Biochemistry of liver&muscles


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Biochemistry of liver&muscles

  1. 1. Biochemistry of the liver
  2. 2. LIVER STRUCTURE sinusoids central veinportal vein bile canaliculi bile duct hepatic artery
  3. 3. Liver’s functions.1. Liver is a main organ which is responsible for dividing of nutritional substances in our organism (for example, glucose, triacylglicerides and ketone bodies).2. Hepatocytes synthesizes as lot of blood plasma proteins and lipoproteins, low-weight bioactive substances (creatin, 25-oxicalciferol, hem), cholesterol.3. Synthesis of urea (final product of nitrogen metabolism) also takes place in the liver.4. Liver synthesizes bile acids and excrete a bile into intestinal tract. This process plays a very important role in lipids digestion and excretion of cholesterin and some products of metabolism into intestine.5. Liver play a big desintoxification role, inactivates endogenic and exogenic substances (drugs, some hormones, different toxins).6. Liver is a depo for iron, some another metals, vitamines A, D, E, B12, folic acid.
  4. 4. Role of the liver in carbohydrate metabolism. From intestine glucose pass into the liver, where most part of it undergone the phosphorillation. Glucose-6-phosphate formed in result of this reaction, which catalyzed by two enzymes – hexokinase and glucokinase.Glucose-6-phosphate is a key product of carbohydrates metabolism. In the liver this substance can metabolized into different ways depend of liver’s and whole organism’s necessity.
  5. 5. The fate of glucose molecule in the cell Glucose Pentose phosphate Glycogenesis pathway supplies (synthesis of the NADPH for lipid glycogen) is synthesis and activated in well Glucose-6- pentoses for nucleic fed, resting state phosphate acid synthesis Gluconeoge nesis Ribose, is activated NADPHGlycogen if glucose is Glycogenolysis required (degradation of glycogen) Pyruvate Glycolysis is activated if energy is required TCA cycle
  6. 6. • Synthesis of glycogen. Content in the liver – 70-100g• Glucose-6-phosphatase catalize dephosphorillation of glucose-6-phosphate and formation of free glucose• Excess of glucose-6-phosphate, which not used for synthesis of glycogen will follow to form free glucose• Glucose-6-phosphate decomposed to H2O and CO2, and free energy for hepatocytes formed.• Part of glucose-6-phosphate oxidized in pentosophosphate cycle.• Hepatocytes content full set of gluconeogenesis necessary enzymes. So, in liver glucose can be formed from lactate, pyruvate, amino acids, glycerol.• Gluconegenesis from lactate takes place during intensive muscular work. Lactate formed from glucose in muscles, transported to the liver, new glucose formed and transported to the muscles
  7. 7. Role of the liver in lipid metabolism.In the liver all processes of lipid metabolism take place. Most important of them are following:Lipogenesis (synthesis of fatty acids and lipids). Substrate for this process – acetyl-CoA, formed from glucose and amino acids, which are not used for another purposesLiver more active than another tissues synthesizes saturated and monounsaturated fatty acids. Fatty acids then used for synthesis of lipids, phospholipids, cholesterol ethers.Liver play a central role in synthesis of cholesterin, because near 80 % of its amount is synthesized there. Biosynthesis of cholesterin regulated by negative feedback. When the level of cholesterin in the meal increases, synthesis in liver decreases, and back to front. Besides synthesis regulated by insulin and glucagon.Liver is a place of ketone bodies synthesis. These substances formed from fatty acids after their oxidation, and from liver transported to another tissues, first of all to the heart, muscles, kidneys and brain
  8. 8. Role of the liver in protein metabolism.Liver has full set of enzymes, which are necessary for amino acids metabolism. Amino acids from food used in the liver for following pathways:1. Protein synthesis.2. Decomposition for the final products.3. Transformation to the carbohydrates and lipids.4. Interaction between amino acids.5. Transformation to the different substances with amino group.6. Release to the blood and transport to another organs and tissues.
  9. 9. Liver synthesizes 100 % of albumins, 90 % of α1-globulines, 75 % of α2-globulines, 50 % of β- globulins, blood clotting factors, fibrinogen, protein part of blood lipoproteins, such enzyme as cholinesterase.Liver can synthesize non-essential amino acids.Liver synthesizes purine and pyrimidine nucleotides, hem, creatine, nicotinic acid, choline, carnitine, polyamines.
  10. 10. Role of the liver in detoxification processes.A xenobiotics is a compound that is foreign to the body. The principal classes of xenobiotics of medical relevance are drugs, chemical cancerogens, and various compounds that have found their way into our environment by one route or another (insecticides, herbicides, pesticides, food additions, cosmetics, domestic chemical substances).Some internal substances also have toxic properties (for example, bilirubin, free ammonia, bioactive amines, products of amino acids decay in the intestine).Moreover, all hormones and mediatores must be inactivated.Reactions of detoxification take place in the liver.Big molecules like bilirubin excreted with the bile to intestine and leaded out with feces. Small molecules go to the blood and excreted via kidney with urine.
  11. 11. General ways of xenobiotics biotransformation and their localization in cell REACTION ENZYME LOCALIZATION PHASE IHydrolysis Esterase Microsomes, cytosol, lysosomes, blood Peptidase lysosomes Epoxide hydrolase Microsomes, cytosol Azo- and nitro-reduction Microflora, microsomes, cytosolReduction Carbonyl reduction Cytosol, blood, microsomes Disulfide reduction Cytosol Sulfoxide reduction Cytosol Alcohol dehydrogenaseOxidation Cytosol Aldehyde dehydrogenase Mitochondria, cytosol Aldehyde oxidase Cytosol Xanthine oxidase Cytosol Monoamine oxidase Mitochondria Diamine oxidase Cytosol Flavin-monooxygenases Microsomes Cytochrome P450 Microsomes PHASE II Glucuronide conjugation Microsomes Sulfate conjugation Cytosol, microsomes Glutathione conjugation Cytosol Amino acid conjugation Mitochondria, cytosol Acetylation Mitochondria, microsomes Methylation Cytosol, microsomes, blood
  12. 12. The metabolism of xenobiotics has 2 phases:In phase 1, the major reaction involved is hydroxylation, catalyzed by members of a class of enzymes referred to as monooxygenases or cytochrome P-450 species. These enzymes can also catalyze deamination, dehalogenation, desulfuration, epoxidation, peroxidation and reduction reaction. Hydrolysis reactions and non-P-450-catalyzed reactions also occur in phase 2.
  13. 13. Cytochrom P450The highest concentration – in endoplasmic reticulum ofhepatocytes (microsomes).Hem containing protein.Catalyzes monooxigenation of oxygen atom into substrate;another oxygen atom is reduced to waterElectrons are transferred from NADPH to cytochromeP450 through flavoprotein NADPH-cytochrome P450reductase.
  14. 14. [1] In the resting state, the heme iron istrivalent. Initially, the substrate bindsnear the heme group.[2] Transfer of an electron from FADH2reduces the iron to the divalent form thatis able to bind an O2 molecule.[3] Transfer of a second electron and achange in the valence of the iron reducethe bound O2 to the peroxide.[4] A hydroxyl ion is now cleaved fromthis intermediate. Uptake of a protongives rise to H2O and the reactive formof oxygen mentioned above. In this ferrylradical, the iron is formally tetravalent.[5] The activated oxygen atom insertsitself into a C–H bond in the substrate,thereby forming an OH group.[6] Dissociation of the product returnstheenzyme to its initial state.
  15. 15. In phase 2, the hydroxylated or other compounds produced in phase 1 are converted by specific enzymes to various polar metabolites by conjugation with glucuronic acid, sulfate, acetate, glutathione, or certain amino acids, or by methylation.In certain cases, phase 1 metabolic reaction convert xenobiotics from inactive to biologically active compounds. In these instances, the original xenobiotics are referred to as prodrugs or procarcinogens. In other cases, additional phase 1 reactions convert the active compounds to less active or inactive forms prior to conjugation. In yet other cases, it is the conjugation reactions themselves that convert the active product of phase 1 to less active or inactive species, which are subsequently excreted in the urine or bile. In a very few cases, conjugation may actually increase the biologic activity of a xenobiotics.
  16. 16. There are at least 5 types of phase 2 reactions:• Glucuronidation. UDP-glucuronic acid is the glucuronyl donor, and a variety of glucuronyl transferases, present in both the ER and cytosol, are the catalysts. Molecules such as bilirubin, thyroxin, 2-acetylaminofluorene (a carcinogen), aniline, benzoic acid, meprobromate (a tranquilizer), phenol, crezol, indol and skatol, and many steroids are excreted as glucuronides. The glucuronide may be attached to oxygen, nitrogen, or sulfur groups of substrates.2. Sulfation. Some alcohols, arylamines, and phenols are sulfated. The sulfate donor in these and other biologic sulfation reactions is adenosine 3´- phosphate-5´-phosphosulfate (PAPS); this compound is called active sulfate
  17. 17. 3. Conjugation with Glutathione. Glutathione (γ- glutamylcysteinylglycine) is a tripeptide consisting of glutamic acid, cysteine, and glycine. Glutathione is commonly abbreviated to GSH; the SH indicates the sulfhydryl group of its cysteine and is the business part of the molecule. A number of potentially toxic electrophilic xenobiotics (such as certain carcinogens) are conjugated to the nucleophilic GSH. The enzymes catalyzing these reactions are called glutathione S-transferases and are present in high amounts in liver cytosol and in lower amounts in other tissues.
  18. 18. Acetylation. These reactions is represented by X + Acetyl- CoA → Acetyl-X + CoA, where X represents a xenobiotic. These reactions are catalyzed by acetyltransferases present in the cytosol of various tissues, particularly liver. The different aromatic amines, aromatic amino acids, such drug as isoniazid, used in the treatment of tuberculosis, and sulfanylamides are subjects to acetylation. Polymorphic types of acetyltransferases exist, resulting in individuals who are classified as slow or fast acetylators, and influence the rate of clearance of drugs such as isoniazid from blood.5. Methylation. A few xenobiotics (amines, phenol, tio- substances, inorganic compounds of sulphur, selen, mercury, arsenic) are subject to methylation by methyltransferases, employing S-adenosylmethionine as methyl donor. Also catecholamines and nicotinic acid amid (active form of vitamin PP) are inactivated due to methylation. Very important way of detoxification is ureogenes (urea synthesis). Free ammonia, which formed due to metabolism of amino acids, amides and amines, removed from organism in shape of urea.
  19. 19. Musclestructure
  20. 20. Proteins of muscles3 types:•proteins ofsarcoplasma•proteins ofmiofibrils•proteins ofstroma
  21. 21. Proteins of Sarcoplasma•Miogen fraction(enzymes of glycolysisetc.)•Albumins•Globulins•Myoglobin(chromoprotein,provides the red colorto muscles, responsiblefor oxygen storage)
  22. 22. Proteins of Stroma•collage•keratin•elastinare constituents ofconnective tissue ofvessel walls, nerves,sarcolema.
  23. 23. Proteins of Miofibrils•Myosin (56-60 %)•Actin (20-25 %)•Tropomyosin (10-15 %)•Troponin complex (4-6 %)
  24. 24. Structure of filaments and myofibrils Sarcoplasma of striated muscle fibers contains myofibrils oriented along which are built of 2 types protein filaments: thick and thin
  25. 25. •Muscle contraction is carried out due to thesliding of thick and thin filaments•Chemical energy – ATP hydrolysis•Contraction is regulated by Ca2+ concentration
  26. 26. Structure of Thick Filament•Thick filaments consist of myosin molecules•Myosin molecule built of 2 heavy (200000 Da)and 4 light (16000-25000 Da) chains•Heavy chains are coiled around each other andform the “tail” of the molecule•2 light chains form the globular head of themolecule•The head has ATP-ase properties
  27. 27. About 400 molecules of myosin arecombined in the thick filament
  28. 28. About half of molecules is directedto one end of filament, another half– to another end
  29. 29. The structure of thin filaments are proteins actin, tropomyosin andtroponinTwo forms of actin: globular G-actin and fibrillarF-actin.Globular actin molecules noncovalently connected to form F-actin.Two F-actin chains screwed into a spiral.In the groove spiral F-actin is located tropomyosin.With one molecule of tropomyosin contact 7 pairs of actin.At 1 tropomyosin molecule is 1 molecule of globular protein troponin.
  30. 30. •Two forms of actin: globular G-actin and F-actin fibrillar.Globular actin molecules nonсovalently connected toform F-actin.Two F-actin chains screwed into a spiral.Troponin is composed of 3 subunits (C, I, T).
  31. 31. Myofibrils contain approximately 2500 filaments.In a thick thread miozynovu contributes 6 thin
  32. 32. •structural unit of myofibrils - sarcomereboth ends of thick filaments myosin freethin filament with one end attached to the Z-disc
  33. 33. The sliding filament model describes themechanism involved in muscle contraction. [1 ] In the initial state, the myosin heads are attached to actin. When ATP is bound, the heads detach themselves from the actin (the “plasticizing” effect of ATP). [2 ] The myosin head hydrolyzes the bound ATP to ADP and Pi, but initially withholds the two reaction products. ATP cleavage leads to allosteric tension in the myosin head. [3 ] The myosin head now forms a new bond with a neighboring actin molecule. [4 ] The actin causes the release of the Pi, and shortly afterwards release of the ADP as well. This converts the allosteric tension in the myosin head into a conformational change that acts like a rowing stroke.
  34. 34. Red fibers provide for their ATPrequirementsmainly (but not exclusively) fromfatty acids, which are brokendown via β-oxidation,the tricarboxylic acid cycle, andthe respiratory chain (right part ofthe illustration). The red color inthese fibers is due to themonomeric heme proteinmyoglobin, which theyuse as an O2 reserve. Myoglobinhas a much higher afinity for O2than hemoglobin and thereforeonly releases its O2 when there isa severe drop in O2 partialpressure