Abstract considered to the ‘hub’ of the wheel. A

Abstract The citric acid cycle, also known as the Krebs cycle or tricarboxylic acid cycle, is central to the formation of usable energy forms in cells. This essay will give detail on how this is achieved and the cycle’s links to other metabolic pathways such as oxidative phosphorylation. It will also explore how the cycle functions in anabolic and catabolic forms while replenishing used intermediates before examining how the cycle is regulated.Introduction The citric acid cycle being named “the hub of the metabolic wheel” is testament to its importance within the cell and within the organism. Andreas (1) described the fact that because its of such importance that it is logical to assume that it was one of the first components of the cell metabolism to be established. The oxidation of fuel molecules means that they lose one of their electrons. This is the main role of the citric acid cycle; to harvest the electrons from fuel molecules. This allows the fuels to be used by the body to produce energy in the form of ATP. The cycle also acts to provide a ‘carbon skeleton’ for biosynthesis due to its supply of precursors for more complex molecules. The citric acid cycle is part of a complex chain of processes which allow the cell to produce ATP. For instance, the citrate cycle is preempted by glycolysis (via the pyruvate dehydrogenase complex) and is followed by oxidative phosphorylation. Although, the citrate acid cycle is of such importance that it is individually considered to the ‘hub’ of the wheel. A background description of the citric acid cycleAs previously mentioned, the main role of the citric acid cycle is to obtain electrons from carbon fuel molecules. This is done through a series of reactions which aims to regenerate oxaloacetate for the prolonged continuation of the cycle. Acetyl coenzyme A (acetyl coA) is the input to start the cycle and is derived from glycolysis but first has to go through an intermediate stage, sometimes called the ‘link reaction’ which uses the pyruvate dehydrogenase complex. Pyruvate, the product of glycolysis, releases CO2 and 2 electrons to form acetyl coA which can then enter the cycle. Glycolysis takes place in the cytoplasm of the cell while the citric acid cycle occurs in the mitochondria, specifically the mitochondrial matrix.As pyruvate, a two carbon compound, enters the cycle it reacts with oxaloacetate to form a six carbon compound. After this, the six carbon compound undergoes two decarboxylation reactions, producing a molecule of CO2 and NADH each time. This produces a new four carbon compound. This four carbon compound is further reacted to reform oxaloacetate which allows the cycle to begin again. During this stage, a single molecule of ATP, FADH2 and a further molecule of NADH are all produced. How the citric acid cycle links to oxidative phosphorylation The citric acid cycle produces just one molecule of ATP with each ‘turn’, it insteads converts NAD to NADH and FAD to FADH2. This is done by using electrons to reduce the two molecules. The reason for this is to allow the reduced NAD and reduced FAD to then be used in the next stage of ATP production, oxidative phosphorylation. When these are oxidised again, the electrons are transferred to oxygen and are then able to flow through the electron transport chain causing a proton gradient to form. This gradient is then used to drive ATP synthesis using ATP synthase with the help of the enzyme ATPase, to form ATP from ADP and inorganic phosphate (Pi). This is by far the main source of ATP in eukaryotes and makes up 90% of ATP available to humans. Catabolic and anabolic function of the citric acid cycleThe citric acid cycle plays a hugely significant role and almost all metabolic pathways are connected to the cycle (2). This means that the cycle has roles in both catabolic and anabolic reactions. A catabolic reaction is one that releases energy by breaking a compound down where as an anabolic reaction uses energy to ‘build’ compounds.  This means that the cycle is known as an amphibolic pathway (3).The cycle previously described of regenerating oxaloacetate is one which contains several stages involving the breakdown of certain compounds forming catabolic reactions. The breakdown of the six carbon compound, citrate, formed by oxaloacetate and coA is an example of this. The reduction of NAD and FAD (to NADH and FADH2) is coupled by the reduction of the six carbon compound and intermediates. The citrate and its intermediates are also decarboxylated to release two molecules of CO2. This is eventually exhaled from the body as waste material. However, the citric acid cycle also has a role in the building of certain compounds and ‘materials’ needed in the eukaryote giving it an anabolic function as well as its catabolic roles. The cycle can build a carbon skeleton for biosynthesis by providing the necessary biosynthetic precursors. The points at which the intermediates of the cycle are removed in order to make up these precursors is shown by Figure 1. The figure demonstrates that the anabolic role of the citric acid cycle is extensive, with precursors being formed for such a wide variety of substances that a given eukaryote needs such as amino acids, fatty acids and chlorophyll. The intermediates from all stages of the cycle can be used but only when the cell has received all the energy that it needs. This is prioritised over the formation of biosynthetic precursors. The intermediates form vital early stages of the substances shown in Figure 1 and are therefore very important to the eukaryote as a whole. The drawing off of these intermediates can leave the cycle diminished and unable to carry out its primary function of extracting electrons from carbon fuel sources. The low levels of oxaloacetate means that even though it is naturally recycled, the cycle can’t continue as the ‘threshold’ level is not being met. Subsequently, the intermediates must be replenished for the cycle to continue. This is done by converting pyruvate from glycolysis directly into oxaloacetate. This allows acetyl coA to enter and start the cycle by combining with the four carbon compound. The conversion is done through a carboxylation reaction and is catalysed by a specific enzyme called pyruvate carboxylase. This reaction is shown at the top of Figure 1 (indicated by the green arrow). It is also worth mentioning that because of its cyclical nature, any of the intermediates can be replaced when too much is used up in other reactions. Control of the citric acid cycle As the citric acid cycle is so integral to the proper functioning of the cell and eukaryote as a whole, the pathway must be stringently regulated for the cell to continue as normal. Firstly, the cycle can only occur under aerobic conditions (ie when oxygen is readily available). This is because after the NAD and FAD molecules are reduced to become NADH and FADH2, they have to transfer the electrons to oxygen which is known as the final electron acceptor. This allows the next stage in ATP production, oxidative phosphorylation to occur, as previously described. Without the presence of oxygen this transfer cannot occur so the NAD and FAD molecules cannot be reused in the citric acid cycle. The citric acid cycle is also controlled by the level of exercise undertaken by the cell. Pyruvate dehydrogenase, involved in the conversion of pyruvate to acetyl coA is inhibited by the presence of ATP but its activity increases when high volumes of ADP and Pi are present. If strenuous activity is being undertaken then there will be  shortage of ATP and an excess of ADP and Pi leading to greater pyruvate dehydrogenase activity and an increase in input to the citric acid cycle. The cycle is also regulated by two enzymes within the cycle called isocitrate dehydrogenase and-Ketoglutarate dehydrogenase. These allow for further control over the activity of the cycle. ConclusionThe citric acid cycle is, in terms of energy supply, the most important metabolic pathway (2). It has both catabolic and anabolic functions, helping it to oxidise fuel molecules and provide a carbon skeleton for biosynthesis, respectively. The cycle is a series of reactions aiming to allow the aerobic conversion of carbon fuel molecules to usable ATP. The cycle can be controlled and regulated through various processes and has such a vital role that it is rightly considered the ‘hub of the metabolic wheel’.Bibliography Wagner, A., (2014). Arrival of the Fittest (first ed.). New York: Penguin Group. p. 100Akram M., (2014). Citric acid cycle and role of its intermediates in metabolism.                                        Baldwin, J. E., & Krebs, H. (1981). The evaluation of metabolic cycle. Nature, 292, 291–381.   General reference resources extensively usedStryer L., Gatto G., Tymoczko J., Berg J.,  (2015). Biochemistry, 8th edition, WH Freeman. Chapter 17, p 495-522