Integration of Metabolism 1. made by: Noor M. ALnairat. Sheet No. 18

Transcription

1 Integration of Metabolism 1 made by: Noor M. ALnairat Sheet No. 18 Data :24/11/2016

2 SLIDE 2: Metabolism Consist of Highly Interconnected Pathways The basic strategy of catabolic metabolism is to form ATP, NADPH, and building blocks for biosynthesis. 1. ATP is the universal currency of energy Energy source in muscle contraction, active transport, signal amplification, and biosynthesis. - Main goal of metabolism is to form ATP. - Biosynthesis of fatty acids and other molecules. - All processes within the cell occur in the presence of ATP. - ATP is used in sodium-potassium bump, phosphorylation reactions. SLIDE 3: 2. ATP is generated by the oxidation of fuel molecules such as glucose, fatty acids, and amino acids. The common intermediate in most of these oxidations is acetyl CoA. The carbon atoms of the acetyl unit are completely oxidized to CO2 by the citric acid cycle with the concomitant formation of NADH and FADH2. These electron carriers then transfer their high potential electrons to the respiratory chain. SLIDE 4: - Acetyl coa leaves the citric acid cycle as two molecules og carbon dioxide. - NADPH is the major electron donor. 3. NADPH is the major electron donor in reductive biosynthesis. In most biosynthesis, the products are more reduced than the precursors, and so reductive power is needed as well as ATP. The high-potential electrons required to

3 drive these reactions are usually provided by NADPH. The pentose phosphate pathway supplies much of the required NADPH. - All reduction biosynthesis reactions such as; fatty acids, cholesterols, prostaglandins, vitamin D, and steroid hormones need NADPH. - Major source of NADPH is the pentose phosphate pathway. Slide 5: 4. Biomolecules are constructed from a small set of building blocks The metabolic pathways that generate ATP and NADPH also provide building blocks for the biosynthesis of more-complex molecules. For example, acetyl CoA, the common intermediate in the breakdown of most fuels, supplies a two-carbon unit in a wide variety of biosynthesis, such as those leading to fatty acids, prostaglandins, and cholesterol. -acetyl coa is the common intermediate of the breakdown of molecules (catabolic pathway), also has an important role in the biosynthesis of molecules (anabolic pathway). - Fatty acid synthesis starts with acetyl coa which later turns to malonyl coa - Ketone body and cholesterol synthesis start with acetyl coa. SLIDE 6: 2:52 5. Biosynthetic and degradative pathways are almost always distinct For example, the pathway for the synthesis of fatty acids is different from that of their degradation. This separation enables both biosynthetic and degradative pathways to be thermodynamically favorable at all times. - Biosynthetic and degradative pathways are always distinct, means that they do not take place at the same time. - Enzymes used in the biosynthesis are different from those used in the degradation process in order to control the metabolic pathways.

4 SLIDE 7: Metabolic Regulation 3:15 Anabolism and catabolism must be precisely coordinated 1. Allosteric interactions Enzymes that catalyze essentially irreversible reactions are likely control sites, and the first irreversible reaction in a pathway (the committed step) is nearly always tightly controlled. -enzymes that undergo allosteric regulation are mostly important irreversible enzymes (control sites). -they take inhibitors and activators, as they are multiple subunits. SLIDE 8: Covalent modification 3:57 Some regulatory enzymes are controlled by covalent modification in addition to allosteric interactions. For example, the catalytic activity of glycogen phosphorylase is enhanced by phosphorylation, whereas that of glycogen synthase is diminished. Some enzymes get activated when phosphorylated, while others get inactivated. One pathway is active at a time under the effect of hormones (anabolic or catabolic). Slide 9 : Enzyme levels The amounts of enzymes, as well as their activities, are controlled. The rates of synthesis and degradation of many regulatory enzymes are altered by hormones.

5 Enzymes level (amount)is under the control of genetic factors + hormones. Hormones control the synthesis, degradation, activation and inhibition of enzymes Slide 10 : 5:40 Hormones like insulin are anabolic hormones, which means Insulin favors glycogen formation. Gluconeogenesis, ketogenesis are inhibited by insulin. It inhibits the catabolic pathways. Insulin activate intracellular amino acids, glucose, fatty acids synthesis And help in their transportation. Catabolic hormones: glucagon and epinephrine increase the amount of glucose in the blood by stimulating glucogenolysis, gluconeogenesis ketogenesis. Insulin and the other have opposing action. Glucagon is inhibited by high levels of glucose. When glucose levels are low in blood, stimulation of glucagon and inhibition of insulin takes place. Glucagon mechanism is to increase glucose levels in blood. Slide 11 Glucagon is stimulated by some amino acids and epinephrine. Glucagon is inhibited by the high levels of glucose in the blood. Slide 12 Regulation takes mints to days depending on the type of control and differ from one tissue to another, just like the synthesis of enzymes.

6 Slide : Compartmentation The metabolic patterns of eukaryotic cells are markedly affected by the presence of compartments.the fates of certain molecules depend on whether they are in the cytosol or in mitochondria, and so their flow across the inner mitochondrial membrane is often regulated. - The metabolic pathways occur in different sites of the cell. - Glycolysis, fatty acids synthesis, cholesterol synthesis, glycogen synthesis take place in the cytosol. - Catabolic reactions like citric acid cycle, fatty acid oxidation, ketone body formation, take place in the mitochondria matrix. - pathways between the mitochondria and cytosol are, gluconeogenesis and urea synthesis. Slide 15: Metabolic specializations of organs 8:00 Regulation in higher eukaryotes is enhanced by the existence of organs with different metabolic roles. Metabolic specialization is the result of differential gene expression. Each enzyme has its own favorable source of energy. Slide 16: Major Metabolic Pathways and Control Sites 8:16 1. Glycolysis 2. Citric acid cycle and oxidative phosphorylation 3. Pentose phosphate pathway 4. Gluconeogenesis 5. Glycogen synthesis and degradation

7 6. Fatty acid synthesis and degradation Slide : 1. Glucose 6-phosphate 8:31 Stored as glycogen, degraded to pyruvate, or converted into ribose 5- phosphate.. Glucose 6-phosphate can be formed by the mobilization of glycogen or it can be synthesized from pyruvate and glucogenic amino acids by the gluconeogenic pathway. -3 important compounds because they share in more than one pathway. - Glucose 6-phosphate ( glycolysis, glycogen synthesis, pentose phosphate pathway, gluconeogenesis ) 4 pathways.

8 SLIDE 19,,23: Pyruvate 10:00 Primarily from glucose 6-phosphate, alanine, and lactate. Pyruvate can be reduced to lactate by LDH to regenerate NAD+. This reaction enables glycolysis to proceed transiently under anaerobic conditions in active tissues such as contracting muscle. The lactate formed in active tissue is subsequently oxidized back to pyruvate, in other tissues. The essence of this interconversion buys time and shifts part of the metabolic burden of active muscle to other tissues. Another readily reversible reaction in the cytosol is the transamination of pyruvate, an α-ketoacid, to alanine, the corresponding amino acid. Conversely, several amino acids can be converted into pyruvate. Thus, transamination is a major link between amino acid and carbohydrate metabolism. A third fate of pyruvate is its carboxylation to oxaloacetate inside mitochondria, the first step in gluconeogenesis. This reaction and the subsequent conversion of oxaloacetate into phosphoenolpyruvate bypass an irreversible step of glycolysis and hence enable glucose to be synthesized from pyruvate. A fourth fate of pyruvate is its oxidative decarboxylation to acetyl CoA. This irreversible reaction inside mitochondria is a decisive reaction in metabolism: It commits the carbon atoms of carbohydrates and amino acids to oxidation by the citric acid cycle or to the synthesis of lipids.

9 Notes for the previous slides: Pyruvate is involved in 4 chemical pathways: 1. Pyruvate lactate + NAD + - Reduction reaction by LDH. - Reversible but in other tissues (lactate to pyruvate). - Anaerobic glycolysis. 2. Pyruvate Alanine (amino acid). - Transamination reaction. - Pyruvate = alpha- ketoacid - Occurs in the cytosol. - Reversible (alanine to pyruvate). 3. Pyruvate oxaloacetate - Carboxylation of pyruvate - Occurs inside the mitochondria. - The first step of gluconeogenesis. - Irreversible. - Fill- up reaction when shortage of glucose. 4. Pyruvate Acetyl coa - Oxidative decarboxylation of pyruvate.

10 - Inside the mitochondria (citric acid cycle). - Irreversible. So pyruvate is involved in four chemical pathways; glycolysis, citric acid cycle, transamination to form alanine and anaerobic glycolysis to form lactate. SLIDE 24: Acetyl CoA 12:04 The major sources of this activated two-carbon unit are the oxidative decarboxylation of pyruvate and the β-oxidation of fatty acids. Acetyl CoA is also derived from ketogenic amino acids. The fate of acetyl CoA, in contrast with that of many molecules in metabolism, is quite restricted. The acetyl unit can be completely oxidized to CO2 by the citric acid cycle. Alternatively, 3-hydroxy-3-methylglutaryl CoA can be formed from three molecules of acetyl CoA. This six-carbon unit is a precursor of cholesterol and of ketone bodies, which are transport forms of acetyl units released from the liver for use by some peripheral tissues. A third major fate of acetyl CoA is its export to the cytosol in the form of citrate for the synthesis of fatty acids. Acetyl coa is involved in four chemical pathways; - Citric acid cycle. - Fatty acid synthesis and degradation. - Ketone body formation.

11 - Cholesterol synthesis. Acetyl coa is synthesized from pyruvate by oxidative decarboxylation. Acetyl coa Leaves the citric acid cycle as two molecules of carbon dioxide. SLIDE 26: Regulation of Glycolysis 13:00 - Rate limiting step in glycolysis includes the enzyme phosphofructokinase. - Note that not all irreversible steps are important, as they are not considered a control step. - Phosphofructokinase is an important step because fructose 1, 6- bisphosphate is present in glycolysis only. - Phosphofructokinase (degradation of glucose) - Activated by F-2,6-BP - Activated by AMP (ATP has been consumed, we need energy degradation of glucose). - Inhibited by ATP and citrate (high energy phosphate and citrate means the citric acid cycle is active, no need for more ATP, degradation of glucose must stop). SLIDE 27: Regulation of Gluconeogenesis Fructose 1, 6- bisphosphatase - Activated by citrate - Inhibited by AMP. - Inhibited by F-2, 6-BP.

12 Note the differences between slides 26 and 27; If you go through the inhibitors and activators of the two enzymes; phosphofructokinase (glycolysis), and fructose 1,6- BP (glycogenesis), you notice that they opposite each other. SLIDE 28: Regulation of the Pentose Phosphate Pathway 14:35 - Glucose 6-phosphate dehydrogenase (G-6-PD). - Main goal of the pentose phosphate pathway is to generate NADPH. - The enzyme lactonase results in 6- phosphogluconate. - Glucose 6- phosphate dehydrogenase in included in the oxidation part of the pathway, which is regulated. - Deficiency in the enzyme G-6-PD results in drug induced hemolytic anemia. SLIDE 29: Regulation of Fatty Acid Synthesis 15:27 -Acetyl coa carboxylase - A very important enzyme. - A target of the drugs that inhibit fatty acid synthesis to control obesity and diabetes.

13 - To fight obesity and diabetes, you should find something to inhibit the enzyme Acetyl coa carboxylase, inhibit fatty acid synthesis. SLIDE 30: Control of Fatty Acid Degradation - Carnitine acetyltransferase - Carnitine is a carrier derived from lycine. - inhibited by malonyl coa. SLIDE 31-34: Each Organ Has a Unique Metabolic Profile 17:50 1. Brain. Glucose is virtually the sole fuel for the human brain, except during prolonged starvation. It consumes about 120 g daily, which corresponds to an energy input of about 420 kcal, accounting for some 60% of the utilization of glucose by the whole body in the resting state. Much of the energy, estimates suggest from 60% to 70%, is used to power transport mechanisms that maintain the Na+-K+ membrane potential required for the transmission of the nerve impulses. This danger point is reached when the plasma-glucose level drops below about 2.2 mm /L (40 mg/dl) Fatty acids do not serve as fuel for the brain; because they are bound to albumin in plasma and so do not traverse the blood-brain barrier. In starvation, ketone bodies generated by the liver partly replace glucose as fuel for the brain. -brain consumes most of the carbohydrates (glucose) supplied about 60%. -If a person consumes 160g carbohydrates per day, 120g would be consumed by the brain. -shortage of glucose and oxygen affect the brain.

14 -emergency cases, oxygen and glucose must be supplied first. -hyperglycemia and hypoglycemia both lead to coma. - If glucose level is below 40 or 2.2 mmol/l, coma occurs. -in hypoglycemia, administrating glucose leads to patient waking up. -in hyperglycemia, adding glucose has no effect on the patient, as a second step, insulin is supplied. -brain depends mainly on glucose, except in starvation when it starts using ketone bodies. *Note: starvation, like diabetes. In diabetic patients, glucose is available but circulating in blood, not present in cells (not intracellular). Glucose is beneficial only when present in cells. Degradation of lipids leads to the increase of ketone body formation, which then results in ketosis and acidosis (lethal). Diabetic patients should not reach the stage of acidosis or ketosis. **Why doesn t the brain consume fatty acids? 1- In order not to compete with the heart, which uses fatty acids as a source of energy. 2- Fatty acids cannot cross the BBB, because fatty acids circulate in blood attached to the protein albumin, so become a large molecule. - Glucose, Oxygen and Ketone bodies can cross the BBB, because they circulate freely in the blood (not attached to other molecules) - Albumin s molecular weight= Dalton. Molecules with a molecular weight > albumin s molecular weight, can t cross BBB. Molecules with a molecular weight < albumin s molecular weight, can cross BBB. - Fatty acids are the main source of energy. 3- The brain is an aerobic organ (needs oxygen).

15 SLIDE 34-37: Muscle 23:47 The major fuels for muscle are glucose, fatty acids, and ketone bodies. Muscle differs from the brain in having a large store of glycogen (1200 kcal. In fact, about 3/4 of all the glycogen in the body is stored in muscle. This glycogen is readily converted into glucose-6-p for use within muscle cells. Muscle, like the brain, lacks glucose 6-phosphatase, and so it does not export glucose. Rather, muscle retains glucose, its preferred fuel for bursts of activity. In actively contracting skeletal muscle, the rate of glycolysis far exceeds that of the citric acid cycle, and much of the pyruvate formed is reduced to lactate, some of which flows to the liver, where it is converted into glucose. These interchanges, known as the Cori cycle shift part of the metabolic burden of muscle to the liver. In addition, a large amount of alanine is formed in active muscle by the transamination of pyruvate. Alanine, like lactate, can be converted into glucose by the liver. Why does the muscle release alanine? Muscle can absorb and transaminate branched-chain amino acids; however, it cannot form urea. Consequently, the nitrogen is released into the blood as alanine. -Muscles can use any of the three molecules. -3/4 Glycogen stored in muscles. -amount of glycogen stored in the muscles is larger than the amount stored in the liver. -But the percentage of glycogen per weight is larger in liver than in muscles, because of the large muscles weight. -glycogen in muscles is about 1% of muscle mass, 10% of liver mass. -What is the amino acid that indicates protein degradation? Alanine.

16 -Cori cycle in liver. SLIDE 38: Heart 25:55 Unlike skeletal muscle, heart muscle functions almost exclusively aerobically, as evidenced by the density of mitochondria in heart muscle. Moreover, the heart has virtually no glycogen reserves. Fatty acids are the heart's main source of fuel, although ketone bodies as well as lactate can serve as fuel for heart muscle. In fact, heart muscle consumes acetoacetate in preference to glucose. -heart uses only fatty acids, because it is an aerobic source of energy Kcal available in the form of fatty acids. -heart, kidney, and other organs are surrounded by lipids. -severe diet can leads to heart and kidney issues, because of the surrounding lipids supporting consumption. -uses ketone bodies and lactate starvation.

17 SLIDE 39: Adipose tissue 27:38 The triacylglycerols stored in adipose tissue are an enormous reservoir of metabolic fuel. In a typical 70-kg man, the 11 kg of triacylglycerols have an energy content of 100,000 kcal. Adipose tissue is specialized for the esterification of fatty acids and for their release from triacylglycerols. In human beings, the liver is the major site of fatty acid synthesis. Recall that these fatty acids are esterified in the liver to glycerol phosphate to form triacylglycerol and are transported to the adipose tissue in lipoprotein particles, such as very low density lipoproteins.. - Liver synthesizes and exports lipids. - fatty + glycerol (reach adipose tissues) triglycerol - Lipids support important organs like the heart and kidneys. SLIDE 39: Adipose tissue 27:31 The triacylglycerols stored in adipose tissue are an enormous reservoir of metabolic fuel. In a typical 70-kg man, the 11 kg of triacylglycerols have an energy content of 100,000 kcal. Adipose tissue is specialized for the esterification of fatty acids and for their release from triacylglycerols. In human beings, the liver is the major site of fatty acid synthesis. Recall that these fatty acids are esterified in the liver to glycerol phosphate to form triacylglycerol and are transported to the adipose tissue in lipoprotein particles, such as very low density lipoproteins..

18 - Adipose tissue uses fatty acids as source of energy. - Stores high energy, up to 100,000 kcal. - Liver is the major site of fatty acid synthesis. - Glucose is the main source of lipids (triglycerides). - Triglycerides do not reach adipose tissues readymade. - Fatty acids + glycerol triglycerides (for storage). SLIDE 43: Kidneys 30:00 The kidneys require large amounts of energy to accomplish the reabsorption. Although constituting only 0.5% of body mass, kidneys consume 10% of the oxygen used in cellular respiration. Much of the glucose that is reabsorbed is carried into the kidney cells by the sodiumglucose cotransporter. During starvation, the kidney becomes an important site of gluconeogenesis and may contribute as much as 1/2 of the blood glucose. - All metabolic pathways are present in kidneys (glycolysis, gluconeogenesis, fatty acid synthesis and degradation. - Although a kidney is about 0.5% of the body mass, but consumes about 10% of oxygen used in cellular respiration. - In the case of starvation, gluconeogenesis, kidneys generate half of the blood glucose, with the help of the liver. SLIDE 45:. Liver 30:45 The metabolic activities of the liver are essential for providing fuel to the brain, muscle, and other peripheral organs. Indeed, the liver, which can be from 2% to 4% of body weight, is an organism's metabolic hub (center of metabolism). Most compounds absorbed by the intestine first pass through the liver, which is thus able to regulate the level of many metabolites in the blood. - The liver is a glucostat organ, responsible for the blood glucose level control.

19 - In the case of increased blood glucose level, the liver stimulates glycogen synthesis. - In the case of low blood glucose level, the liver stimulates glycogenlysis (glycogen degradation). - All metabolites and drugs undergo absorption in the intestines and pass through the liver. - What do the intestines use as a source of energy? Amino acids, mainly glutamine, which is nontoxic, a carrier, neutral, can pass the BBB and transports ammonia to the liver to synthesize urine. - RBCs use glucose for energy - NOTE: -fasting differs from starvation: *fasting- overnight fast (only one night), body has enough stored glycogen to survive. * Starvation - three or more days without food, no enough glycogen stored. -exercise vs. severe (strenuous) exercise: * exercise like walking, does not consume high levels of energy. * Severe exercise like; swimming and running, consumes high levels of energy. - Total vs. net: * Total consumption of high energy phosphate in urea formation = 4 ATP * Net consumption of high energy phosphate in urea formation = 1 ATP

20 Although I can t ensure success, but I ll do whatever it takes to deserve it