Metabolic Biochemistry - Metabolic Significance of Malonyl-Coa - Assignment Example

Metabolic Biochemistry Name Institution 1-What is the metabolic significance of malonyl-CoA? Why? The metabolic significance of malonyl-CoA is that it aids in oxidation of cardiac fatty acids. Apart from aiding in oxidation of fatty acids, malonyl-CoA also regulates the intake of food into the body. Increased malonyl-CoA inhibits the intake of fatty acids into the body. The two metabolic roles are significance because of a number of reasons. The first is obesity (Nelson, D. LCox & Lehninger, 2013). Increased fatty acids intake results to body weight. Unchecked fatty acids intake without enough oxidation leads of the accumulation of the fatty into the adipose tissues in the body and this can lead to obesity. Obesity is normally a prerequisite to many heart problems. Obesity is a crucial contributor in the development of diabetes, insulin resistance and heart disease. Accumulation of fatty acids in the heart vessels is also a health risk as it leads to a number of complications which include high blood pressure. The health risks involved with high intake of fatty acids into the body makes the metabolic role of malonyl-CoA in the body significant. 2-. It has been stated that fatty acids cannot yield a net gain in carbohydrates during beta oxidation. Why can fatty acid with an odd number of carbon atoms be considered to break this rule, to certain extent? The oxidation of fatty acids with an odd number of carbons is similar to the oxidation of fatty acids with even number of carbons. However, unlike the even-numbered fatty acids, the final products for odd-numbered fatty acids are acetyl-CoA and propionyl-CoA. Propionyl-CoA is first carboxylated into D-stereoisomer of methylmalonyl-CoA using a bicarbonate ion (Lennarz & Lane, 2013). This reaction involves ATP, a biotin co-factor, and propionyl-CoA carboxylase enzyme. The carbon from the bicarbonate ion is added to propionyl-CoA’s middle carbon leading to the formation of D-methylmalonyl-CoA. The D conformation is however enzymatically altered to the L conformation. This is done by methylmalonyl-CoA epimerase enzyme. The L conformation then undergoes intermolecular rearrangement to form succinyl-CoA. This process is catalysed by methlymalonyl-CoA mutase. Succinyl-CoA then enters the citric acid cycle. Unlike acetyl-CoA which goes into the citric acid cycle through merging with an existing oxaloacetate molecule, succinyl-CoA goes into the cycle independently. This makes it to add to the population of molecules in the cycle. Some of the intermediates in the citric acid cycle are extracted and converted to glucose. This makes odd-numbered fatty acids to yield a net gain in carbohydrates during beta oxidation. 3- Although 40-50% of the RNA being synthesised in bacterial cells at any given time is messenger RNA (mRNA), only about 3% of the total RNA in the cell in mRNA. Explain this seeming paradox. Despite a large proportion of RNA synthesized in bacterial cells is mRNA, the percentage of mRNA is about 3% only. The reason for this seeming paradox is degradation of messenger RNA. The messenger RNA is normally removed from the cellular circulation by the cellular RNA degradation machinery (McGavock, 2005). The time taken before a messenger RNA is removed from the cellular circulation depends on stabilizing or destabilizing structural characteristics or features of RNA. The degradation of the messenger RNA can also caused by changing environmental parameters. The degradation of the messenger RNA depending on the changes in the environment is part of the strategy used by bacteria to respond quickly to the changing environmental parameters. The messenger RNA present in the bacterial cell therefore degrades or is removed in order to allow other new messengers with information that is meant to adapt the bacteria to the new changes in the environment to enter the bacterial cell. The rapid degradation of messenger RNA therefore accounts for the low proportion of these cells in the bacterial cells. 4- Describe some of the metabolic differences between heart, liver, and adipose tissue. There are a number of metabolic differences between the heart, liver and adipose tissue. The heart muscles, for instance, function aerobically. The heart has practically no glycogen reserves. Its fuel of choice is fatty acids. Other sources of fuel for the heart include ketone bodies, glucose and lactate. The main metabolic function of adipose tissue us storage of triacylglyocerols and the release of fatty acids when they are needed. Fatty acid synthesized in the liver are normally esterified with glycerol to triacyclglycerols and transported to the adipose tissue. The adipose then stores the triacylglyocerols pending their use in the body (Lennarz & Lane, 2013). The liver is the main organ where metabolism occurs in an organism. It maintains the level of blood glucose as well as regulating the concentration of blood metabolites. The liver stores glucose in form of glycogen to be used when need arises. It also synthesizes fatty acids, bile salts and cholesterol. 5- Although oxygen does not participate directly in the Kerbs cycle, this cycle operates only when oxygen is present. Why? The Krebs cycle is part of an intricate multi-step process known as cellular respiration. Some of the parts of this process require the use of oxygen. The main parts of the cellular respiration process are glycolysis and Krebs cycle. Glycolysis precedes Krebs cycle and this process requires the use of oxygen. This process takes place in the cell’s cytoplasm. The process needs to use two ATP molecules (Tropp, 2012). During the oxidation of glucose, where glucose is broken down to three-carbon sugar molecules, two NADH and four ATP molecules are created. NADH and the three-carbon sugar, otherwise known as pyruvate, are taken to the Krebs cycle in order to create more ATP. Absence of oxygen in the glycolysis process prevents pyruvate from entering the Krebs cycle. Instead, it is oxidized to produce lactic (Lennarz & Lane, 2013). Since the Krebs cycle cannot take place without pyruvate, oxygen is necessary at the glycolysis stage to ensure that pyruvate is availed to the Krebs cycle. This therefore makes oxygen necessary in the Krebs cycle. 6- Describe how pharmacogenomics may be applied to modern medicine. Pharmacogenomics can be used in the development of drugs. Pharmacogenomics is involved with studying about individuals respond to drugs. While studying the action of drugs in individuals, researchers in this field focus on two main determinants. The first determinant is the amount of a drug that is needed to reach a certain target in the body. The second determinant is how well the target cells such as neurons or heart tissue respond to the drug (McGavock, 2005). The field looks at how different genes respond to different drugs. Information can be helpful in the medical field in the sense that it helps in making clinical decisions in terms of the type of medicine to use on a patient or the dosage to be used, and whether there is need to adjust the dosage for different individuals in order to enhance their response to the drug. Information from this field can also help in the development of drug safety measures. 7- By careful surgery, it is possible to connect the circulatory systems of two mice so that the same blood circulates through both animals. In these so called parabiotic mice, products released into the blood by one animal reach the other animal by the shared circulation. Both animals are free to eat independently. When an ob/ob mouse (both copies of the OB gene are defective) and a normal OB/OB mouse are made parabiotic, what will happen to the weight of each mouse? The mutant ob/ob mouse is obese. This is because its body does not produce functional leptin which signals it to eat less as well as be more physically active since the OB genes are defective. However, when the circulatory system of the ob/ob mouse is connected to the circulatory system of the normal (OB/OB) mouse, the leptin that is produced in the body of the normal mouse, which helps eat to eat normally and be active physically, gets to the hypothalamus of the ob/ob (obese) mouse (Nelson, Cox & Lehninger, 2013). This will trigger the ‘eat less’ response in this mouse which will make it to lose weight. For the normal (OB/OB) mouse, it will maintain its normal weight because it has adequate leptin in its blood to continually trigger the ‘eat less’ response. This will allow it to retain its normal weight as well as avoid becoming obese because of its regulated eating as well as physical activity. 8- The average person with a computer linked to the internet receives hundreds of spam e-mails for all kinds of pills and potions guaranteed to enlarge, shrink or rejuvenate various anatomical or biochemical entities. Among this spam, one can find offers for human growth hormone pills guaranteed to make one young again. Why is this unlikely? The human growth hormone pills are unlikely to make one young again. The main reason as to why this is unlikely is because hormone growth hormones cannot be absorbed when taken through the mouth. This means that the hormones will not reach the necessary body organs the initiate the desired growth or effect (Nelson, Cox & Lehninger, 2013). Normally, growth hormones in human beings are produced by the pituitary glands. These hormones are then injected into the bloodstream where they are taken to the liver. The liver converts these hormones into growth factors, which are then used by the body to initiate growth of the different parts. Although they are produced naturally by the body, their production declines with age. This has led to the development of artificial growth hormones that are injected into the growth to induce growth (McGavock, 2005). The inability of growth hormones to be absorbed into the body through the mouth means that one is unlikely to experience the desired growth by using growth hormone pills. 9- When radioactivity-labelled [14-C]-glucose is added to the balanced diet of adult rats, there is no increase in the total amount of stored triacylglycerol’s, but the triacylglycerol’s become radioactivity labelled with 14-C. Explain. Radioactivity-labelled glucose added to the balance diet of adults does not increase the total amount of stored triacylglycerols. This is because radioactivity-labelled glucose is not metabolized once it has been taken up by the cells. When radioactivity-labelled glucose is taken up by the cells in the body of the rats, it is phosphorylated (Tropp, 2012). This process prevents from further metabolism that leads to formation of triacylglycerols. In addition, after being phosphorylated, the glucose is trapped into the cells. Triacylglycerols become radioactivity labelled with 14-C because of the presence of radioactivity labelled glucose in the cells. Since the glucose is trapped in the cells, triacylglycerols in the cells get contaminated with with 14-C therefore resulting to the labelling. The inability of the radioactivity labelled glucose to be metabolized into triacylglycerols explains why there is no increase in the amount of triacylglycerols after radioactivity labelled glucose is added to the diet (Nelson, Cox & Lehninger, 2013). The trapping of the glucose in the cells, on the other hand, explains why triacylglycerols in the cells is labelled with 14-C. 10- Some microorganisms of the genera Nocardia and Pseudomonas can grow in an environment where hydrocarbons are the sole source of food. These bacteria oxidise straight-chain hydrocarbons, such as octane, to their corresponding carboxylic acids: Octane + NAD + oxygen octanoic acid + NADH How can these bacteria be used to clean up oil spills? What might be a limiting factor to the efficiency of this process? These microorganisms are able to grow in an environment that has hydrocarbons only as the source of food. This is because the microorganisms oxidize hydrocarbons to fatty acids. They then use the fatty acids generated through the oxidization as a source of energy. This is also done through the oxidation process where the fatty acids are converted to carbon IV oxide, water and energy in form of ATP (Tropp, 2012). The ability of the microorganisms to break down hydrocarbons to fatty makes it theoretically possible for them to be used to clean up oil spills. This is because oil is basically a hydrocarbon and treatment of oil spills with the microorganisms can clean them through breaking them to fatty acids. The limiting factor to the efficiency of this process is the extremely high hydrophobicity of hydrocarbons. This makes it difficult to achieve close contact between the bacterial enzymes and the substrate making the process hard to achieve. 11- Cells of E. coli are growing in a medium containing lactose as the sole carbon source. Indicate whether each of the following changes would increase, decrease or not change the expression of the lac operation, and why: a) Addition of a high concentration of glucose. Addition of high concentration of glucose reduces the lac operation. This is because increase in glucose leads to a reduction in eAMP. An eAMP-CRP complex is needed in order to strongly bind the RNA polymerase to the lac promoter (Nelson, Cox & Lehninger, 2013). The reduction of eAMP due to increased concentration of glucose therefore reduces the expression of lac operation. b) A mutation that prevents dissociation of the lac repressor from the operator. A mutation that prevents dissociation of the lac repressor from the operator reduces the expression of the lac operation (McGavock, 2005). This is because a repressor which binds permanently to the lac operator prevents the binding of RNA polymerase. This therefore prevents the expression of the lac operation. c) A mutation that completely inactivates beta-galactosidase. A mutation that completes inactivates beta-galactosidase reduces the expression of lac operation. This is because if beta-galactosidase is inactivated, lactose is not converted to allolactose (McGavock, 2005). This means that the normal inducer of lac operation is absent hence the expression of lac operation reduces. d) d) A mutation that prevents binding of CAP to its near-the-lac promoter A mutation that prevents the binding of CAP to its near the lac promoter reduces the expression of lac operation. This is because the presence of eAMP, CRP binds to a spot close to the lac promoter and considerably improves transcription of the operation through steadying the open complex of RNA polymerase (McGavock, 2005). Therefore, mutations that hinder the binding of the CRP to DNA reduce the expression of lac operation. 12- The death cap mushroom, Amanita phalloides, contains several dangerous substances, including the lethal alpha-amanitin. This toxin blocks RNA elongation in people who have consumed the mushroom by binding to eukaryotic RNA polymerase II with very high affinity. It is deadly in distress (caused by some of the other toxins). These symptoms disappear, but about 48 hours later, the mushroom-eater dies, usually from liver dysfunction. Speculate as to why it takes this long for alpha amanitin to kill. During the alpha amanitin poisoning, alpha amanitin penetrates pore 1 and start regulating translocation. In this regulation, it stops elongation. The binding of the alpha to pore does not, however, affect NTP loading in the active site. This is because NTP is located far away from the active site (Tropp, 2012). Alpha aminitin prevents translocation through preventing the flexing of the bridge helix to allow the DNA movement. The inhibition of alpha amanitin depends with its association with RNAPII. In some cases, RNAPII and alpha amanitin form a single phosphosdiester. In other cases, multiple phosphodiester bonds form. This allows for elongation to take place albeit at a highly reduced rate. The ability of elongation taking place despite the presence of alpha amanitin due to the formation of multiple bonds explains why it takes long to kill. This is because provided elongation is taking place, normal body functions will take place and this prolongs the poisoning effect of alpha amanitin. 13- Pharmacogenomics, the study of how genetic variation influences drug metabolism, is a rapidly expanding area of modern molecular biology. However, the enzymes which govern drug metabolism often operate by the same principle of induction, seen in microbial systems. Illustrate how this might be so, using examples that you have encountered in this subject. Enzyme induction is normally mediated by the binding of a chemical activator to a CYP isozyme intracellular receptor, eventually generating increased CYP genes transcription. This ligand-activated transcription leads to translation of mRNA resulting to increased CYP protein synthesis. All CYP isozymes do not respond equally to a certain inducer (Lennarz & Lane, 2013). Exposure of CYP isozymes to a chemical activator can lead to increased induction in some CYP isozymes and not in others. Although there are differences in terms of the extent of induction for different CYP isozymes, there are familiar cellular signalling mechanisms in all induction processes. Generally, enzyme induction involves the activation of receptor transcription factors like constitutive androstane receptor, pregnane X receptor, and aryl hydrocarbon receptor. All these processes are similar in all enzyme induction activities. 14-Acetyl-CoA carboxylate is the principal regulatory enzyme of fatty acid biosynthesis. It adds a molecule of carbon dioxide to acetyl-CoA to produce malonyl-CoA. Two properties of the enzyme are as follows: a) The addition of citrate or isocitrate raises the Vmax of the enzyme by as much as a factor of 10. b) The enzyme exists in two interconvertible forms that differ markedly in their activities: Protomer (inactive)  filamentous polymer (active) Citrate and isocitrate bind preferentially to the filamentous form, and palmitoyl-CoA binds preferentially to the protomer. Explain how these properties are consistent with the regulatory role of acetyl-CoA in the biosynthesis of fatty acids. Acetyl CoA carboxylate plays a crucial role in regulation of degradation of fatty acids. Malonyl CoA which is a product of carboxylase reaction is normally present in high levels when fuel molecules are plentiful. Malonyl CoA prevents entry of fatty acetyl CoA to mitochondria matrix through inhibiting carnitine acyltransferase I when it is abundant. Malonyl CoA is an effective inhibitor of carnitine acyltransferase I especially in muscle and heart muscles which have a small fatty synthesis capacity (Lammert & Zeeb, 2014). The inhibitory effect of malonyl CoA makes it necessary for acetyl CoA carboxlate to have the two mentioned properties in order to cancel out the inhibitive effect of malonyl CoA. Raising the Vmax of the enzyme to a factor of 10 after addition of citrate or isocitrate makes it possible for acetyl CoA to regulate the biosynthesis of fatty acids in the presence of malonyl CoA. References Nelson, D. L., Cox, M. M., & Lehninger, A. L. (2013). Lehninger principles of biochemistry. New York: W.H. Freeman.Top of Form Lennarz, W. J., & Lane, M. D. (2013). Encyclopedia of biological chemistry. London: Academic Press Top of FormLammert, E., & Zeeb, M. (2014). Metabolism of human diseases: Organ physiology and pathophysiology. Wien: SpringerTop of Form Tropp, B. E. (2012). Molecular biology: Genes to proteins. Sudbury, Mass: Jones & Bartlett Learning.Top of Form McGavock, H. (2005). How drugs work: Basic pharmacology for healthcare professionals. Oxford: Radcliffe Pub. Bottom of Form Bottom of Form Bottom of Form Bottom of Form Read More