1 amino acid metabolism

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1 amino acid metabolism

  1. 1. Amino Acid Metabolism
  2. 2. + Incorporation of NH4 Into Organic Compounds + - Carbamoyl1) NH4 + HCO3 + 2 ATP Phosphate NH2CO2PO3-2 + 2 ADP + Synthase I + Carbamoyl Phosphate Pi + 2 H (CPS-I) TCA Cycle O Glutamate + NH3+2) NH4 + - O 2 CCH 2 CH 2 CCO 2 - dehydrogenase - O 2 CCH 2 CH 2 CHCO 2 - a-Ketoglutarate NADPH + H+ NADP + Glutamate 2
  3. 3. + Incorporation of NH4 Into Organic Compounds (Cont.) 3) NH3+ + - O 2 CCH 2 CH 2 CHCO 2 - + NH4 + 2 ATP Glutamate Glutamine Synthase Mg++ O NH3+ H2 NCCH 2 CH 2 CHCO 2 - GlutamineN of glutamine donated to other compoundsin synthesis of purines, pyrimidines, 3and other amino acids
  4. 4. Biosynthesis of Amino Acids: TransaminationsAmino Acid1 +a-Keto Acid2 Amino Acid2 +a-Keto Acid1 NH3+ O - O 2 CCH 2 CH 2 CHCO 2 - + R-CCO 2 - Glutamate Pyridoxal phosphate (PLP)- Dependent Aminotransferase O NH2 - O 2 CCH 2 CH 2 CCO 2 - + R-CHCO 2 - a-Ketoglutarate 4
  5. 5. Transaminations: Role of PLP CO2 - CHO H N CHCH2 CH2 CO2- C HO CH2 OPO3-2 HO CH2 OPO3-2 H3 C N H3 C + N H + NH3 + H2 O H - - O 2 CCH 2 CH 2 CHCO 2 Tautomerization O CO2 - - - O 2 CCH 2 CH 2 CCO 2 N CCH2 CH2 CO2- CH2 NH2 CH2 HO CH2 OPO3-2 HO CH2 OPO3-2 H3 C N H2 O H3 C + N + H H 5
  6. 6. Transaminations Glutamate-Pyruvate AminotransferaseGlutamate (Alanine Transferase ALT) a-Ketoglutarate + +Pyruvate Alanine Glutamate-Oxaloacetate Aminotransferase (Aspartate Transferase AST)Glutamate a-Ketoglutarate + +Oxaloacetate AspartateBlood levels of these aminotransferases, also called transaminases,are important indicators of liver disease 6
  7. 7. Metabolic Classification of the Amino Acids • Essential and Non-essential • Glucogenic and Ketogenic 7
  8. 8. Non-Essential Amino Acids in Humans• Not required in diet• Can be formed from a-keto acids by transamination and subsequent reactions • Alanine • Glycine • Asparagine • Proline • Aspartate • Serine • Glutamate • Cysteine (from Met*) • Glutamine • Tyrosine (from Phe*) * Essential amino acids 8
  9. 9. Essential Amino Acids in Humans• Required in diet• Humans incapable of forming requisite carbon skeleton • Arginine* • Lysine • Histidine* • Methionine • Isoleucine • Threonine • Leucine • Phenylalanine • Valine • Tryptophan * Essential in children, not in adults 9
  10. 10. Glucogenic Amino Acids• Metabolized to a-ketoglutarate, pyruvate, oxaloacetate, fumarate, or succinyl CoA • Aspartate • Methionine • Alanine • Asparagine • Valine • Serine • Arginine • Glutamine • Cysteine • Phenylalanine • Glutamate • Glycine • Tyrosine • Proline • Threonine • Isoleucine • Histidine • Tryptophan 10
  11. 11. Ketogenic Amino Acids• Metabolized to acetyl CoA or acetoacetate • Isoleucine • Lysine • Leucine • Phenylalanine • Threonine • Tyrosine • Tryptophan 11
  12. 12. Amino Acids Formed From a-Ketoglutarate O - O 2 CCH 2 CH 2 CCO 2 - a-Keto- 4 Steps Transamination or glutarate Glutamate dehydrogenase + CO2- N NH3+ H H Proline- - 5 Steps O 2 CCH 2 CH 2 CHCO 2Glutamate NH3+ + Glutamine H3 NCH 2 CH 2 CH 2 CHCO 2 - Ornithine synthase Urea Cycle O NH3+ NH2 NH3+ +H2 NCCH 2 CH 2 CHCO 2 - H2 N=C-HNCH 2 CH 2 CH 2 CHCO 2 - Arginine Glutamine 12 Guanidino group
  13. 13. GABA Formation Glutamate NH3+ decarboxylase NH3+ - O 2 CCH 2 CH 2 CHCO 2 - - O 2 CCH 2 CH 2 CH 2 Glutamate Gamma-aminobutyrate CO2 (GABA)GABA is an important inhibitory neurotransmitterin the brainDrugs (e.g., benzodiazepines) that enhance the effectsof GABA are useful in treating epilepsy 13
  14. 14. Arginine Synthesis: The Urea Cycle NH3+ N-Acetylglutamate NHCOCH3 - synthase O 2 CCH 2 CH 2 CHCO 2 - - O 2 CCH 2 CH 2 CHCO 2 - CoASAc Glutamate N-Acetylglutamate Activates 4 Steps Carbamoyl NH3+ CPS-I phosphate + NH4+ + HCO3- NH2CO2PO3-2 H3 NCH 2 CH 2 CH 2 CHCO 2 - Ornithine NH3+ Ornithine Transcarbamoylase (OTC) NH2 CONH CH 2 CH 2 CH 2 CHCO 2 - (mitochondria) Citrulline 14Ureido group
  15. 15. The Urea Cycle (Contd.) NH3+ + Asp NH3+ NH3-CHCH2CO2- + -NH2 CONH CH 2 CH 2 CH 2 CHCO 2 CO2- H2 N=C-HNCH 2 CH 2 CH 2 CHCO 2 - Citrulline Arginosuccinate NH-CHCH2CO2- synthase CO2- Arginosuccinate Ornithine Transcarbamoylase (mitochondria) H CO2- Fumarate NH3+ Urea + - O2 C H H3 NCH 2 CH 2 CH 2 CHCO 2 - H2NCONH2 Argino- succinase Ornithine TCA Cycle NH2 NH3+ Arginase + H2 N=C-HNCH 2 CH 2 CH 2 CHCO 2 - 15 Arginine
  16. 16. Urea Formation• Occurs primarily in liver; excreted by kidney• Principal method for removing ammonia• Hyperammonemia: • Defects in urea cycle enzymes (CPS, OTC, etc.) • Severe neurological defects in neonates • Treatment: » Stop protein intake » Dialysis » Increase ammonia excretion: Na benzoate, Na phenylbutyrate, L-arginine, L-citrulline 16
  17. 17. Blood Urea Nitrogen• Normal range: 7-18 mg./dL• Elevated in amino acid catabolism• Glutamate N-acetylglutamate CPS-1 activation• Elevated in renal insufficiency• Decreased in hepatic failure 17
  18. 18. Synthesis of Nitric Oxide NH2 NH3+ + Arginine H2 N=C-HNCH 2 CH 2 CH 2 CHCO 2 - Nitric oxide synthase (NOS) NH3+ NH2 CONH CH 2 CH 2 CH 2 CHCO 2 - + NO Citrulline 18
  19. 19. Nitric Oxide• Cell messenger• Implicated in a wide range of physiological and pathophysiological events:• Vasodilation: • Activates guanylyl cyclase cGMP • Nitroglycerin Glycerin + NO • Sildenafil (Viagra): in vascular smooth muscle: Blocks Phospho- diesterase-5 NO cGMP GMP 19
  20. 20. Review Questions 20
  21. 21. Which one of the following doesnot belong on this list? A. Carbamoyl phosphate B. Urea C. Glutamate D. GlutamineExplain your answer: 21
  22. 22. A glucose metabolite formed in the transamination of alanine ___________Derivatives of this vitamin are involved in transamination reactions ______________An amino acid, not found in peptides, that is formed in the urea cycle ______________The amino acid that is the immediate precursor of urea and 22 NO ____________
  23. 23. Decarboxylation of ___________affords ___________, an importantinhibitor of neurotransmission in theCNSExplain the importance of the BloodUrea Nitrogen (BUN) test:____________________________________________________________________ 23
  24. 24. Categorize the following amino acidsas glucogenic (G) or ketogenic (K);essential (E) or non-essential (NE): Leucine: G K E NE Phenylalanine: G K E NE Glutamate: G K E NE 24
  25. 25. Formation of Serine CO 2 - CO 2 - Dehydrogenase GlycolysisGlucose H C OH C=O NAD+ NADH + CH2 OPO3-2 H+ CH2 OPO3-2 3 Steps 3-Phospho- 3-Phospho- glycerate hydroxypyruvate Pyruvate Inhibits Glutamate Transaminase a-Ketoglutarate - CO 2 CO 2 - Phosphatase H C NH3 + H C NH3 + CH2 OH CH2 OPO3-2 Serine (Ser) 3-Phosphoserine 25
  26. 26. Conversion of Serine to Glycine H Dihydrofolate H2 N N N reductase CO 2 -Folate N N CH2 NHR H C NH3 + OH H Serine Tetrahydrofolate CH2 OH (FH4) Serine hydroxymethyl transferase (PLP-dep.) H N Key intermediate CO 2 - in biosynthesis of N CH2 Glycine H C NH3 + purines and N formation of H2 C H thymine Important in N5, N10-Methylene FH4 biosynthesis of heme, porphyrins, and purines 26
  27. 27. Sulfur-Containing Amino Acids Methionine Synthase NH3+ NH3+ (Vit. B12-dep.) - - HSCH 2CH 2CHCO 2 + 5-Methyl CH 3SCH 2CH 2CHCO 2 + FH4 FH4 Methionine L-Homocysteine (Essential) CO 2 - Cystathionine H C NH3 + Serine b-synthase CH2 OH (PLP-dep.) Cystathionine NH3+ OH NH3+ lyase - SCH 2CH 2CHCO 2CH 3CHCH 2CO 2 - + HSCH 2CHCO 2 - CH2CHCO2- Cystathionine b-Hydroxy- Cysteine NH3+ butyrate (Non-essential) 27
  28. 28. HomocysteineHomocysteinuria • Rare; deficiency of cystathionine b-synthase • Dislocated optical lenses • Mental retardation • Osteoporosis • Cardiovascular disease deathHigh blood levels of homocysteine associated withcardiovascular disease • May be related to dietary folate deficiency • Folate enhances conversion of homocysteine to methionine 28
  29. 29. Methionine Metabolism: Methyl Donation NH2 N N S-Adenosyl methionine N N NH3+ synthase + - - O2 CCHCH2 CH2 -S-H2 C O CH 3SCH 2CH 2CHCO 2 ATP NH3 + CH3 Methionine OH OH SAM Decarboxylase S-Adenosyl Methionine NH2 NH2 (SAM) N N NDecarboxylated N CO2 SAM N R-H N N N Methyl- -O transferases + + 2 CCHCH2 CH2 -S-H2 C O H3 NCH2 CH2CH 2-S-H2C O NH3 + R-CH3 CH3 S-Adenosyl OH OH homocysteine 29 OH OH
  30. 30. Polyamine Biosynthesis Ornithine decarboxylase NH3+ (ODC) + + + NH3 (PLP-dep.) H3 NCH 2 CH 2 CH 2 CHCO 2 - H3N Ornithine Putrescine (from urea cycle) CO2 Decarboxylated SAM Spermidine H + synthase + + N+ NH3H3N N 5’-Methylthio- H Spermine H H adenosine synthase Spermine 5’-Methylthio- H + + +N NH3 adenosine H3N H Decarboxylated Spermidine SAM 30
  31. 31. Polyamines• Spermidine and spermine found in virtually all procaryotic and eucaryotic cells• Precise role undefined • Bind to nucleic acids• Inhibition of biosynthetic pathway: CO2H a-Difluoromethyl- NH2 ornithine (DFMO) H2N (Eflornithine) - inhibits ODC; CHF2 used to treat Pneumocystis carinii infectons 31
  32. 32. Creatine and Creatinine Arginine-glycine transamidinase NH2 NH2 NH3+ (Kidney) + +H2 N=C-HNCH 2 CH 2 CH 2 CHCO 2 - H2 N=C-HNCH 2 CO 2 - Glycine Ornithine Arginine Guanidoacetate SAM + ATP H Guanidoacetate N O Methyltransferase S-Adenosyl- (Liver) homocysteine Creatinine HN + ADP (Urine) N Non-enzymatic (Muscle) NHPO3-2 CH3 + Creatine kinase H2 N=C-NCH 2 CO 2 - NH2 (Muscle) CH3 + Creatine H2 N=C-NCH 2 CO 2 - ADP Phosphocreatine + Pi CH3 ATP 32
  33. 33. Creatine and CreatinineCreatine: • Dietary supplement • Used to improve athletic performanceCreatinine: • Urinary excretion generally constant; proportional to muscle massCreatinine Clearance Test: • Compares the level of creatinine in urine (24 hrs.) with the creatinine level in the blood • Used to assess kidney function • Important determinant in dosing of several drugs in patients with impaired renal function 33
  34. 34. Histidine Metabolism: Histamine Formation + NH3 H N CH2CHCO2 - Histidine H decarboxylase N CH2CH2NH2 N N Histidine CO2 HistamineHistamine: • Synthesized in and released by mast cells • Mediator of allergic response: vasodilation, bronchoconstriction (H1 receptors) • H1 blockers: Diphenhydramine (Benadryl) Loratidine (Claritin) • Stimulates secretion of gastric acid (H2 receptors) • H2 blockers: Cimetidine (Tagamet); ranitidine (Zantac) 34
  35. 35. Review Questions 35
  36. 36. This amino acid, formed from serine usinga folate-derived coenzyme, is a keybuilding block in the biosynthesis ofheme and purines ________________ 36
  37. 37. High blood levels of this amino acid, which isnot found in peptides, are associated withincreased risk of cardiovascular disease ________________Explain why a person found to have highlevels of this amino acid might benefit fromthe use of folic acid __________________ 37
  38. 38. NH2 N N N N + - O2 CCHCH2 CH2 -S-H2 C O NH3 + CH3 OH OHWhat is the name of the above compound?Explain the importance of the abovecompound in the cell: 38
  39. 39. Name:An arginine metabolite, formed mainly inmuscle and excreted in the urine, that issometimes used as a dietary supplementto improve athletic performance ___________An amino acid, which upon decarboxylation,produces a compound some of whose biologicaleffects are blocked by cimetidine (Tagamet)_________________ 39
  40. 40. Phenylalanine and TyrosinePhenylalanine H H2N N N H(Essential) Tetrahydrobiopterin H NH3+ + HN N CHCHCH 3 CH2CHCO2- O H HO OH O2 Phenylalanine-4- NADP+ Monooxygenase (Phenylalanine H2O NADPH + H+ hydroxylase) HO N N H2N NH3+ Dihydrobiopterin + CH2CHCO2- HN N CHCHCH 3 Tyrosine H (Non-essential) O HO OH 40
  41. 41. Phenylketonuria (PKU) Disease• Deficiency of Phe hydroxylase• Occurs in 1:16,000 live births in U.S.• Seizures, mental retardation, brain damage• Treatment: limit phenylalanine intake• Screening of all newborns mandated in all states Tyr Phe Phenylpyruvate Transamination (urine) O 41 CH2CCO2-
  42. 42. Catecholamine Biosynthesis HO Catechol HO Tyr hydroxylase NH3+ NH3+ CH2CHCO2- O2 HO CH2CHCO2- Tyrosine Dihydroxyphenylalanine (DOPA)HO DOPA Epinephrine (Adrenaline) decarboxylase CO2HO CHCH2NHCH3 HO OH Methyl Dopamine transferase hydroxylase S-Adenosyl- HO HO CH2CH2NH2 homocysteine SAM Dopamine HO CHCH2NH2 DOPA, dopamine, norepinephrine, Norepinephrine 42 OH and epinephrine are all neurotransmitters
  43. 43. L-DOPA in Parkinsonism Blood Brain L-DOPA L-DOPA DopamineHO CH3 BlocksHO CH2 -C-CO2H Carbidopa NHNH2 Parkinsonism associated with dopamine in brain through loss of Dopamine neurons in basal ganglia. Carbidopa + L-DOPA Blood Brain Barrier 43
  44. 44. Monoamine Oxidase (MAO) HO MAO HO (in mitochondria) HO CHCH2 NHR CHCHO HO R R R R’ Aldehyde dehydrogenase OH H Norepi HO OH CH3 Epi H H Dopamine CHCO2H HO Urinary RMAO inhibitors (e.g., tranylcypromine) are useful metabolitein the treatment of depression R=OH Vanillylmandelic acid (VMA) Brain levels of dopamine and norepi.; also R=H Homovanillic acid (HVA) serotonin 44
  45. 45. Tyramine OH OH MAO CH2 CH2 NH2 CH2 CHO Tyramine ( blood pressure)• Tyramine found naturally in several types of cheese; also beer and red wine.• Tyramine intake can cause hypertensive crisis in persons taking a MAO inhibitor ( norepi release) 45
  46. 46. Catechol-O-Methyl Transferase (COMT) HO HO COMT HO CHCH2 NHR CH3O CHCH2NHR SAM S-Adenosyl- Active R homocysteine Rcatecholamine Inactive metabolite • COMT found in cytoplasm • Terminates activity of catecholamines • Catecholamine excretion products result from combined actions of MAO and COMT • Inhibitors of COMT (e.g., tolcapone) useful in Parkinson’s disease 46
  47. 47. Homogentisic Acid FormationHO HO Transamination O NH3+ CH2CHCO2- CH2CCO2- Tyrosine p-Hydroxyphenyl- pyruvate Deficient in O2 alkaptonuria p-Hydroxyphenyl- pyruvate OH Homogentisate dioxygenase dioxygenase (ascorbate-dep.) Cleavage of aromatic ring CO2 CH2 CO2- O2 Fumarate + acetoacetate OH Homogentisate 47
  48. 48. Alkaptonuria• Deficiency of homogentisate dioxygenase• Urine turns dark on standing • Oxidation of homogentisic acid• Asymptomatic in childhood• Tendency toward arthritis in adulthood 48
  49. 49. Melanin FormationHO HO Tyr hydroxylase NH3+ NH3+ CH2CHCO2- O2 HO CH2CHCO2- Tyrosine DOPA Tyrosinase O Melanin Highly colored(Black polymer) polymeric intermediates O CH2CHCO2 - NH3 + Melanin formed in skin (melanocytes), eyes, and hair In skin, protects against sunlight Dopaquinone Albinism: genetic deficiency of tyrosinase 49
  50. 50. Tryptophan Metabolism: Serotonin Formation +Indole ring NH3 + NH3 CH2 CHCO2 - CH2CHCO2 - CH2CH2NH2 Trp hydroxylase HO HO Decarboxylase N H O2 N N H H Tryptophan 5-Hydroxy- CO2 5-Hydroxy- (Trp) tryptophan tryptamine (5-HT); Serotonin 50
  51. 51. Serotonin• Serotonin formed in: • Brain (neurotransmitter; regulation of sleep, mood, appetite) • Platelets (platelet aggregation, vasoconstriction) • Smooth muscle (contraction) • Gastrointestinal tract (enterochromaffin cells - major storage site)• Drugs affecting serotonin actions used to treat: • Depression •Serotonin-selective reuptake inhibitors (SSRI) • Migraine • Schizophrenia • Obsessive-compulsive disorders • Chemotherapy-induced emesis• Some hallucinogens (e.g., LSD) act as serotonin agonists 51
  52. 52. L-Tryptophan• Food supplement promoted for serotonin effects• L-Tryptophan disaster (1989): • Eosinophilia-myalgia syndrome (EMS) • Severe muscle and joint pain • Weakness • Swelling of the arms and legs • Fever • Skin rash • Eosinophilia • Many hundreds of cases; several deaths • Traced to impurities 52
  53. 53. Serotonin Metabolism: 5-HIAA CH2CH2NH2 CH2CHO HO MAO HO N N H H Serotonin Dehydrogenase CH2CO2H HOCarcinoid tumors: • Malignant GI tumor type N H • Excretion of large amounts of 5-HIAA 5-Hydroxyindole acetic acid (5-HIAA) (Urine) 53
  54. 54. Serotonin Metabolism: Melatonin CH2CH2NH2 CH2CH2NHCOCH3HO H3CO 2 Steps N N H H Serotonin Melatonin Melatonin: • Formed principally in pineal gland • Synthesis controlled by light, among other factors • Induces skin lightening • Suppresses ovarian function • Possible use in sleep disorders 54
  55. 55. Tryptophan Metabolism:Biosynthesis of Nicotinic Acid + NH3 CH2 CHCO2 - CO2 H Several steps N N H Tryptophan Nicotinic acid (Niacin) Nicotinamide adenine dinucleotide (NAD) 55
  56. 56. Review Questions 56
  57. 57. This neurotransmitter is formed by oxidation oftryptophan, followed by decarboxylation ____________This natural catecholamine is used as a drug totreat Parkinson’s disease ____________________.This drug’s effectiveness can be enhanced byusing ________________,a potent decarboxylase inhibitor.This compound is found in high levels in the bloodof patients with PKU disease ___________ 57
  58. 58. Name the enzyme that catalyzes each of thefollowing reactions and explain the importanceof each reaction HO HO HO CHCH2 NHR CH3O CHCH2NHR R RHO O NH3+HO CH2CHCO2- O CH2CHCO2 - NH3 + 58

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