Gluconeogenesis: Fructose 1, 6 Bisphosphatase Deficiency

Gluconeogenesis: Fructose 1, 6 Bisphosphatase Deficiency Ashley Woodin Introduction Fructose-1, 6-bisphosphate is a key regulatory step in gluconeogenesis, as well as many other intracellular metabolic pathways. During gluconeogenesis there is an important process in which there is a conversion of glucose to pyruvate which is known as glycolysis. This process will require three irreversible steps that have a very high negative free energy that is in the forward reaction. So, in order to have a conversion from pyruvate into glucose, the pathway will require the use of enzymes, which will allow the bypassing of these irreversible steps. One of the enzymes that is used in this process is called Fructose 1, 6-bisphosphatase (Kelley, 2006). This step is a very important step in gluconeogenesis, being that it needs to have fructose bisphosphatase to catalyze the conversion of fructose-1, 6-bisphosphate into fructose 6-phospahate, and inorganic phosphate, that without it can block the pathway. Its activity is high regulated by the levels of Adenosine Monophosphate, fructos e 2, 6-bisphosphate and also citrate (Kelley, 2006). When deficiencies are present in this pathway and devoid of this conversion, glycerol into glucose, it will lead to fasting hypoglycemia, lactic acidosis and other physiological conditions. This enzyme is highly active within the liver and the intestines. Therefore, when the liver glycogen stores are no longer available, the physical properties of the body will fight for its homeostasis (Eren, 2013) by converting a three carbon based molecule such as non-carbohydrate precursors, like lactate, glycerol as well as pyruvate, in order to maintain blood glucose levels (Eren, 2013). There is a physiological change in the body there is a need for glucose to be synthesized. When there is a high demand upon glucose synthesizes, the gluconeogenic pathway is increased exponentially. This demand typically occurs during high cardio, pregnancy and lactation (Wallace, 2002). There can also be an increase demand upon gluconeogenesis when the body is in a fasting state (Wallace,2002). Hypoglycemia has a high dependence upon gluconeogenesis formation, because it is the key metabolic pathway which will protect this physiological problem. Moreover, hypoglycemia is a very life-threating situation. Within the gluconeogenesis metabolic pathway, Fructose 1, 6-bisphosphatase is very crucial; as it aids in biochemical reactions and many of the physiological functions of the body. Structure and Properties Fructose 1,6-bisphosphate with six carbon sugar molecules is also known as the Harden-young ester, it has fructose sugars which are phosphorylated on the C1 and C6 (Diwan, 2006). However, before this step can be achieved it needs to start from the beginning in gluconeogenesis. It is important to note that glycolysis and gluconeogenesis are not reversed pathways. It’s clear to see that glycolysis and gluconeogenesis will have a lot of the same enzymes embedded within each other; however these two functional pathways are not the reverse of each other. Moreover, the irreversible steps, that are high exergonic, in glycolysis are bypassed in the gluconeogenesis pathway (Berg JM, 2002). In fact, each of the pathways is so tightly controlled by the intercellular as well as the intracellular signals, and they are highly regulated so that glycolysis and gluconeogenesis will not occur in the same cell at the same time (Berg JM, 2002). Looking at the glyconeogenic pathway the ability to see that there is a conversion of pyruvate into glucose (Berg JM, 2002). These conversions are achieved by Non-carbohydrate precursors of glucose, in which they are either first being converted into pyruvate, or they will enter the pathway at later pathway intermediates like oxaloacetate and dihydroxyacetone phosphate . There are currently three major non-carbohydrate precursors that are looked at, and they are lactate, amino acids, and glycerol. The first (1) precursor stated above is lactate, it has a formation that is by the active skeletal muscle, this occurs at a when the rate of glycolysis has reach its maximum of the oxidative metabolism (Berg JM, 2002). The amino acids with a carbon skeleton (Brandt, 2003) are derived from the amount of proteins that are in the diet, as well as starvation, from the breaking down of the proteins that are housed within the skeletal muscle (Berg JM, 2002). Lastly, the glycerol will obtain fat cells by the hydrolysis of triacylglycerols which wi ll yield glycerol as well as the lipids (Berg JM, 2002). As stated above, before looking at fructose-1,6-bisphosphate the beginning steps in gluconeogenesis needs to be looked at. Biosynthesis. We began synthesis by looking at the glycolysis pathway, there are a lot of enzymes that are used to synthesize glucose from a pyruvate stage. There are three reactions in glycolysis which we termed irreversible (specifically those catalyzed by pyruvate kinase, phosphofructokinase, and hexokinase) are not used in gluconeogenesis synthesis (Selinsky, 2002). These three (3) reactions of Glycolysis have such a large negative delta G in the forward direction that they are essentially irreversible, which is why bypass is used by enzymes in order for them to be synthesize. The delta G will make a determination of the proper direction of the carbon flow through the pathway (Brandt, 2003). Gluconeogenesis needs to be more exergonic, so in order to make that happened six ATPs are consumed (Miles, 2003).The first step or bypass, is by converting 3 carbon pyruvate into 4 carbon intermediate oxaloacetate , biotin-requiring reaction catalyzed (King, 2014), this is called pyruvate carboxylate (Sel insky, 2002). This mitochondrial enzyme will convert the pyruvate into oxaloacetate. Pyruvate carboxylase is a mitochondrial. The biotin is interconnected heavily as it is bound to the amino group covalently on the lysine side chain of the pyruvate carboxylase (Brandt, 2003).   Pyruvate carboxylase catalyzes formation between the biotin (Biotin has a 5-carbon side chain whose terminal carboxyl is in an amide linkage to the e-amino group of a lysine of the enzyme (Diwan, 2007)), and carbon dioxide carbonate by having a covalent bond. When there is a reaction that is ATP- dependent, the carbonate will then be put into action and transferred to the pyruvate substrate, in order to make a molecule oxaloacetate (Brandt, 2003). the high and low amount of concentration of acetyl CoA and ATP will ultimately decide is the oxaloacetic acid will survive or diminish (Ophardt, 2003). If there is a lower amount of acetyl- CoA and higher concentrations of ATP than the pathway will continue (Ophardt, 2003). A Transport of oxaloacetate out of mitochondria Oxaloacetate Malate NADH + H + NAD + Malate Oxaloacetate NADH + H + NAD + Inner mito are seen in this first bypass step. The Using a specific enzyme the Oxaloacetate will now be able to be converted into phosphoenolpyruvate , by the enzyme phosphoenolpyruvate carboxykinase (Selenski, 2005). This Mg ²+ enzyme will require is GTP being the donor for when there is the possibility for a phosphoryl transfer reaction, thus losing the loss of a CO ² molecule. Therefore, within this first step bypass synthesis, the reaction has gone from, phosphoenolpyruvate to pyruvate, and overall one (1) ATP is gained. In returning to phosphoenolpyruvate from pyruvate, the equivalent of 2 ATP must be consumed (Selinsky, 2002). Note that the CO ² that was gained in the pyruvate in the beginning of the pyruvate carboxylase step, has now been loss in the phosphoenolpyruvate carboxykinase. The second (2) bypass Now, to go from phosphoenolpyruvate to fructose-1, 6-bisphosphate into 6-bisphosphate, with this reaction the same reaction can be used, entirely by the concentrations of substrates and products (Selinsky, 2002). Because the reaction being exponentially endergonic, thus irreversible, the transition from the fructose 6-phosphate uses a catalyst from a different Mg ² + enzyme called the dependent fructose 1, 6-bisphosphatase, (Lehninger, ) This will promote an irreversible hydrolysis at the C-1 phosphate (Lehninger,). This is the third (3) bypass of gluconeogenesis which is the final step and in most tissues gluconeogenesis would end at the fructose 6-phosphate which was generated by fructose 1, 6 bisphosphatase being converted into glucose 6-phosphate. So, basically instead of having free glucose being generated, glucose 6-phosphate would be converted in glycogen ( Tymoczko, 2013). In this final step of gluconeogenesis, free glucose is will take shelter in the liver. Glucose 6-phosphate is then transported into the lumen if the endoplasmic recticulum, thus it is then hydrolyzed to glucose by the glucose 6-phosphatase (Tymoczko, 2013). Note that each of the step reactions that have been achieved, to the formation of glucose from pyruvate is considered energetically unfavorable, unless there are coupling reactions which are favorable (Tymoczko, 2013). In the end of this biosynthesis there are six (6) nucleoside triphosphate molecules that have been hydrolyzed in order to achieved a synthesize of glucose from pyruvate (Tymoczko, 2013). Regulation Gluconeogenesis is highly regulated by a series of regulations. The steps are broken down and now they have to be a regulation in gluconeogenesis. It is obvious that it’s going to have a direct correlation contrast to glycolysis. Consider the first stage in which energy is needed (Tymoczko, 2014). The main site of regulations is seen when the there is a regulation in the activity of PFK-1 and F1,6BPase and this would be the most important site for the controlling of the flux which is toward glucose oxidation or even when there is glucose synthesis. As described in control of glycolysis, this is predominantly controlled by fructose-2,6-bisphosphate, F2,6BP which is a powerful negative allosteric effector of F1,6Bpase activity (King, 2004). â€Å"Acetyl CoA is an allosteric effector of both glycolysis and gluconeogenesis. Acetyl-CoA inhibits pyruvate kinase and reciprocally activates pyruvate carboxylase (Miles,2003). Second, insulin and glucagon are very important when regulating pathway (Wallace,2002). There will be a decline in the response to the glucagon stimulation, when the level of Fructose 2,6 bisphosphate decline in the hepatocytes (King, 2014). Once these signals are stimulated the signals will be excited through an activation of the cAMP-dependent protein kinase (King, 2014). Both the PFK2 and fructose bisphosphatase are present in the 55-kd polypeptide chain (Tymoczko, 2013). here is a substrate enzyme which is bifunctional (King, 2014) which contains a N-terminal regulatory domain (Tymoczko, 2013) being responsible for the synthesis of the hydrolysis of fructose 2, 6- bisphosphate and that is the protein kinase a phosphatase domain. Therefore once the PFK-2 is phosphorylated by PKA it will start to dephosphorlate, by acting as a phosphatase (King, 2014). â€Å"AMP will ultimately enhances the inhibition of Fructose-2,6-BP. Note that these allosteric effectors of fructose-1, 6-bisphosphatase all are allosteric effectors of phosphofructokinase (Miles, 2003). These effectors reciprocally regulate both enzymes. Furthermore, fructose 1, 6-bisphosphase once it’s active, its activity will be highly regulated by the ATP to ADP concentration (Tymoczko, 2014). When this is high then gluconeogenesis can proceed to its highest potential. PROKARYOTES VERSUS EUKARYOTES Gluconeogenesis conversion happens in both the eukaryotic and prokaryotes, however it is very important to know its difference. In eukaryotes the lactate that is formed anaerobically within the muscles will be converted to glucose in liver and kidney, thus being stored as glycogen or even being released as blood glucose (Davis, 2014). In prokaryotes the production of the G3P product of photosynthesis will be converted in a starch form and then further stored in the chloroplasts or even being converted into glucose and sucrose, where it is then exported to the other tissues for starch storage (Davis, 2014). As stated above when it comes to the biosynthesis of all eukaryotes, it is an requirement for survival, because so much of the homeostasis of the body (e.g., the brain and the nervous system),glucose from the blood as the primary fuel source ( Nelson, 2012). Just alone the human brain will require as much as 120 g of glucose with a one day period (Nelson, 2012). When considering eukaryotes gluconeogenesis will primarly occur in the liver and also in the kidney but not much. In prokaryotes the seedlings, will find that it stores the fate and proteins, which are then converted into disaccharide sucrose foe the ability of transport throughout the plant that is developing (Nelson, 2012). â€Å"The glucose and its derivatives are precursors in the synthesis of plant cell walls, nucleotides and coenzymes, and a variety of other essential metabolites† (Nelson, 2012). There are many small organisms that are capable to grow on what are plain organic compounds like acetate, lactate, and propionate. They then will convert to glucose by gluconeogenesis (Nelson, 2012). Defects Pathway Although the pathway may be highly regulated, there are still possibilities for defects to occur. As stated in the beginning of this paper fructose 1, 6-bisphosphatase is very crucial; as it aids in biochemical reactions and many of the physiological functions of the body. In the mechanism of fructose 1, 6- bisphosphatase, there is the Glu98 which will activate a molecule consisting of water. That water molecule will than attack the phosphorus atom on the 1-phosphate of fructose 1,6-bisphosphate (Kelly, 2006).â€Å"The hydrolysis of a phosphate ester can proceed through an intermediate of metaphosphate (dissociative mechanism) or through a trigonal bipryamidal transition state (associative mechanism)† (Kelly, 2006). Fructose-1,6-bisphosphatase which catalyzes the hydrolysis of D-fructose-1,6-bisphosphate (FBP) to D-fructose-6-phosphate (F6P) and inorganic phosphate (Pi), it is the very key to the eyzamatic process of gluconeogenesis (Sato, 2004). phosphofructokinase is also an important catalyze reaction, because it will catalyze the reverse reaction, â€Å"the phosphorylation of F6P during glycolysis, the unidirectional FBPase regulates the flux of sugar metabolism† (Sato,2004). Furthermore, the enzymatic block can lead to the high amount of accumulation of gluconeogenic precursors (e.g. certain amino acids, lactic acid, and ketoacids) (Kelley, 2006). Therefore, when there is a fructose 1,6 bisphosphatase deficiency is an inherited as an autosomal recessive disorder and a person would have what is called a severe lactic acidosis and also with a diagnose of hypoglycemia. Disease Population in the United States In the United States alone about 10 percent of this nations population is diagnosed with hypoglycemia, from the defect in the enzyme fructose 1, 6, bisphosphatase. This disease affects those who are typically obese and or have type 2 diabetes. In order to try and control the diseas population treatments are use, like Metformin. Metformin is an anti-hyperglycemic reagent that has been used in the patients for over the past several years, in obese patients or overweight patients whose blood glucose levels cannot be controlled non-pharmacologically (Salpeter, 2010). â€Å"Fructose 1,6-BPase is a target for the development of drugs in the treatment of non-insulin dependent diabetes, which afflicts over 15 million people in the United States† (Kelley, 2006). Today it is still unknown on how fructose-1, 6 bisphosphatase is genetically inherited, there are still ongoing studies. Some of the ongoing studies that were seen is if Reye syndrome and sudden infant death, have a direct correlation to a defect in this enzyme, however the research still continues. As stated above, the primary target for hypoglycemia is still heavily looked upon in the obese community, and overweight community, because they are more susceptible to getting diabetes. As see fructose 1, 6 bisphosphatase is the key precursor for the gluconeogenesis pathway to occur. It is very important that the sugar intake is watch closely, when children are at a young age. According to a recent study, it is shown that fructose intolerant is seen in late infancy stage and only after they have a dietary ingestion of foods that are containing fructose or sucrose. Foods such as such as fruits, juices are the primary transportantion. The organs commonly affected by fructose bisphosphatase deficiency are liver, kidney cortex and intestinal mucos (Frazier, 2013). Overall Pathway of Gluconeogenesis Now, putting the metabolic pathway all together, Conclusion Fructose 1, 6 bisphosphatase is a very crucial enzyme to the continuance of gluconeogenesis regulation. With the literature that has been conducted, it lays out step by step why this metabolic biosynthesis pathway is vital to eukaryotic and prokaryotic. There are ways to combat this disease, and that is by maintaining a healthy diet. This entail will work to defeat the affects that this has on the population. BIBLIOGRAPHY Brandt, M. Amino Acid Breakdown. 2003. Retrieved from https://www.rose-hulman.edu/~brandt/Chem330/Amino_acid_breakdown.pdf. (Accessed December 5, 2014). Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002. Chapter 16, Glycolysis and Gluconeogenesis. Diwan, J. Gluconeogenesis: Regulation of Glycolysis Gluconeogenesis. Retrieved from http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb1/part2/gluconeo.htm#intro. (Accessed December 5, 2014). Frazier D. Glycogen Storage Disease Laboratory. 2013. Retrieved from http://pediatrics.duke.edu/divisions/medical-genetics/biochemical-genetics-laboratory/glycogen-storage-disease-laboratory/tes-8. (accessed on December 5, 2014) 2014). King, M. Gluconeogenesis: Endogenous Glucose Synthesis. 2014. Retrieved from http://themedicalbiochemistrypage.org/gluconeogenesis.php#. (Accessed December 5, 2014). Kelley, M. Fructose 1-6 Bisphosphatase. Retrieved from http://faculty.uca.edu/mkelley/4121 Web pages/Student_Webpages_2006/Aanu ogunbanjo web things/The webbie.html. (Accessed December 5, 2014). UC Davis. 2013. Gluconeogenesis. Retrieved from http://www-plb.ucdavis.edu/courses/bis/105/lectures/Gluconeogenesis.pdf. (Accessed December 5, 2014). Lehniger, Nelson, and Cox. Principles of Biochemistry. 2002. Retrieved from http://www.irb.hr/users/precali/Znanost.o.Moru/Biokemija/Literatura/Lehninger Principles of Biochemistry, Fourth Edition David L. Nelson, Michael M. Cox.pdf. (accessed on December 5, 2014). Miles, B. Gluconeogenesis. 2003. Retrieved from https://www.tamu.edu/faculty/bmiles/lectures/gluconeogenesis.pdf. (Accessed December 5, 2014). Ophart, C. Glycogenesis, Glycogenolysis, and Gluconeogenesis. 2003. Retrieved from http://www.elmhurst.edu/~chm/vchembook/604glycogenesis.html. (Accessed December 5, 2014). Selinsky, B. Biosynthesis: Gluconeogenesis. 2005. Retrieved from http://www22.homepage.villanova.edu/barry.selinsky/CHM%204622/Carbohydrate%20II%20M16%2005.pdf. (Accessed December 5, 2014). Salpeter SR. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Retrieved from http://www.bibliotecacochrane.com/pdf/CD002967.pdf. (Accessed December 5, 2014). Wallace C., Barritt G. Gluconeogenesis. 2002. Encyclopedia of life sciences: p:1-8. (Accessed December 5, 2014).

godfater character comparison Essay examples -- essays research papers

Comparison of the Characters Michael Sonny in â€Å"The Godfather† At a first glance Michael and Sonny appear to be quite different. Upon further observation, however, they do have some similarities. Although they are very different in their personality, values, and tempers, they are similar in areas of loyalty, their respect for their father, and their strong family ties. Their personalities are a study in contrasts. Sonny is brash and arrogant, where as Michael is calm and cool. When Don Corleone was in the hospital and Sonny was placed in charge, the family became kind of careless. He didn’t seem to care what could happen due to his actions. He wanted to kill the police captain and didn’t think about the repercussions. Tom has to tell him that it wouldn't be good to kill a cop, but they end up doing it anyway. I think Michael was pushed into it because of his loyalty to the family. He is more calculating in manner. Near the end when he "takes care of all the family business" on the day of the Baptism is a prime example of this. Because he was this way, the objects of his violence had no idea that it was coming. Their senses of values are also very dissimilar. Michael is a man of honor. He doesn't run around having affairs with different women. He only marries twice because his first wife was killed in the explosion. Sonny is an adulterer. He is with another woman during his sisters wedding, along with a few other times throughout the movie. The two brothers h...

Unit 2 M1

Unit 2 m1 Compare the aims and objectives of different types of business. I am going to compare a profit making and non-profit making business. All profit making business or organisation’s main goal is to maximizing profit- try to make the most profit possible. This is most likely to be the aim of business owners and shareholders. Another objective that other businesses have is to survive in the market – survival. It is a short term objective, possibly for small business just starting out, or when a new firm enters the market or at a time of crisis.However, Non-profit organisations are established around a variety of different sectors. These include social services, sports, cultural groups, education, and support groups. Their main objectives include: assisting others to participate in society, providing care and treatment, providing opportunities for people to engage in sporting teams, and promoting cultural or social values. TESCOS Tesco is a large business and it has a lot of aims and objectives. Some of which are: â€Å"To grow the UK core†.Tesco wish to expand on the number of stores in the UK and all over the world, also the number of services they provide. This is as relevant today as it was in 1997. The UK is the largest business in the Group and a key driver of sales and profit. Their objective is to â€Å"improve the shopping trips and driving a strong pace† This year, they are making a ? 1 billion commitment to improve the shopping trip, driving a strong pace of improvement in the things that are important to its customers which will involve the need to use revenue and capital investment.These changes will strengthen the shopping trip for customers, and consequently deliver improved performance for shareholders. â€Å"To be an understanding international retailer in stores & online† and â€Å"to respect their markets outside the UK† In 1997, their international businesses generated 1. 8% of the Group’s profits. In addition, today, they represent 30% and they’re now either number one or number two in eight of their 12 markets outside the UK. So they’re already ‘successful’ and are working  to be an outstanding international retailer in stores and online.OXFAM Oxfam focuses on five areas that are informed by their beliefs as an organization. They are: * All human lives are of equal value. Everyone has fundamental rights which must be recognized and upheld at all times. * Poverty makes people more vulnerable to conflicts and natural disasters. Much of this suffering is unnecessary, and we must relieve it. * Unequal power relations – gender, race, class, caste and disability – make people more vulnerable to poverty and suffering.Women, who make up the majority of the world's poor people, are especially disadvantaged. Unequal power relations must be addressed wherever they occur. * In a world rich in resources, poverty is a morally indefensib le injustice. It can and must be overcome. Too often, poverty is the result of powerful people's decisions. We must challenge and remove unjust policies and practices. * With the right resources, support, and training, people living in poverty can solve their own problems. We're all responsible for working together to overcome poverty and suffering.

Philosophy of David Hume Essays - 1927 Words

The human brain starts working the moment you are born and never stops until you stand up to speak in public. –( George Jessel ). One can say or try and dissect the brain and try to figure what’s going on inside of it and that’s what Philosophers today try to accomplish, but a question can be raised from this. Why is that why must the brain be dissected? This question is raised for the simple fact that Philosophers really want to know what’s going on the human brain. This can also go back to â€Å"knowing† and believing in something that can be proven as a fact. We will also take a look into induction which is the process of deriving general principles from particular facts or instances, and generalization the act or process of perceiving†¦show more content†¦The two general problems posed by Hume is how do we, as human beings, form opinions about certain issues that we may or may have not personally observed. The second part of his argu ment questions various people that have drawn conclusions from something they haven’t seen. In the article, Hume rarely refers to this particular issue as induction; he uses the term generalization a lot to discuss the topic. This issue has been around for a very long time looking back into our world’s storied history. We look at our observations in the past to sometimes speculate things that we will see in the future. For example, all of our life’s we have only seen one particular type of species of squirrels. This is the typical brown squirrel that one would see on a daily basis. Everywhere and every time someone mentions a squirrel you would envision something brown. You wouldn’t think that it was any way possible for there to be another type/color squirrel. This â€Å"assumption† was believed to be true for a long time until someone discovered a black squirrel and also a gray squirrel which proved those initial thoughts to be in correct. 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