Metabolic Processes: Regulation and Malfunction
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Metabolism is many coordinated chemical reactions occurring within a cell of an organism to sustain life (Berg et al. 2006). Obtaining nutrients, generating wastes, growing, reproducing, adapting to different environments are all chemical processes that occur in a human body to maintain a living state (Deborah, 2009). Many specific enzymes catalyse different chemical reactions in a metabolic pathway. Metabolic pathways are irreversible however; the reaction can be reversed by another pathway or an enzyme (Berg et al. 2006). For example, the glycolytic pathway can be reversed by gluconeogenesis.
Metabolic pathways can be separated into catabolic, anabolic and amphibolic reactions. Catabolism breaks down complex molecules like proteins and lipids into smaller and simpler molecules like amino acids and fatty acids; this reaction releases chemical energy, adenosine tri-phosphate (ATP) and reduced electron carriers NADH, NADPH and FADH2 (David & Michael, 2005). These cofactors are important in metabolism as they are recycled by oxidative phosphorylation and reused by the glycolysis and the TCA cycle. An example of catabolic reaction can include oxidation of glucose during aerobic respiration; glycolysis, breakdown of glucose to pyruvate acid (Joyce, 2007). Anabolic reactions require energy which is obtained from the chemical energy produced in the catabolic process. The energy is used for maintenance and growth of the cell. Small, precursor molecules like monosaccharides, amino acids and nucleotides synthesise into macromolecules like polysaccharides, proteins and nucleic acids. Example of anabolic pathway can include, gluconeogenesis, a builds up a molecule of glucose from pyruvate (David & Michael, 2005). Both catabolic and anabolic pathways together are referred to as amphibolic reaction e.g. the TCA cycle, which involves in both the breakdown and synthesis of molecules (Berg et al. 2006).
Regulation in metabolic pathways is essential to maintain a steady balance within the cell, i.e. homeostasis, controlling the flow intermediates through pathways, conserving energy, preventing excess products being made and exhaustion of substrates and/ or substrate cycles (William & Daphne, 2005). There are many ways in which metabolic regulation is carried out. A number of these processes are incorporated in metabolism.
Enzymes play a huge role in regulation of metabolic pathways. Controlling the amount of enzymes and amending the rate of synthesis coordinates the activity in the cell, increasing or decreasing the catalytic activity is stimulated by certain signals (L. Roux, 2010). Allosteric regulation is when a molecule attaches itself at a site on the enzyme other than the active site, changing enzymes activity as shown in figure 1. An allosteric regulator either increases the enzymes activity, known as allosteric activators, or either decreases the enzymes activity, called allosteric inhibitors (David & Michael, 2005). Zymogens also help regulate enzymes activity; they are produced in an inactive form and when this enzyme is required it is transformed into an active form, using proteolysis for this conversion. Zymogens are found inactive in the digestive tract until they are required for digesting; this prevents damage to the stomach (Berg et al. 2006). Deficiency of a proteolytic enzyme, can lead to many problems such as alkaline excess in blood which can cause anxiety (Enzyme Essentials, 2006).
Regulation of pathways by Feedback inhibition. The inhibitor is the product made from the reaction further on, in the pathway. When the product builds up, it feeds back into the process, inhibiting the enzymes activity which is involved in its synthesis. Once the product level decreases, the pathway begins again. Feedback inhibition prevents excess product being made (William & Daphne, 2005).
Committed steps are also very unique in regulating the pathways. They occur early on in the pathway, which ensures that the rest of the pathway takes place (Bryant Miles, 2003).
Regulation of metabolism can take place in different compartments in the cell, e.g. in a eukaryotic cell. Compartmentalisation helps to organise diverse or opposing metabolic pathways to take place e.g. mitochondria, in the matrix the TCA cycle takes place and in the inner membrane of the mitochondria the electron transport chain pathway occurs (Bryant Miles, 2003).
Glycolysis Regulation and Malfunction
Glycolysis is the breakdown of six carbon sugar, glucose, to two molecules of pyruvate and energy (Regina, 10 Steps of Glycolysis). The ATP energy produced from glycolysis can be used in many different pathways e.g. the red blood cells require energy as they do not have mitochondria, to produce energy. This catabolic pathway can occur in both aerobic and anaerobic conditions (fermentation). It is the first stage of cellular respiration. In glycolysis there are ten steps in which only three steps are regulatory steps as shown in figure 2. There are only three key enzymes, which are important in regulating the flow of intermediates throughout the pathway (Joyce, 2007).
Enzyme hexokinase, catalyses the first regulatory step in the glycolytic pathway. This enzyme helps trap the glucose molecule inside the cell by phosphorylation using ATP, making the glucose more chemically reactive (Berg et al. 2006). The reaction is activated by high levels of ADP. The reaction is inhibited high levels of the product produced, glucose-6-phosphate and high ATP (Joyce, 2007).
Enzyme phosphofructokinase is the second unique pacemaker in the glycolytic pathway- controls the rate of the reaction. It converts fructose 6-phospate to fructose 1, 6-biphosphate. This third reaction is a unique, irreversible reaction. Phosphofrucktokinase is activated by two allosteric activators AMP and F,2,6 biphosphate when cellular energy is limited, overcoming the inhibitory effect of ATP. The ATP and AMP both compete for the PFK enzymes allosteric effector site and therefore, a high level of AMP activates the pathway. The enzyme is allosterically inhibited by high ATP concentrations, high NADH and citrate; these inhibitors slow down the rate of degradation of glucose, which can then be stored as glycogen (Joyce, 2007).
Pyruvate kinase is the last regulatory step in glycolysis; it converts phosphoenolpyruvate to pyruvate, the main product of glycolysis, which is then metabolised to acetyl-CoA (pyruvate dehydrogenase reaction) to be used as an intermediate in the TCA cycle. This enzyme is regulated by allosteric effectors and by covalent modification (phosphorylation). The enzyme, pyruvate kinase, activity is enhanced by F,1,6 biphosphate and inhibited by high ATP concentrations.
Glycolytic malfunctions are very uncommon as the regulations of intermediates are efficient in maintaining the pathway. However, a deficiency of a certain enzyme in the glycolytic pathway causes many mutations. A pyruvate kinase deficiency is usually recessively inherited disorder. This enzyme is important for red blood cells; a lack of this enzyme would result in haemolytic anaemia (Chad, 2010). Tarui disease is a phosphofructokinase deficiency in the metabolic pathway. It is a glycogen storage disease (GSD) type VII as shown in figure 3. There are eight different types of GSds; deficiencies of different enzymes (Wayne, 2010). In type VII deficiency, breakdown of glycogen to glucose (glycolysis) for energy cannot take place in during exercise, increasing the levels of G-6-P in muscles; which then results in muscle pain, fatigue (The Association for Glycogen Storage Disease, 2010).
Gluconeogenesis Regulation and Malfunction
Gluconeogenesis is an anabolic pathway, the production of glucose from non carbohydrate precursor such as: pyruvate (product from the glycolytic pathway). This pathway occurs when there is an insufficient level of glucose in our body. Degradation of glycogen occurs. Glucose is an important molecule for producing energy. However, limited ATP energy is produced by glycolysis and therefore, glucose needs to be consumed in the diet. Gluconeogenesis is a very costly process, it uses a lot of energy: four molecules of ATP, two molecules of GTP and two molecules of NADH. This pathway works in the opposite direction of glycolysis; it produces glucose rather than breaking it down. However, it is not entirely a reverse of glycolysis, due to the irreversible steps as shown in figure 4. The intermediates are all the same in both pathways except, oxaloacetate; a unique intermediate to gluconeogenesis. There are also four unique enzymes used to bypass the irreversible steps 1, 3 and 10 of glycolysis, these are: pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1, 6-biphosphatase and glucose-6-phosphatase (Joyce, 2007).
First step in gluconeogenesis occurs in the mitochondria, converts pyruvate to oxaloacetate (OAA) by pyruvate carboxylase, this enzyme requires biotin as a cofactor. OAA is used as a precursor in the TCA cycle. A deficiency of this enzyme is very rare; however, it can cause many problems in metabolism such as: hypoglycemia especially during times of prolonged fasting, without oxaloacetate this pathway cannot carry on (Richard, 2009). Hypoglycemia is having low glucose levels in blood. The red blood cells and the brain are dependent on glucose for energy. As the pathway cannot proceed on with this gluconeogenesis or the TCA cycle, the energy is taken from glycolysis. Therefore, it results in deficiency of glucose (Richard, 2009).
Phosphoenolpyruvate carboxykinase (PEPCK) is the second unique enzyme which converts OAA to phosphoenolpyruvate. This step also requires energy from ATP to decarboxylate the OAA to PEP. Fructose 1, 6-biphosphatase converts fructose 1, 6-biphosphate to fructose-6-phospate. This step bypasses the irreversible step three in glycolysis. Glucose-6-phosphatase the fourth and final unique step; converts G-6-P to glucose, the first irreversible step of glycolysis. However, this enzyme is not present in all tissues; it is present in the liver- tissues which can affect the blood glucose homeostasis. So, the gluconeogenesis pathway stops at G-6-P (Joyce, 2007).
Hormonal regulation action
In glycolysis and gluconeogenesis, hormones (glucagon and insulin) regulate pathways at points where different enzymes are used. As shown in figure 5, glucagon is secreted by alpha cells of the pancreas into the bloodstream when there is a decrease in blood glucose level (James, 2010), stimulating gluconeogenesis by increasing the enzyme PEPCK and inhibiting pyruvate kinase in glycolysis (enhancing release of glucose from glycogen) This hormonal regulation prevents hypoglycemia (Eric & Tony, 2009). Insulin is secreted from the beta cells of pancreas, when blood glucose levels are high (James, 2010). Therefore, gluconeogenesis is inhibited by reducing the enzyme PEP carboxykinase and glycolysis pathway is stimulated by activating pyruvate kinase (converting glucose into glycogen). This hormonal regulation prevents hyperglycemia (Eric & Tony, 2009).
Malfunction of blood glucose regulation can cause many diseases. Examples for high glucose levels: diabetes mellitus (type I insulin-dependent and type II non-insulin dependent), liver disease and hyperthyroidism. Examples of low glucose levels: hypothyroidism and hyperinsulinism. Diabetes is a common failure of metabolism regulation. However, it can lead to serious complications if not controlled (Izak, 2001).
In conclusion, it is very important for metabolic pathways to be coordinated; to make sure that organism maintains life by performing efficiently and effectively. There are several different ways in which metabolic processes are regulated: different types of enzymes play a huge role in regulation of pathways, allosteric regulators either increase or decrease the rate of reactions. Feedback inhibition prevents excess product being made and committed steps in pathways, ensures that the rest of the pathway takes place. However, there are many consequences, health problems, if the organism's regulation malfunctions. Without metabolism, organisms would not be alive.
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