krebs cycle. Glucose has 6 carbon atoms within the molecule and pyruvate has 3 carbon atoms. Each carbon atom will ultimately be lost completely as a single carbon dioxide molecule. Complete oxidation or effectively the combination of carbon with oxygen.

When demand is high and oxidative processes do not function properly because of the slowness of the process, pyruvate is converted to lactic acid. This can take place outside the mitochondria of the cell as it does not require oxygen and is therefore called anaerobic metabolism (without oxygen). Although ATP is generated very quickly, the process is very inefficient and only 2 ATP units are produced from a single glucose unit. Remember, the 6 -C atom unit of glucose gives two 3-C atom units of pyruvate. Lactic acid also has the same 3-C atoms from the pyruvate.

The glucose to lactic acid process is very important under high energy demand, but this process can only function for a very short period. Lactic acid dissociates or breaks down to produce hydrogen ions and lactate. This is very acidic and unless these products are removed, the cell will be destroyed. In reality fatigue and complete exhaustion set in before this occurs and this can be viewed as the body protecting itself from destruction.

Complete oxidation (aerobic) of glucose intermediates within the mitochondria produces a vastly greater yield of ATP per glucose unit. Respiration increases naturally to ensure a sufficiency of oxygen to do this. Between 36-38 units of ATP are produced aerobically compared to the 2 units in the anaerobic process. So, although the lactate route to ATP is fast it is clearly very inefficient and glycogen stores would be depleted very rapidly.

Biologically available energy is not utilised by the dissipation of heat in respiration, but the mitochondria within cells contain groups of organised enzymes and are responsible for the use of this biologically available energy. Inorganic phosphate phosphorylates the nucleotide ADP (adenosine 5-diphosphate) to the corresponding ATP (adenosine 5-triphosphate). The high free energy of hydrolysis of ATP comes from the two phosphoanhydride groups within. Direct hydrolysis of ATP would result in heat formation, but the pathway is different. This endergonic biochemical process requires energy, cannot occur spontaneously and is a coupled reaction.

The sequence is thermodynamically unfavoured and would require energy if it were to take place in one step. To render it favourable it can be carried out in two steps, one involving ATP. Phosphorylation by ATP generates energy and forms a very reactive intermediate. This would be catalysed by enzymes in the biological system. Enzymes do not alter the thermodynamic outcome of a reaction, favourable or otherwise, only its velocity.

ATP is regarded as a high energy compound like acetyl-coenzyme A and other nucleoside triphosphates, for example guanosine 5-triphosphate (GTP). Protein synthesis requires both ATP and GDP to trans-phosphorylate yielding ADP and GTP. Although many of these high energy compounds require ATP, the ATP itself can be formed by direct phosphorylation with inorganic phosphate.

Respiration is essentially the controlled oxidation of glucose to yield biologically available energy in the form of ATP. Just as some oxidations require the presence of oxygen and others can be effected in its absence, so respiration is of two types. Oxygen-dependent (aerobic) and oxygen-independent (anaerobic). In both types of respiration, high-energy organic phosphates are produced and serve as phosphate donors for the phosphorylation of ADP. This process is described as substrate phosphorylation.

In aerobic respiration, an additional and quantitatively more important phosphorylation mechanism operates to produce ATP from ADP. It utilises inorganic phosphate and is oxygen-dependent. This highly endergonic process of oxidative phosphorylation stems from an electron transport mechanism as in photosynthesis. However, the flow of electrons originates in the dehydrogenation of respiratory substrates and terminates in the reduction of oxygen to water.

The process by which glucose is degraded during anaerobic respiration is known as glycolysis (splitting of sugar). The biological pathway is referred to as the Embden-Meyerhof pathway after its original formulators. So, how does the process produce ATP?

During glycolysis (hydrolysis of starch or glycogen), glucose is phosphorylated by ATP which in turn loses one phosphate group and changes to ADP. The phosphorylated glucose then enzymatically rearranges (isomerises) to the fructose phosphate derivative, another sugar. The 6-C atom unit of glucose is contracted into a 5-C atom ring and an exocyclic (outside the ring) C-atom. It is again phosphorylated, but this time to fructose-1,6-diphosphate by another ATP to ADP transfer. Two molecules of ATP have been used to convert glucose to fructose-1,6-diphosphate, which is easily split into two 3-C fragments (glyceraldehyde-3-phosphate and dihydroxyacetone-1-phosphate) by an enzyme. These trioses are simple sugars and biochemically interconvertible by enzymatic action.

The dihydroxyacetone-1-phosphate is converted into another molecule of glyceraldehyde-3-phosphate. So far one glucose unit has been converted to two glyceraldehyde-3-phosphate molecules at the expense of two ATP molecules. The oxidation (removal of hydrogen: dehydrogenation) of the aldehyde gives an acid which is phosphorylated by inorganic phosphate (not ATP) to yield 1,3-diphosphoglycerate which is a mixed anhydride of a carboxylic acid and orthophosphoric acid and so has a high free energy of hydrolysis. What this means is that the compound can phosphorylate ADP back to ATP by transfer of one of the phosphate groups.

Two molecules of the glycerate are generated from the original glucose unit so providing two ATP molecules. The sum so far of ATP is zero since two molecules of ATP were consumed (giving ADP) to reach the two molecules of glycerate which now generate two ATP molecules from ADP. The resulting 3-phosphoglycerate is enzymatically isomerised to 2-phosphoglycerate which loses a molecule of water to give phosphoenolpyruvate, another high energy phosphate capable of transfer of the phosphate group to ADP forming ATP. Again two molecules of the high energy phosphate give two ATP molecules and pyruvic acid. Overall, the original glucose unit required two ATP molecules, but ultimately has provided four ATP molecules. A gain of two ATP molecules by the oxidation of glucose -> pyruvate. In humans the enzyme required to convert pyruvate to ethanol is absent so in the fatigued athlete where oxygen is deficient the pyruvate is reduced to lactate directly. The hydrogen removed in the earlier steps of glucose oxidation is transferred from the substrate to an acceptor called nicotinamide adenine dinucleotide (NAD+) forming the reduced acceptor NADH, which now enzymatically releases the hydrogen (REDOX reactions in biology).

Under aerobic conditions, where oxygen is in good supply, the pyruvate is not converted to lactate but undergoes a continuing oxidation to give ultimately carbon dioxide and water. This is called the Krebs cycle also known as the tricarboxylic acid cycle.

Current thinking is that lactate is not produced only in the anaerobic process where oxygen is unavailable. Lactate is formed under these conditions, but also its production is directly related to the rate at which energy is produced. So it would seem that under generally an aerobic state of low work output, some lactate is still formed within some cells, but is easily cleared from the system and no sign of fatigue results. This may be due to blood circulation insufficiency in some parts of the working muscle. However formed lactate is not a metabolic dead-end and the products of glucose cleavage from which it is derived are not wasted. Lactic acid can be reconverted to pyruvate in the same muscle cell by oxidation (loss of hydrogen) when the energy demand is reduced. This would then spare fresh glycogen being consumed or glucose removed from the blood transport system. Glycogen is stored within the muscle cell and cannot be used by other cells, but glucose is freely transported around the body in the blood and taken up as required. Pyruvate formed from lactic acid would be oxidised rather that from glucose or glycogen directly. The glycogen within parts of a muscle may be depleted so lactate could be used by these muscle cells instead of using glucose from the circulation. Lactate can be taken up by the liver and be converted back into glucose and finally end up back in muscle cells as glycogen.

The eventual metabolic fate of lactate can be oxidation or conversion back to glycogen depending on the prevailing energy demands. Cells do not suddenly switch from aerobic to anaerobic metabolism. Lactate formation during exercise is proportional to the rate of energy production and does not start at a certain threshold of intensity (an anaerobic threshold). Lactate is produced continually but only accumulates when the rate of production exceeds the clearance rate. It may be converted back to pyruvate within the same muscle cell when the rate of energy provision from oxidative metabolism is sufficient to meet the demands for energy. This would then spare glucose units from glycogen within the muscle as well as entry of glucose from the circulation, as the pyruvate that is formed could then be oxidised in place of pyruvate formed from glucose or glycogen.

Lactate may leave the muscle cell to be taken up by other muscle cells within the same muscle. Such cells may have exhausted their own supply of glycogen and be in need of suitable carbohydrate to convert back to pyruvate and then either oxidise to produce energy, or use to rebuild the glycogen store in the cell. Lactate may leave the muscle and be taken up by the liver and converted back to glucose. The glucose formed by this process can then be released back into the blood to be taken up by the muscle cell as further fuel for either energy production or glycogen repletion.

  • Therefore, while the eventual metabolic fate of any lactate formed will be oxidation, the immediate fate will depend on the energetic demands on the cell prevailing at that time. The idea that the cell suddenly switches over from aerobic to anaerobic metabolism is no longer tenable. Lactate formation during exercise now appears to be directly proportional to the rate at which energy is being produced and does not start suddenly at a certain point or threshold of exercise intensity (an 'anaerobic threshold'). Instead lactate is being produced continually and only accumulates when the rate at which it is produced exceeds the rate it can be cleared from the system.

Energy from fats

Stored triglycerides in adipose tissue and muscle cells are converted into energy in stages. Firstly, the triglyceride store is mobilised within the adipose tissue to bring about the release of free fatty acids into the circulation. Several hormones control this process the most important being adrenaline and noradrenaline which are released when energy is required - the fight or flight hormones which prepare the body for action. The free fatty acids are then transported in the blood to the working muscle by a carrier the protein called albumin. The glycerol that is released is taken up by the liver and converted to glucose by a process known as gluconeogenesis. The glucose so produced can then be taken up by working muscle to provide energy.

The blood supply containing increased free fatty acids (FFA) levels causes a corresponding increase in the uptake of FFA by the muscle and is related to the rate of blood flowing through the capillaries in the muscle. The FFA entering the muscle can then be oxidised immediately or stored in the muscle as additional triglyceride. To utilise the FFA energy is required so ATP is needed. The activated FFA are then transported to the mitochondria of the cell by a special carrier mechanism. The most critical stages of the utilisation of FFA are the transportation to the muscle and carriage to the mitochondria of the cell when in the muscle. The greater the number of mitochondria in the cell then the larger the capacity to take up fatty acids and oxidise them to produce energy. Once in the mitochondria the activated FFA are broken down and enter the Krebs cycle to be oxidised in the same way as carbohydrate. The number of ATP units depends on the number of carbon atoms in the fatty acid molecule. The longer the fatty acid the more carbon atoms there are and the more energy (number of ATP units) produced. This amount will be in the range 80-200 ATP units for FFA chain lengths of between 10-24 carbon atoms.

So whereas 36-38 ATP units are provided from glucose oxidation, the potential energy yield from fatty acid oxidation is much greater. Consequently any factor which can increase the utilisation of FFA will have a considerable impact on the overall energy generated. However, the rate of oxidation or energy resynthesis from triglyceride is determined by the mitochondria in the cell. The absolute rate may be large but the rate at which ATP is resynthesised is comparatively low.

The fatty acid chain is metabolised in 2-carbon units at a time in the Krebs cycle. The pyruvate from the degradation of glucose under aerobic conditions enters the cycle in the same way and is completely broken down to CO2 and water. The hydrogen that is removed from pyruvate is transferred to NAD+ which constitutes the coenzyme of almost all dehydrogenating enzymes (dehydrogenases). The Krebs cycle is such because the oxaloacetate required and consumed in the first step is regenerated at the end.

Pyruvate is oxidatively decarboxylated to yield an acetyl unit in the form of acetyl-coenzyme A and this undergoes an enzyme-catalyzed condensation with oxaloacetate to give citrate as the first step in the cycle. Fatty acid breakdown commences with the 2-carbon fragment entering the cycle at the same place as pyruvate and so form a common pathway from acetyl-coenzyme A Citrate is enzymatically isomerised via cis-aconitate to isocitrate and this is oxidised (hydrogen removed) and decarboxylated to yield oxoglutarate. This in turn is is oxidatively decarboxylated to succinyl-coenzyme A in a similar way that pyruvate is converted to acetyl-coenzyme A. This is a high energy compound and is used to drive the phosphorylation of GDP to guanosine 5-triphosphate (GTP) and in the process is converted to succinate. Dehydrogenation of succinate to fumarate, the enzymatic hydration of fumarate to malate and finally the dehydrogenation of malate to oxaloacetate complete the cycle.

The operation of the Krebs cycle is confined to small subcellular particles possessing internal structure and containing electron-acceptor systems. These mitochondria can be thought of as corridor containing shelves which hold the correct enzymes in the right sequence so passage down the pathway effects the conversion of acetyl-coenzyme A to oxaloacetate.

Tissues such as the heart and liver are well suited for energy resynthesis from fat oxidation, but the brain and red blood cells are dependent on glycolysis (from carbohydrate) for energy and exclusively use glucose. Skeletal muscle can use a whole variety of different fuels although the capacity to oxidise fatty acids does vary between the types of muscle fibre. The high oxidative capacity fibres are the Type I (or SO: slow, oxidative) fibres and are better able to oxidise fatty acids than the Type IIb (or FG: fast, glycolitic) fibres which are best suited to energy production from carbohydrate.


Another form of fat that can be used to provide energy is formed in the liver as ketones. Under extreme conditions of prolonged exercise or starvation or in diabetes, the excess free fatty acids are released into the circulation and converted by the liver to ketones. The importance of ketones is that they are the only alternative fuel source which can be used by the brain and nervous tissue other than glucose. ketones are taken up by the brain and skeletal muscle and enter the Krebs cycle to be oxidised to produce ATP.

Energy from proteins

Amino acids are metabolised as an energy source along with fat and carbohydrate. The protein does not form only structural tissue and enzymes, but through the process of gluconeogenesis, amino acids can be converted to glucose providing energy to tissues that rely on glucose as a fuel source. The nitrogen must first be removed (deamination) and this is converted to ammonia. The remaining carbon skeleton is then used as the energy source.

Most of the carbons form pyruvate or one of the Krebs cycle intermediates and can easily enter the oxidation pathway and be used to generate ATP within the mitochondria. The toxic ammonia is converted to urea in the liver transported to the kidneys in the blood and passed out of the body in the urine.

The carbon skeletons may be used as an energy source for those tissues that would normally use carbohydrate when this fuel source is reduced. In addition to providing energy, they also make it possible to supply the Krebs cycle intermediates required to replace those that have been lost from the cycle. These would normally be maintained from carbohydrate metabolism but as glycogen stores become depleted and the rate of carbohydrate metabolism reduced an alternative supply of the Krebs cycle intermediates is advantageous. Unless the supply of these intermediates is maintained it is not possible for the Krebs cycle to continue generating ATP from other substrates (fatty acids) if carbohydrate stores are limited. Under conditions where the supply of glucose exceeds the requirement for energy, the carbon skeletons may be converted to fatty acid and stored as triglyceride.

How is this energy used to move muscle?

Isotonic, isokinetic and isometric are different kinds of movements but are all muscle contractions. The same mechanism moves muscle regardless of the type. The Type I muscle fibre are slow to contract and are red in colour. They are relatively resistant to fatigue and have a high oxidative capacity. This means a high potential to generate ATP by the oxidation of carbohydrate, fat (and indirectly protein) in the mitochondria of the cell. They are referred to as the SO (slow, oxidative) fibres. The Type II muscle fibre are divided into IIa, IIb or IIab fibres.


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