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Euopean Journal of Molecular Biology and Biochemistry Fares K. Khalifa. / European Journal of Molecular Biology and Biochemistry. 2015;2(5):206-213. e - ISSN - 2348-2206 Print ISSN - 2348-2192 European Journal of Molecular Biology and Biochemistry Journal homepage: www.mcmed.us/journal/ejmbb REGULATION OF GLUCONEOGENESIS AND PENTOSE PHOSPHATE PATHWAY BY INTRACELLULAR AND EXTERNAL METABOLIC REGULATORS: A REVIEW Fares K. Khalifa* Biochemistry Department, Faculty of Science, King Abdul Aziz University, Saudi Arabia. Biochemistry and Nutrition Department, Women’s College, Ain Shams University, Egypt. Article Info ABSTRACT Received 23/07/2015 The metabolism of sugars is an important source of energy for cells. Animals, including Revised 16/08/2015 humans, typically obtain significant amounts of glucose and other sugars from the Accepted 12/09/2015 breakdown of starch and glycogen in their diets. Glucose can also be supplied via breakdown of cellular reserves of glycogen. Significantly, glucose also can be synthesized Key words:- from noncarbohydrate precursors by a process known as gluconeogenesis. Each of these Endotoxin, Pre- important pathways, as well as the synthesis of glycogen from glucose Another pathway of eclampsia, Normal glucose catabolism, the pentose phosphate pathway, is the primary source of NADPH, the pregnancy, Total reduced coenzyme essential to most reductive biosynthetic processes. For example, cholesterol, LDL- NADPH is crucial to the biosynthesis of fatty acids and amino acids. The pentose Cholesterol, phosphate pathway also results in the production of ribose-5-phosphate, an essential + Triglycerides. component of ATP, NAD , FAD, coenzyme A, and particularly DNA and RNA. INTRODUCTION Gluconeogenesis Gluconeogenesis salvages this pyruvate and The ability to synthesize glucose from common lactate and reconverts it to glucose. metabolites is very important to most organisms. Human metabolism, for example, consumes about 160 ± 20 grams The Substrates of Gluconeogenesis of glucose per day, about 75% of this in the brain. Body In addition to pyruvate and lactate, other non- fluids carry only about 20 grams of free glucose, and carbohydrate precursors can be used as substrates for glycogen stores normally can provide only about 180 to gluconeogenesis in animals. These include most of the 200 grams of free glucose. Thus, the body carries only a amino acids, as well as glycerol and all the TCA cycle little more than a one-day supply of glucose. If glucose is intermediates. On the other hand, fatty acids are not not obtained in the diet, the body must produce new substrates for gluconeogenesis in animals, because most glucose from noncarbohydrate precursors. The term for fatty acids yield only acetyl-CoA upon degradation and this activity is gluconeogenesis. Further, muscles consume animals cannot carry out net synthesis of sugars from large amounts of glucose via glycolysis, producing large acetyl-CoA. Lysine and leucine are the only amino acids amounts of pyruvate. In vigorous exercise, muscle cells that are not substrates for gluconeogenesis. These amino become anaerobic and pyruvate is converted to lactate. acids produce only acetyl-CoA upon degradation [1]. Nearly All Gluconeogenesis Occurs in the Liver Corresponding Author and Kidneys in Animals Interestingly, the mammalian organs that consume the most glucose, namely, brain and Fares K. Khalifa muscle, carry out very little glucose synthesis. The major Email: - [email protected] sites of gluconeogenesis are the liver and kidneys, which account for about 90% and 10% of the body’s 206 | P a g e Fares K. Khalifa. / European Journal of Molecular Biology and Biochemistry. 2015;2(5):206-213. gluconeogenic activity, respectively. Glucose produced by Initiation of gluconeogenesis occurs in the gluconeogenesis in the liver and kidney is released into the pyruvate carboxylase reaction-the conversion of pyruvate blood and is subsequently absorbed by brain, heart, to oxaloacetate. The reaction takes place in two discrete muscle, and red blood cells to meet their metabolic needs. steps, involves ATP and bicarbonate as substrates, and In turn, pyruvate and lactate produced in these tissues are utilizes biotin as a coenzyme and acetyl-coenzyme A as an returned to the liver and kidney to be used as allosteric activator. Pyruvate carboxylase is a tetrameric gluconeogenic substrates [2]. enzyme. Each monomer possesses a biotin covalently linked to the amino group of a lysine residue at the active Gluconeogenesis Is Not Merely the Reverse of site. The first step of the reaction involves nucleophilic Glycolysis attack of bicarbonate oxygen at the P of ATP to form In some ways, gluconeogenesis is the reverse of carbonylphosphate, an activated form of CO2, and ADP. glycolysis. Glucose is synthesized, not catabolized; ATP is Reaction of carbonylphosphate with biotin occurs rapidly consumed, not produced; and NADH is oxidized to NAD+, to form N-carboxybiotin, liberating inorganic phosphate. rather than the other way around. However, The third step involves abstraction of a proton from the C- 2gluconeogenesis cannot be merely the reversal of 3 of pyruvate, forming a carbanion which can attack the glycolysis, for two reasons. First, glycolysis is exergonic, carbon of N-carboxybiotin to form oxaloacetate. with a ∆G° of approximately -74 kJ/mol. If gluconeogenesis were merely the reverse, it would be a Pyruvate Carboxylase is Allostrically Activated by strongly endergonic process and could not occur Acyl-CoEnzyme spontaneously. Somehow the energetics of the process Two particularly interesting aspects of the must be augmented so that gluconeogenesis can proceed pyruvate carboxylase reaction are (a) allosteric activation spontaneously. Second, the processes of glycolysis and of the enzyme by acyl-coenzyme A derivatives and (b) gluconeogenesis must be regulated in a reciprocal fashion compartmentation of the reaction in the mitochondrial so that when glycolysis is active, gluconeogenesis is matrix. The carboxylation of biotin requires the presence inhibited, and when gluconeogenesis is proceeding, (at an allosteric site) of acetyl-coenzyme A or other glycolysis is turned off. Both of these limitations are acylated coenzyme A derivatives. The second half of the overcome by having unique reactions within the routes of carboxylase reaction—the attack by pyruvate to form glycolysis and gluconeogenesis, rather than a completely oxaloacetate—is not affected by CoA derivatives. shared pathway. Activation of pyruvate carboxylase by acetyl-CoA provides an important physiological regulation. Acetyl- Gluconeogenesis—Something Borrowed, Something CoA is the primary substrate for the TCA cycle, and New oxaloacetate (formed by pyruvate carboxylase) is an Gluconeogenesis employs three different important intermediate in both the TCA cycle and the reactions, catalyzed by three different enzymes, for the gluconeogenesis pathway. If levels of ATP and/or acetyl- three steps of glycolysis that are highly exergonic (and CoA (or other acyl-CoAs) are low, pyruvate is directed highly regulated) [3]. In essence, seven of the ten steps of primarily into the TCA cycle, which eventually promotes glycolysis are merely reversed in gluconeogenesis. The six the synthesis of ATP. If ATP and acetyl-CoA levels are reactions between fructose-1,6-bisphosphate and PEP are high, pyruvate is converted to oxaloacetate and consumed shared by the two pathways, as is the isomerization of in gluconeogenesis. Clearly, high levels of ATP and CoA glucose-6-P to fructose-6-P. derivatives are signs that energy is abundant and that The three exergonic regulated reactions—the metabolites will be converted to glucose (and perhaps even hexokinase (glucokinase), phosphofructokinase and glycogen). If the energy status of the cell is low (in terms pyruvate kinase reactions—are replaced by alternative of ATP and CoA derivatives), pyruvate is consumed in the reactions in the gluconeogenic pathway [4]. The TCA cycle. Pyruvate carboxylase activation by acetyl-CoA conversion of pyruvate to PEP that initiates leads to oxaloacetate formation, replenishing the level of gluconeogenesis is accomplished by two unique reactions. TCA cycle intermediates [6].Compartmentalized Pyruvate Pyruvate carboxylase catalyzes the first, converting Carboxylase Depends on Metabolite Connversion and pyruvate to oxaloacetate. Then, PEP carboxykinase Transport catalyzes the conversion of oxaloacetate to PEP. The second interesting feature of pyruvate Conversion of fructose-1,6-bisphosphate to fructose-6- carboxylase is that it is found only in the matrix of the phosphate is catalyzed by a specific phosphatase, fructose- mitochondria. By contrast, the next enzyme in the 1,6-bisphosphatase. The final step to produce glucose, gluconeogenic pathway, PEP carboxykinase, may be hydrolysis of glucose-6-phosphate, is mediated by glucose- localized in the cytosol or in the mitochondria or both. For 6-phosphatase [5]. example, rabbit liver PEP carboxykinase is predominantly mitochondrial, whereas the rat liver enzyme is strictly The Unique Reactions of Gluconeogenesis cytosolic. In human liver, PEP carboxykinase is found both 1-Pyruvate Carboxylase-A Biotin-Dependent Enzyme in the cytosol and in the mitochondria. 207 | P a g e Fares K. Khalifa. / European Journal of Molecular Biology and Biochemistry. 2015;2(5):206-213. Pyruvate is transported into the mitochondrial reason, gluconeogenesis is not carried out in muscle and matrix, where it can be converted to acetyl-CoA (for use in brain. Its membrane association is important
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