1 amino acid metabolism
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1 amino acid metabolism 1 amino acid metabolism Presentation Transcript

  • Amino Acid Metabolism
  • + 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
  • + 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
  • 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
  • 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
  • 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
  • Metabolic Classification of the Amino Acids • Essential and Non-essential • Glucogenic and Ketogenic 7
  • 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
  • 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
  • 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
  • Ketogenic Amino Acids• Metabolized to acetyl CoA or acetoacetate • Isoleucine • Lysine • Leucine • Phenylalanine • Threonine • Tyrosine • Tryptophan 11
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Review Questions 20
  • Which one of the following doesnot belong on this list? A. Carbamoyl phosphate B. Urea C. Glutamate D. GlutamineExplain your answer: 21
  • 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 ____________
  • Decarboxylation of ___________affords ___________, an importantinhibitor of neurotransmission in theCNSExplain the importance of the BloodUrea Nitrogen (BUN) test:____________________________________________________________________ 23
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Review Questions 35
  • This amino acid, formed from serine usinga folate-derived coenzyme, is a keybuilding block in the biosynthesis ofheme and purines ________________ 36
  • 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
  • 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
  • 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
  • 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
  • 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-
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Alkaptonuria• Deficiency of homogentisate dioxygenase• Urine turns dark on standing • Oxidation of homogentisic acid• Asymptomatic in childhood• Tendency toward arthritis in adulthood 48
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Review Questions 56
  • 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
  • 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