The citric acid cycle has been described as the hub of the metabolic wheel. Discuss the roles of the citric acid cycle in the oxidation of various fuel molecules and the provision of carbon skeletons for biosynthesis.AbstractAcetyl CoA carboxylase can only function when the levels of citrate are high enough, but the citrate levels are only high when the levels of ATP and acetyl CoA are high. When the citrate levels are high enough, acetyl CoA carboxylase regulates fatty acid metabolism and control fatty acid synthesis and degradation.
Oxaloacetate is replenished by the attachment of CO2 to pyruvate and at the same time, ATP is hydrolysed using H2O which generates more oxaloacetate needed for the cycle and also ADP, inorganic phosphate and 2H+. Succinate is converted to fumarate by succinate dehydrogenase, creating FADH2 in the process. 2 electrons from FADH2 are transferred to ubiquinone and then the electrons are transferred to the Q-cytochrome C oxidoreductase complex, a component of the electron transport chain.
D-isocitrate is converted to alpha-ketoglutarate which is converted to succinyl-CoA by 2 oxidative decarboxylation reactions. Both reactions generate NADH which can used to generate ATP. IntroductionThe citric acid cycle (also known as the Krebs cycle) is one of the stages of aerobic respiration in eukaryotic organisms. The citric acid cycle is preceded by glycolysis but happens before the final stage of aerobic respiration, oxidative phosphorylation. Glycolysis is a very important step before-hand; it converts carbohydrates (mainly glucose) to pyruvate, which is then further converted to acetyl coenzyme A (acetyl CoA) which is known as the fuel’ for the citric acid cycle. During the citric acid cycle, there are multiple reactions, starting with the condensation reaction of oxaloacetate and acetyl CoA to citryl CoA and citrate, catalysed by citrate synthase. After this, there 8 further reactions: dehydration, hydration, oxidative decarboxylation, oxidative decarboxylation again, substrate level phosphorylation, dehydrogenation, hydration (again) and ending in dehydrogenation again. Since all these reactions are part of a cycle, the final product of the cycle is oxaloacetate- one of the reactants in the first reaction of the cycle. Main bodyThe citric acid cycle has a big link with the oxidative phosphorylation metabolic pathway; the final metabolic pathway of aerobic respiration. During one of the dehydrogenation reactions in the citric acid cycle, succinate is oxidised to fumarate by succinate dehydrogenase and the side reaction of this reaction reduces the hydrogen acceptor FAD to FADH2. Succinate dehydrogenase is an enzyme which highly links to oxidative phosphorylation and the 2 of the electrons from FADH2 are directly carried to the succinate dehydrogenase. The succinate dehydrogenase is then able to transfer these electrons to a coenzyme known as ubiquinone (or sometimes known as coenzyme Q) which is an important coenzyme in the final step of aerobic respiration- oxidative phosphorylation. When the electrons are transferred to ubiquinone, a coenzyme in the electron transport chain, there is a free energy change which allows H+ ions to be pumped out of the mitochondrial matrix and into the intermembrane space. This pumping of protons means that there is a large proton-concentration gradient which provides a significant amount of energy for the production of ATP. After this, the electrons can be carried to the Q-cytochrome C oxidoreductase complex. The citric acid cycle is known as an amphibolic pathway, meaning that is both catabolic (when substances are broken down for energy) and anabolic (the formation of substances needed for bodily functions). An example of a catabolic reaction in the citric acid cycle is the multi-step conversion of D-isocitrate to alpha ketoglutarate and finally to succinyl-CoA. Whilst D-isocitrate is converted to alpha ketoglutarate by oxidative decarboxylation, NAD+ is reduced to NADH (and CO2 is formed as a side product). The NADH formed has high electron transfer potential and this is transferred to the phosphoryl transfer potential of ATP. In another oxidative decarboxylation reaction, alpha ketoglutarate is converted into succinyl-CoA, catalysed by a-ketoglutarate dehydrogenase complex. This reaction also forms NADH which can be transferred to the electron transfer chain to eventually from ATP.The citric acid cycle also has anabolic reactions such as the reaction of oxaloacetate and acetate catalysed by citrate synthase which results in the products citrate and citryl CoA. The citrate produced in this condensation reaction is hugely important in regulating the metabolism (synthesis and degradation) of fatty acids. The citrate produced can stimulate an enzyme called acetyl CoA carboxylase, which is the main enzyme in the regulation of fatty acids. Fatty acids are synthesised by a reaction between acetyl CoA and NADPH. The importance of the citrate is that the level of citrate is only high if the levels of both acetyl CoA and ATP are high and in turn, this means that acetyl CoA carboxylase, the enzyme which stimulates the metabolism (including synthesis) of fatty acids can only be stimulated if there’s a high enough level of citrate. This means that the more acetyl CoA (and ATP) present, the higher the level of citrate and therefore there is more regulation of fatty acid metabolism and so more fatty acid synthesis. Acetyl CoA carboxylase can be inhibited by AMP activated kinase and this would mean that there would be less regulation of fatty acid metabolism and so less fatty acids would be synthesised. Citrate is important because it is able to transfer a phosphate group to acetyl CoA carboxylate which massively decreases the levels of inhibition and therefore there will be more regulation of fatty acid metabolism and so the rate of fatty acid synthesis will increase. Alpha ketoglutarate is an anabolic intermediate in the citric acid cycle. It can be converted to amino acids such as proline and glutamate via a series of long processes. For example, alpha ketoglutarate can be converted to glutamate by an amination reaction. This glutamate can then be converted to proline by 2 reduction reactions involving intermediates like the gamma-carboxyl group of glutamate, aryl phosphate, NADPH and glutamic gamma-semialdehyde. However, the alpha ketoglutarate must be replaced so that these reactions can continue to occur so that more amino acids are made. To replace the alpha ketoglutarate, there is an oxidative deamination reaction in which glutamate is oxidatively deaminated using an enzyme known as glutamate dehydrogenase which ultimately results in the production of alpha ketoglutarate so it can be constantly replaced when needed in the citric acid cycle.Throughout the citric acid cycle, there are many intermediates that are removed from the cycle for biosynthesis (for example, some amino acids such as proline, glutamine and aspartate are generated from intermediates such as oxaloacetate and alpha ketoglutarate- this is also another example of an anabolic reaction of the citric acid cycle) and it is important that these intermediates are replaced so that the citric acid cycle can continue and so that these important biosynthetic processes can continue. Oxaloacetate is a molecule which can be used to generate important substances for bodily functions such as amino acids, glucose, purines and pyrimidines by a process called transamination, which then leads to protein synthesis (an anabolic function of the citric acid cycle). However, if the levels of oxaloacetate drop below a certain level, the citric acid cycle will stop functioning. This would mean that so NADH would be generated so oxidative phosphorylation could not take place which means that no ATP would be produced and a lot of important processes in the body could not take place. Therefore, it is very important that the level of oxaloacetate is maintained. The level can be maintained by a carboxylation reaction catalysed by pyruvate carboxylase in which carbon dioxide attaches to pyruvate and ATP is hydrolysed by using H2O which generates oxaloacetate as well as ADP, an inorganic phosphate molecule and 2H+ . However, it is important that the oxaloacetate is only replenished when the concentration of ATP is low. When the ATP concentration is high, no more oxaloacetate needs to be generated and it can be used in other biosynthetic pathways to make amino acids, purines, glucose, pyrimidines and more. ConclusionIn conclusion, it’s certain the citric acid cycle is the hub of the metabolic wheel. Without the citric acid cycle, many processes and pathways would be significantly impacted. Firstly, without the citric acid cycle, no FADH2 or NADH could be generated which would ultimately result in a huge reduction of ATP production because only the anaerobic process of glycolysis would produce any ATP. Furthermore, if there was inhibition of the citric acid cycle, the catabolic and anabolic functions would be severely impacted; the anabolic reactions which lead to major biosynthetic pathways wouldn’t happen and so important bodily processes such as protein synthesis could not occur. The catabolic functions would also be impacted because less substances could be broken down to release energy and so there would be less energy for the multiple processes and pathways in the body that need energy. It cannot be denied that citric acid cycle is the hub of the metabolic wheel. It is needed for making amino acids, protein synthesis, ATP production by oxidative phosphorylation, regulation of fatty acid metabolism and many other processes and biosynthetic pathways and without it, eukaryotic life would not be the same. References