Integration Of Metabolism

Transcription

1 لكية الطب البرشي البلقاء التطبيقية / املركز أحياها 2016/2022 و من

2 Integration Of Metabolism

3 Metabolism Consist of Highly Interconnected Pathways The basic strategy of catabolic metabolism(in another words degradative pathways) is to form ATP, NADPH, and building blocks for biosyntheses. 1. ATP(which produced by oxidative phosphrylation) is the universal currency of energy Energy source in muscle contraction, active transport, signal amplification, and biosyntheses.

4 2. ATP is generated by the oxidation of fuel molecules such as glucose, fatty acids, and amino acids. The first aim of metabolism(degradative metabolism) is to produce energy. Also it is produce water! 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.

5 3. NADPH is the major electron donor in reductive biosyntheses. In most biosyntheses, the products are more reduced than the precursors, and so reductive power is needed as well as ATP. The highpotential electrons required to drive these reactions are usually provided by NADPH. The pentose phosphate pathway supplies much of the required NADPH. Also PPP produce ribose 5 phosphate which is used in neucleotide metabolism. Synthesis fatty acid, cholesterol, steroid, prostaglandin, all of these need NADPH(electron donar).

6 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 biosyntheses, such as those leading to fatty acids, prostaglandins, and cholesterol. Another example is building of neucleotide we use HCO3- and amino acids like glycine and aspartate etc

7 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. *In the example of fatty acid synthesis & degradation the doctor talk about very important idea (the compartmentation) => FA biosynthesis take place in cytosol FA degradation in mitochondrial matrix This idea will be explained further in the next slides *There is no dout biosynthesis and degradation must not take place at the same time (if happen futile cycle will occur) in another words reciprocal regulation must take place

8 The key compounds of biosynthesis We called it that because they are involved in more than one pathway(in the spoken language they are a مفترق طرقcrossroads of metabolism) Those compounds are: ATP NADPH(e- donor => reductive biosynthesis) NADH & FADH2 (e- carriers for oxidative pathways) Acetyl CoA You should memorize their function, where they are going, from where they are coming

9 Small summarization for the previous slides

10 Metabolic Regulation 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.

11 Allosteric interactions notes Usually happen in the key step(committed step or rate limiting step) in the pathway to control the whole pathway Usually the regulated enzyme is in the first steps Allosteric enzyme usually contain more than one subunit: 1)catalytic bind to substrates 2)regulatory bind to activators and inhibitors Examples: PFK-1 in glycolysis Carbamyl phosphate synthase 1 in urea cycle(activated by N acetyl glutamate) Citrate synthase in CAC

12 2. Covalent modification 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. It is not primitted that two enzymes with reverse functions to be active at the same time (if occur that will lead to futile cycle) The factor(usually phosphorylation or dephosphorylation) that lead to activation of pathway (degradative for example) will lead to inhibition of the reverse one (biosynthesis in this example)

13 3. 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. Hormones can increase the enzyme action by increase its synthesis(by increase its transcription) or decrease its action by increase its degradation (by degradative enzymes) Example: adrenaline & glucagon(catabolic hormones) => signal transduction => increase levels of gluconeogenic and glycogenolytic enzymes The same thing with insulin but with differ impacts

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15 this is the control mechanism of metabolism and some typical response times. Availability of substrate it takes minutes. Allosteric activators and inhibitors minutes. Covalent modification of enzymes minutes to hours. Synthesis of new enzyme molecules hours to days. The most difficult

16 4. 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.

17 Compartmentation of the Major Pathways of Metabolism + cholesterol synthesis + prostaglandin synthesis

18 5. Metabolic specializations of organs. Regulation in higher eukaryotes is enhanced by the existence of organs with different metabolic roles. Metabolic specialization is the result of differential gene expression.

19 Major Metabolic Pathways and Control Sites 1. Glycolysis 2. Citric acid cycle and oxidative phosphorylation 3. Pentose phosphate pathway 4. Gluconeogenesis 5. Glycogen synthesis and degradation 6. Fatty acid synthesis and degradation 7. Nucleotide metabolism

20 Key Junctions: Glucose 6-phosphate, Pyruvate, and Acetyl CoA Key junctions => crossroads in metabolic (تقاطعات طرق) bathways 1. Glucose 6-phosphate. 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.

21 Metabolic Fates of Glucose 6-Phosphate

22 2. Pyruvate Primarily from glucose 6-phosphate, alanine, and lactate. Pyruvate can be reduced to lactate by LDH to regenerate NAD+(anabolic metabolism). 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.

23 Notes After glycolysis take place in the muscle the end product is pyruvate that will enter anaerobic respiration in the muscle and transfer to lactate by the enzyme LDH(reversible step) this step is important because it give NAD+ to continue glycolysis Then, lactate enter the blood stream and go to the liver where it is oxidized back to pyruvate then pyruvate converted to glucose and glucose return to muscle where another cycle take place

24 Another readily reversible reaction in the cytosol is the transamination of pyruvate, an α-ketoacid, to alanine, the corresponding amino acid. Several amino acids can be converted into pyruvate. Thus, transamination is a major link between amino acid and carbohydrate metabolism. *sometimes when there is low levels of lactate in muscles alanine me be transported to liver for gluconeogenesis

25 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. Need biotin

26 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. This step take place by the pyruvate DH complex => 3 subunits & 2 coenzymes(tpp & lipoic acid)

27 Major Metabolic Fates of Pyruvate and Acetyl CoA in Mammals glycolysis LDH PYR. carboxylase PYR. DH complex transamination CAC + energy In cytosol in mitochondria

28 3. Acetyl CoA. 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.

29 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. Doctor focus on from where acetyl CoA come and what is synthesized by it

30 Regulation of Glycolysis F-2,6BP & AMP => low energy level => all energy consumed => we need ATP synthesis ATP => high energy level => there is enough energy => we need inhibition of ATP synthesis => G6F enter other pathway such as glycogen formation

31 Regulation of Gluconeogenesis Gluconeogenesis => we need energy => we need glucose

32 Regulation of the Pentose Phosphate Pathway

33 Regulation of the Pentose Phosphate Pathway notes The previous two steps are the irreversible steps of PPP PPP have two type of steps: Oxidative steps => first 2 steps Nonoxidative steps => such as steps done by transketolase & transaldolase Here we need pyrodoxin phosphate as coenzyme for carbon switching PPP importance: Ribose 5 P => neucleotide metabolism NADPH => In adipose tissue for lipid synthesis In RBCs it is resist oxidative strees and prevent RBCs degradation It is convert glutathione from oxidized to reduced form which will convert H2O2 to H2O & O2 => so that there is no H2O2 accumulation and there is no hemolysis of RBCs

34 Regulation of Fatty Acid Synthesis Palmitoyl CoA is an end product of FA synthesis => feed back inhibition

35 Control of Fatty Acid Degradation Malonyl CoA present in FA synthesis and inhibit FA degradation => prevent formation of futile cycle Carnitine is a carrier for activated FA it is give the FA to the mitochondrial matrix and return back to intermembrane space by carnitine acyltransferase 2 Activation of fatty acid need ATP so that we say that: palmitic acid(16c) give 131 ATP with net of 129 & stearic acid give 148 with net of 146 Palmitic acid(16c) => 8 acetyl CoA + 7 NADH + 7 FADH2

36 Each Organ Has a Unique Metabolic Profile 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(increase with mental & physical exersize). 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.

37 This danger point is reached when the plasmaglucose level drops below about 2.2 mm /L (40 mg/dl) if glucose reach this level there is a severe hypoglycemia and will lead to coma and may lead to death if he isn t given aid 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 (mainly acetoacetate) generated by the liver partly replace glucose as fuel for the brain.

38 Notes about glucose levels The normal level of glucose in the fasting state is from and in normal conditions When this level decrease from 70 (reach about 60) symptoms begin to appear such as tremolo & sweating & irritability and by the level of 50 symptoms increase and by the level of 40 coma occur Brain completely depends on glucose for energy and water to circulate glucose in blood and need O2 continuously Glucose penetrate BBB readily (don t need insulin) If there is any shortage in glucose or O2 (either for few seconds) that will lead to coma and may cause death so that when someone have stroke he must be given aid rapidly and he must be given any source of sugar to avoid his death

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40 2. Muscle 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 because of its size ). 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(don t do gluconeogenesis). Rather, muscle retains glucose, its preferred fuel for bursts of activity(at the second is FA then In starvation ketone bodies(amino acids) ). لمعرفة المزيد عن <= نسب الغاليكوجين في الجسم الن الدكتور قال نسب بعيدة عن المنطق

41 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. Lactate formation is faster than CAC in the term of energy use and if you less fit and blood supply for muscle isn t enough lactate will accumulate cause muscle contraction and painful sensation and fatigue

42 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(val Leu Ile); however, it cannot form urea. Consequently, the nitrogen is released into the blood as alanine.=> carrier for ammonia to the liver where it is converted to urea

43 Metabolic Interchanges between Muscle and Liver liver=> the only place for urea synthesis Kidney=> the only place for excretion Muscles & peripheral tissues=> carriers for amino acids that carry ammonia (mainly glutamine which is neutral, nontoxic, penetrate easily BBB) And glucose precursors (alanine & lactate) for glucose production that utilizes in energy production

44 3. Heart 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. The doctor consider an important points about causes of utilization of FA in heart : To prevent competition in the same source between heart and brain There is no need as long as FA is an available source of energy

45 4. Adipose tissue 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(also other parts when there is excess) in lipoprotein particles, such as VLDL, for store and utilization.

46 Triacylglycerols are not taken up by adipocytes; rather, they are first hydrolyzed by an extracellular lipoprotein lipase for uptake. This lipase is stimulated by processes initiated by insulin. After the fatty acids enter the cell, the principal task of adipose tissue is to activate these fatty acids and transfer the resulting CoA derivatives to glycerol in the form of glycerol 3-phosphate. This essential intermediate in lipid biosynthesis comes from the reduction of the glycolytic intermediate dihydroxyacetone phosphate. Thus, adipose cells need glucose for the synthesis of triacylglycerols.

47 Triacylglycerols are hydrolyzed to fatty acids and glycerol by intracellular lipases. The release of the first fatty acid from a triacylglycerol, the ratelimiting step, is catalyzed by a hormone-sensitive lipase that is reversibly phosphorylated. The hormone epinephrine (or glucagon) stimulates the formation of cyclic AMP, the intracellular messenger in the amplifying cascade.

48 Synthesis and Degradation of Triacylglycerols by Adipose Tissue

49 5. Kidneys 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 sodium-glucose cotransporter. Also it is the second major site of gluconeogenesis (after the liver)

50 During starvation, the kidney becomes an important site of gluconeogenesis and may contribute as much as 1/2 of the blood glucose.

51 6. Liver 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.

52 بالتوفيق للجميع END of Metabolism Part I >> مالحظة يرجى العودة للساليدات في part 2 الن الدكتور لم يضف شيء جديد