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Protein metabolism

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protein metabolism

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Protein metabolism

  1. 1. PROTEIN METABOLISM Dr. Ifat Ara Begum Assistant Professor Dept. of Biochemistry Dhaka Medical College Dhaka
  2. 2. AMINO ACIDS Any molecule that contains the amino and carboxylic acid functional groups. Or Organic acids containing amino groups are known as amino acids.
  3. 3. STRUCTURE OF AMINO ACID A central carbon atom to which 4 diff groups of atoms are attached: An Amino group (NH2)  A Carboxylic acid group (COOH)  A Hydrogen atom (H)  A Radical or R group: H, CH3, CH3-CH2 etc.
  4. 4. CONTD The acidic and basic properties of NH2 & COOH groups make the AA molecule “Amphoteric”
  5. 5. FATE OF ABSORBED AMINO ACIDS Anabolic fates: Synthesis of:  Tissue protein (structural/enzyme/hormone)  NPN subs  FA, ketone bodies, Steroids (via acetyl co A, end product of catabolism of AA C skeleton)  Glucose/glycogen (via pyruvate & TCA cycle intermediates).
  6. 6. CONTD. Catabolic fates: Through transamination and deamination, each AA produces NH3 & their corresponding C-skeleton (α-keto acid).  NH3 is converted to urea via urea cycle in liver & then excreted with urine.
  7. 7. CONTD.  C-skeleton is catabolized to – 1. Pyruvate & TCA cycle intermediates (if glucogenic AA) 2. Acetyl co A /Aceto acetyl co A ( if ketogenic AA) 3. CO2, H2O & ATP through oxidation in TCA cycle.
  8. 8. PROTEIN TURNOVER  It is the rate at which proteins are constantly being degraded & again resynthesized. It is 150-300gm/D (i.e.1- 2% of total body protein) in adult. [Total body protein in 70kg adult is 12- 14kg]
  9. 9. CONTD  If a cell takes up as much AA as it loses, it is in a state of dynamic equilibrium.  If the loss is greater, the cell wastes & if the gain is greater, the cell grows.  Not only the proteins, practically, all the materials in the body, even the depot fat, are in a state of dynamic equilibrium.
  10. 10. AMINO ACID POOL It is the free amino acid content distributed throughout the extracellular fluid/body. Quantitatively, it is about 100 gm in an adult individual . Plasma AA level varies throughout the day fm 4- 8mg/dl.
  11. 11. CONTD It is constantly undergoing depletion due to disposal of AA through diff metabolic processes usually at a rate equal to the rate by which AA feeds the pool. It is always being reestablished by AA coming from three sources- dietary protein, endogenous AA synthesis & endogenous protein break down.
  12. 12. SOURCES OF AA IN AA POOL 1. Dietary protein 2. break down of tissue proteins 3. biosynthesis of NEAAs.
  13. 13. FATE OF AA IN AA POOL Biosynthesis of :  structural protein, e.g. tissue proteins  Functional proteins, e.g. Hb, myoglobin, enz, protein hormones.  Small peptides of biological importance, e.g. glutathione, endorphins & encephalin.  NPN subs, e.g. urea, uric acid, creatinine, ammonia. Catabolism of AA to give α-keto acids & ammonia.
  14. 14. INTERMEDIARY METABOLISM OF AMINO ACIDS Protein synthesis & synthesis of NPN substance Transamination & Deamination Urea cycle Catabolism of AA C-skeleton & synthesis of glucose, FA, steroids, ketone bodies, etc. Oxidation of AA C-skeleton via TCA cycle
  15. 15. NITROGEN BALANCE It is the diff b/w N-intake & N- loss/excretion N-intake occurs in the form of protein/AA N-excretion occurs through urine, sweat & stool
  16. 16. CONTD 3 types :  N-equilibrium: seen in normal individual, where intake equals to excretion.  Positive N balance: seen during growth, pregnancy, etc , where intake is more than loss.  Negative N balance: seen in DM, TB, malignancy, surgery, starvation, trauma, etc, where loss is more than intake.
  17. 17. 1. TRANSAMINATION It is the transfer of amino group from an AA to a keto acid with simultaneous production of a corresponding keto acid & AA respectively. Site: cytoplasm of liver, kidney, heart, sk. Muscle, brain.
  18. 18. CONTD All AAs except Lys, Thr & Pro undergo transamination. Usually 3 keto acids mostly participate in transamination. These are α-KG (keto acid of Glu), OA ( keto acid of Asp), pyruvate (keto acid of Ala). All reactions are reversible & are catalyzed by aminotransferases /transaminases. It needs pyridoxal PO4 as co-enzyme.
  19. 19. CONTD
  20. 20. ROLE OF PYRIDOXAL PO4 IN TRANSAMINATION It acts as an intermediate carrier of an NH2 group. It accepts the -NH2 group from AA to form pyridoxamine PO4 , which in turn gives the -NH2 group to α-keto acid.
  21. 21. EXAMPLE OF TRANSAMINASES Alanine transaminase Aspartate transaminase Glutamate transaminase.
  22. 22. IMPORTANCE OF TRANSAMINATION Funneling of NH2 group of diff AAs ultimately to α-KG to form Glu & Glu is the major AA that undergoes oxidative deamination to liberate free NH3, which is converted to urea. Biosynthesis of NEAA by adding NH2 group to their corresponding keto acid (C-skeleton), thus equalize the quantities of NEAA.
  23. 23. CONTD Formation of C-skeleton (keto acid) of AAs that later on can be catabolized/oxidized. Provides a link b/w carbohydrate, protein & fat metabolism, since the keto acids generated by transamination of AA can form compounds common to their metabolic cycle.
  24. 24. 2. DEAMINATION Deamination means removal of –NH2 group from an AA in the form of NH3 with simultaneous formation of its corresponding keto acid. Mitochondria of Liver and kidney are the main site of deamination. It also may occur in heart, sk. Muscle etc. It may be oxidative/non-oxidative.
  25. 25. A) OXIDATIVE DEAMINATION An oxidation (dehydrogenation) process, where an amino acid is converted into the corresponding keto acid by the removal of the amine functional group as ammonia .The ammonia eventually goes into the urea cycle. It is catalyzed by one of the following enzymes: L-AA oxidase / D-AA oxidase /Glu DH.
  26. 26. CONTD
  27. 27. CONTD Oxidative deamination occurs primarily on Glu because Glu is the end product of many transamination reactions. If this is true, then how are the other amino acids deaminated? The answer is that a combination of transamination and deamination of Glu occurs which is a recycling type of reaction for Glu. The original amino acid loses its amine group in the process.
  28. 28. B) NON-OXIDATIVE DEAMINATION -NH2 groups of serine, homoserine, threonine, etc are removed non- oxidatively by a group of dehydratases to release ultimately NH3 & corresponding keto acids. It is catalyzed by one of the following enzymes: dehydratases or Desulfhydrases.
  29. 29. DIFF B/W TRANS DEAMINATION Transamination Oxidative deamination It is the transfer of amino group from an AA to a keto acid with simultaneous production of a corresponding keto acid & AA respectively. Reactions are catalyzed by aminotransferases /transaminases. It needs pyridoxal PO4 as co- enzyme. An oxidation (dehydrogenation) process, where an amino acid is converted into the corresponding keto acid by the removal of the amine functional group as ammonia . It is catalyzed by L-AA oxidase / D-AA oxidase /Glu DH.
  30. 30. DIFF B/W TRANS DEAMINATION Transamination Oxidative deamination The most usual and major keto acid involved with transamination reactions is α-KG, an intermediate in the citric acid cycle. A specific example is the transamination of alanine to make pyruvic acid and glutamic acid. Oxidative deamination occurs primarily on glutamic acid because glutamic acid was the end product of many transamination reactions. A specific example is the deamination of glutamic acid to make NH3 and α-KG
  31. 31. METABOLISM OF AMMONIA Source: 1. Deamination of amino acids 2. Glutamine by glutaminase enzyme in kidney. 3. Catabolism of purine & pyrimidine 4. Bacterial degradation of urea in to NH3 in intestinal lumen (action of bacterial urease).
  32. 32. CONTD Disposal of NH3: 1. formation of urea through urea cycle and its excretion with urine. 2. Excretion of NH3 with urine as NH4+. 3. Formation of glutamate in liver. (NH3 is added with α-KG to form glutamate). 4. Formation of glutamine in liver, kidney, muscle, brain. (Glutamine is the temporary non-toxic storage & transport form of NH3. NH3 is added with glutamate to form glutamine).
  33. 33. NH3 INTOXICATION (HEPATIC ENCEPHALOPATHY) Toxicity resulting from hyperammonemia. (Normal P/NH3 conc. 10-80 µg/dl or 5-50 µmol/L) Occurs due to hepatic dysfunction leading to impairment of urea cycle and/or deficiency of urea cycle enzymes.
  34. 34. CONTD Brain tissue is mostly affected & there is reduced cerebral activity. In neuron, excess NH3 converts α-KG to Glu, then to Glutamine. This causes rapid ↓ of α-KG, leading to suppression of TCA cycle. There is ATP depletion , ultimately producing s/s like tremor, slurring of speech, blurring of vision, coma, death.
  35. 35. 3. UREA CYCLE The urea cycle (Ornithine cycle) is a cycle of biochemical reactions occurring in many animals that produces urea ((NH 2)2CO) from ammonia (NH3 ) It occurs in liver Consists of five reactions: two mitochondrial and three cytosolic
  36. 36. 3. UREA CYCLE The cycle converts two amino groups (one from NH4 + and one from Asp) and a carbon atom (from HCO3 −) to the relatively nontoxic excretion product , urea at the cost of four "high-energy" phosphate bonds (3 ATP hydrolyzed to 2 ADP and one AMP) Ornithine is the carrier of these carbon and nitrogen atoms.
  37. 37. Step Reactants Products Catalyzed by Location 1 NH4 + + HCO3 − + 2ATP carbamoyl phosphate + 2ADP+ Pi CPS1 (carbamoyl PO4 synthase 1) mitochondri a 2 carbamoyl phosphate + Ornithine Citruline + Pi OTC (ornithine transcarbamy- lase) mitochondri a 3 citrulline + aspartate + ATP Arginosuccin -ate+AMP+ PPi ASS (arginosuccinat e synthetase) cytosol 4 arginosuccinate Arg+ fumarate ASL (AS lyase) cytosol 5 Arg +H2O Ornithine+ urea ARG1 (arginase 1) cytosol
  38. 38. INBORN ERROR OF PROTEIN METABOLISM Alkaptonuria Homocystinuria Phenylketonuria Albinism Maple syrup urine disease Hyperhomocysteinemia Defects in urea cycle