Amino acids metabolism new


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Amino acids metabolism new

  1. 1. GENERAL PATHWAYS OF AMINO ACIDS METABOLISMDigestion and absorbtion of proteins in the gastrointestinal tract. Nitrogenous balance.
  2. 2. Proteins function in the organism. All enzymes are proteins. Storing amino acids as nutrients and as buildingblocks for the growing organism. Transport function (proteins transport fatty acids,bilirubin, ions, hormones, some drugs etc.). Proteins are essential elements in contractile andmotile systems (actin, myosin). Protective or defensive function (fibrinogen,antibodies). Some hormones are proteins (insulin, somatotropin). Structural function (collagen, elastin).
  3. 3. GENERAL PATHWAYS OF AMINO ACIDS METABOLISM Proteins of food Metabolites of Amino acids glycolysis and Krebs cycle Anabolic ways Catabolic waysSynthesis of Synthesis of Trans- Deami- Decar-cell and peptide ami- nation boxila-extracell physiologi- nation tionproteins cally active substances AminesProteins and peptides Urea, CO2, H2O of the organism
  4. 4. Nitrogen Balance (NB): Nitrogen balance is a comparison between Nitrogen intake (in the form of dietary protein) and Nitrogen loss (as undigested protein in feces,NPN as urea, ammonia, creatinine & uric acid in urine,sweat & saliva & losses by hair, nail, skin). NB is important in defining1.overall protein metabolism of an individual2.nutritional nitrogen requirement.
  5. 5. Nitrogenous balanceIt may be positive, negative and neutral (zero).Positive nitrogenous balance – the amount of nitrogen entered theorganism is more than amount of nitrogen removed from theorganism. It occurs in young growing organism, duringrecovering after severe diseases, at the using of anabolicmedicines pregnancy, lactation and convulascenceNegative nitrogenous balance – the amount of nitrogen removedfrom the organism is more than amount of nitrogen entered theorganism. It occurs in senile age, destroying of malignant tumor,vast combustions, poisoning by some toxins. High loss of tissueproteins in wasting diseases like burns, hemorrhage & kidneydiseases with albuminurea (High breakdown of tissue proteins )in hyperthyroidism, fever, infectionZero nitrogenous balance – the amount of nitrogen removed from theorganism is equal to the amount of nitrogen entered the organism. Itoccurs in healthy adult people Normal adult: will be in nitrogen equilibrium, Losses = Intake
  6. 6. A deficiency ofeven one aminoacid results in anegative nitrogenbalance.In this state, moreprotein isdegraded thansynthesized.
  7. 7. Protein Requirement for humans in Healthy and Disease ConditionsThe normal daily requirement of protein foradults is 0.8 g/Kg body wt. day-1.• That requirement is increased in healthyconditions:during the periods of rapid growth, pregnancy,lactation and adolescence.• Protein requirement is increased in diseasestates:illness, major trauma and surgery.• RDA for protein should be reduced in:hepatic failure and renal failure
  8. 8. Biological Value for Protein (BV)BV is : a measure for the ability of dietaryprotein to provide the essential amino acidsrequired for tissue protein maintenance.•Proteins of animal sources (meat, milk, eggs)have high BV because they contain all theessential amino acids.•Proteins from plant sources (wheat, corn,beans) have low BV thus combination of morethan one plant protein is required (avegetarian diet) to increase its BV.
  9. 9. Protein digestion Chemical composition of digestive juices.Gastric juice contains water, enzymes, hydrochloric acid,mineral salts and other compounds. About 2,5 l ofgastric juice is secreted per day.The role of hydrochloric acid in digestion. Denaturate proteins (denaturated proteins easierundergo digestion by pepsin than native proteins). Stimulates the activity of pepsin. Hydrochloric acid has bactericidial properties. Stimulates the peristalsis. Regulate the enzymatic function of pancreas.
  10. 10. Digestion in StomachStimulated by food acetylcholine, histamine and gastrin arereleased onto the cells of the stomachThe combination of acetylcholine, histamine and gastrin causethe liberation of the gastric juice. Mucin - is always secreted in the stomach HCl - pH 0.8-2.5 (secreted by parietal cells) Pepsinogen (a zymogen, secreted by the chief cells)
  11. 11. Proteolytic enzymes and their activation.Three enzymes are in gastric juice: pepsin, gastricsin and rennin. All these enzymes cleaveproteins or peptides.Pepsinogen (MW=40,000) is activated by the enzyme pepsin, which is already present in thestomach and by hydrochloric acid.Pepsinogen cleaved off to become the enzyme pepsin (MW=33,000) and a peptide fragment tobe degraded.Pepsin partially digests proteins by cleaving the peptide bond formed by aromatic aminoacids: Phe, Tyr, Trp
  12. 12. Optimal pH for gastricsin is 2,0-3,0. The ratio betweengastricsin and pepsin in gastric juice is 1:5,5. This ratio can bechanged in some pathological states.Rennin also possesses a proteolytic activity and causesa rapid coagulation of ingested casein. But this enzymeplays important role only in children because the optimal pHfor it is 5-6.
  13. 13. Digestion in the DuodenumStimulated by food secretin and cholecystokinin regulate thesecretion of bicarbonate and zymogens trypsinogen,chymotrypsinogen, proelastase and procarboxypeptidase bypancreas into the duodenumBicarbonate changes the pH to about 7 The intestinal cells secrete an enzyme called enteropeptidase that acts on trypsinogen cleaving it into trypsin
  14. 14. Enteropeptidase secreted by the mucosa of duodenum initiatesthe activation of the pancreatic proenzymes 14
  15. 15. Proteolytic enzymes exhibit the preference for particulartypes of peptide bondsProteinases preferentially attacks the bond after:Pepsin aromatic (Phe, Tyr) and acidic AA (Glu, Asp)Trypsin basic AA (Arg, Lys)Chymotrypsin hydrophobic (Phe, Tyr, Trp, Leu) and acidic AA (Glu,Asp)Elastase AA with a small side chain (Gly, Ala, Ser)Peptidases:Carboxypeptidase A nearly all AA (not Arg and Lys)Carboxypeptidase B basic AA (Arg, Lys)aminopeptidase nearly all AAProlidase proline 15Dipeptidase only dipeptides
  16. 16. The splitting of elastin in an intestine is catalyzed by elastaseand collagen is decomposed by collagenase.Digestion of protein takes place not only in the intestinal cavitybut also on the surface of mucosa cells.
  17. 17. Mechanism of amino acid absorbtion.This explanation is called the sodium cotransporttheory for amino acid transport; it is also called secondaryactive transport of amino acid.Absorption of amino acids through the intestine mucosa can occur far more rapidly than protein can be digested in the lumen of theintestine.Since most protein digestion occurs in the upper small intestinemost protein absorption occurs in the duodenum and jejunum.
  18. 18. Most proteins are completely digested to free amino acidsAmino acids and sometimes short oligopeptides are absorbed by thesecondary active transportAmino acids are transported via the blood to the cells of the body.
  19. 19. The sources of amino acids:1) absorption in the intestine; 2) formation during the protein decomposition; 3) synthesis from the carbohydrates and lipids.Using of amino acids:1) for protein synthesis;2) for synthesis of nitrogen containing compounds (creatine, purines,choline, pyrimidine);3) as the source of energy (oxidation – deamination, transamination,decarboxilation);4) for the gluconeogenesis;5) for the formation of biologically active compounds.
  20. 20. Overview of Amino Acid Catabolism: Interorgan Relationships
  21. 21. Overview of Amino Acid Catabolism: Interorgan Relationships• Liver – Synthesis of liver and plasma proteins – Catabolism of amino acids • Gluconeogenesis • Ketogenesis • Branched chain amino acids (BCAA) not catabolized • Urea synthesis – Amino acids released into general circulation • Enriched in BCAA (2-3X)
  22. 22. Overview of Amino Acid Catabolism: Interorgan Relationships• Skeletal Muscle – Muscle protein synthesis – Catabolism of BCAA • Amino groups transported away as alanine and glutamine (50% of AA released) – Alanine to liver for gluconeogenesis – Glutamine to kidneys• Kidney – Glutamine metabolized to a-KG + NH4 • a-KG for gluconeogenesis • NH4 excreted or used for urea cycle (arginine synthesis) – Important buffer from acidosis
  23. 23. PROTEIN TURNOVERProtein turnover — the degradation and resynthesisof proteinsHalf-lives of proteins – from several minutes to many yearsStructural proteins – usually stable (lens protein crystallin livesduring the whole life of the organism)Regulatory proteins - short lived (altering the amounts of theseproteins can rapidly change the rate of metabolic processes)How can a cell distinguish proteins that are meantfor degradation?
  24. 24. Ubiquitin - is the tag that marksproteins for destruction ("blackspot" - the signal for death)Ubiquitin - a small (8.5-kd) proteinpresent in all eukaryotic cellsStructure: extended carboxyl terminus(glycine) that is linked to otherproteins; lysine residues for linkingadditional ubiquitin molecules
  25. 25. Proteasomes degrade regulatory proteins (short half-life)and abnormal or misfolded proteins - hollow cylindric supramolecule, 28 polypeptides Protein-Ub - four cyclic heptamers (4 × 7 = 28) regulation of - the caps on the ends regulate the entry of proteins into cell cycle, destruction chamber, upon ATP apoptosis, hydrolysis - inside the barrel, differently angiogenesis specific proteases hydrolyze target protein into short (8 AA) peptides cytosolic - Ub is not degraded, it is peptidases Ub + short peptides AA released intact 25
  26. 26. GENERAL WAYS OF AMINO ACIDS METABOLISMThe fates of amino acids:1) for protein synthesis;2) for synthesis of other nitrogen containing compounds(creatine, purines, choline, pyrimidine);3) as the source of energy;4) for the gluconeogenesis.
  27. 27. The general ways of amino acids degradation:  Deamination  Transamination  Decarboxilation The major site of amino acid degradation - the liver. Deamination of amino acids Deamination - elimination of amino group from amino acid withammonia formation. Four types of deamination: - oxidative (the most important for higher animals), - reduction, - hydrolytic, and - intramolecular
  28. 28. Reduction deamination:R-CH(NH2)-COOH + 2H+ → R-CH2-COOH + NH3 amino acid fatty acid Hydrolytic deamination:R-CH(NH2)-COOH + H2O → R-CH(OH)-COOH + NH3 amino acid hydroxyacid Intramolecular deamination:R-CH(NH2)-COOH → R-CH-CH-COOH + NH3 amino acid unsaturated fatty acid
  29. 29. General scheme of oxydative transaminationR CH COOH + HOOC C CH2CH2COOH NH2 Oaminokyselina amino acid 2-oxoglutarate 2-oxoglutarát aminotransferase aminotransferasa pyridoxalfosfát pyridoxal phosphateR C COOH + HOOC CH CH2CH2COOH O NH22-oxokyselina 2-oxo acid glutamát glutamate 29
  30. 30. Glutamate dehydrogenase (GMD, GD, GDH)• requires pyridine cofactor NAD(P)+• GMD reaction is reversible: dehydrogenation with NAD+, hydrogenation with NADPH+H+• two steps:• dehydrogenation of CH-NH2 to imino group C=NH• hydrolysis of imino group to oxo group and ammonia 30
  31. 31. In transaminations, nitrogen of most !AA is concentrated in glutamateGlutamate then undergoesdehydrogenation + deamination and releases free ammonia NH3 31
  32. 32. Oxidative deaminationL-Glutamate dehydrogenase plays a central role in amino aciddeaminationIn most organisms glutamate is the only amino acid that hasactive dehydrogenasePresent in both the cytosol and mitochondria of the liver
  33. 33. Transamination of amino acids Transamination - transfer of an amino group from an α - amino acid to an α -keto acid (usually to α -ketoglutarate) Enzymes: aminotransferases (transaminases). α -keto acidα -amino acid α -keto acid α -amino acid
  34. 34. There are different transaminasesThe most common:alanine aminotransferase alanine + α-ketoglutarate ⇔ pyruvate +glutamateaspartate aminotransferaseaspartate + α-ketoglutarate ⇔ oxaloacetate + glutamateAminotransferases funnel α -amino groups from a variety ofamino acids to α-ketoglutarate with glutamate formationGlutamate can be deaminated with NH4+ release
  35. 35. Mechanism of transaminationAll aminotransferases require theprosthetic group pyridoxalphosphate (PLP), which is derivedfrom pyridoxine (vitamin B6).Ping-pong kinetic mechanismFirst step: the amino group ofamino acid is transferred topyridoxal phosphate, formingpyridoxamine phosphate andreleasing ketoacid.Second step: α-ketoglutaratereacts with pyridoxaminephosphate forming glutamate
  36. 36. Ping-pong kinetic mechanism of aspartate transaminaseaspartate + α-ketoglutarate ⇔ oxaloacetate + glutamate
  37. 37. Decarboxylation of amino acids Decarboxylation – removal of carbon dioxide from amino acid with formation of amines. amineUsually amines have high physiological activity(hormones, neurotransmitters etc). Enzyme: decarboxylases Coenzyme – pyrydoxalphosphate
  38. 38. DECARBOXYLATION OF AMINO ACIDS α-decarboxilation ω-decarboxilation Decarboxilation with transaminationDecarboxilation with conjugation of two molecules
  39. 39. Significance of amino acid decarboxylation1. Formation of physiologically active compounds glutamate gamma-aminobutyric acid (GABA) histidine histamine
  40. 40. 1) A lot of histamine is formed in inflamatory place;It has vasodilator action;Mediator of inflamation, mediator of pain;Responsible for the allergy development;Stimulate HCI secretion in stomach. -CO22) Tryptophan → SerotoninVasokonstrictorTakes part in regulation of arterial pressure, bodytemperature, respiration, kidney filtration, mediator ofnervous system3) Tyrosine → DopamineIt is precursor of epinephrine and norepinephrine.mediator of central nervous system4) Glutamate → γ -aminobutyrate (GABA)Is is ingibitory mediator of central nervous system. Inmedicine we use with anticonvulsion purpose (action).
  41. 41. 2. Catabolism of amino acids during the decomposition of proteinsEnzymes of microorganisms (in colon; dead organisms)decarboxylate amino acids with the formation of diamines.ornithine putrescine lysine cadaverine