Slide2: N.B. Essential AA M Invites W & K For TV & L in Home Regularly (VITAL LYMPH)


Slide3: Pure Ketogenic AA Leucine (L) HMG-CoA Mixed AA Phenylalanine Tryptophan Lysine Tyrosine Isoleucine Pure 14 glucogenic AA TIL


Slide5: α- Keto Iso Caproic α- Keto Methyl Valeric α- Keto Iso Valeric Mitochondrial HMG - CoA Propionyl CoA Acetyl CoA Acetoacetyl CoA Methyl Malonyl CoA Succinyl CoA TCA


Slide6: Acetaldhyde


Slide7: Glycine Cleavage System: NH3+CH3. THF+ CO2+ NADH.H+   Glycine (NH2-CH2.COOH)+THF + NAD Glycine Oxidase System: Glycine (NH2-CH2.COOH) + FAD  + NH3 Glycine accept OH. CH3  Serine: Glycine +CH3. THF+ H2O   Serine (CH2.CH.COOH)+THF + NAD Oxidative decarboxylation Stone


Slide8: Glycine & Creatine Synthesis :


Conjugation Reactions of Glycine:Aminolevulinic Acid Synthesis (Porphyrins & Heme Synthesis).: Conjugation Reactions of Glycine: Aminolevulinic Acid Synthesis (Porphyrins & Heme Synthesis).


Slide10: (γ- GlutamylCysteinyl Glycine) Conjugation Reactions of Glycine: Glutathione (GSH) Synthesis.


Glutathione : Glutathione Biologically active Tripeptide ATP – dependent synthesis GST to for mercapturic acid (N-Acetyl Cysteinyl- toxin) R. Br + GSH  R. SG  NACT (mercapturic acid ) GINTH transfers H from GSH to disulfide bond of insulin between A & B chains  inactivates insulin. AA Transport ( γ-Glutamyl Cycle) Cofactor for PG synthase, LT synthase & SAM formation Functions: GSH-Pxd & GSH-Red for(MetHb(Fe3+))& ROS(HO▪)


Slide14: Conjugation Reactions of Glycine: Purine Ring Synthesis.


Slide15: Conjugation Reactions of Glycine: Bile Salts (Acids) Synthesis. Cholic A. + Glycine  Glycocholate. Chenodeoxycholic A. + Glycine  Glycodeoxy-cholate. Conjugation Reactions of Glycine: Detoxification of Aromatic Compounds.


Slide16: OH Offers Important function in ph/de-ph covalent modification of pr.


Metabolism of Serine: Metabolism of Serine Glucose Glycolysis 3-Phospho- glycerate 3-Phospho- hydroxypyruvate 3-Phosphoserine Serine (Ser) Pyruvate Dehydrogenase NAD+ NADH + H+ Glutamate a-Ketoglutarate Transaminase Phosphatase (Non- Essential AA) Glycolysis Serine dehydratase PLP H2O NH3


Conversion of Serine to Glycine: Conversion of Serine to Glycine Reversible Reaction


Slide19: Serine plays a role in Trans- Sulfuration Serine is the sulfur acceptor by which homocysteine gets ride of its sulfur and serine is converted into cysteine. Cystathionine is an intermediate. Serine plays a role in One carbon Metabolism Beta Carbon of Serine is taken by THF and involved in formation of N5, N10 methylene THF. Serine plays a role in synthesis of phospholipids Decarboxylation  Ethanolamine  Phosphatidyl EA Methylation of EA  Choline  Phosphatidyl Choline (lecithin) Serine + Palmityl CoA  Sphingosine


Sulfur-Containing Amino Acids: PLP= Pyridoxal phosphate TA DA DC ALA Cystathionine b-synthase (PLP-dep.) Sulfur-Containing Amino Acids Methionine L-Homocysteine Methionine Synthase (Vit. B12-dep.) + FH4 + 5-Methyl FH4 Serine Cystathionine Cystathionase Cysteine (Non-essential) + Homoserine OH NH2


Slide23: Essential Glucogenic AA Catabolism: via being homocysteine, which is converted into homoserine (Trans-sulfuration) and then ultimately into propionyl CoA  succinyl CoA. Function: - Trans-methylation: is achieved by its role in formation of SAM & methyl transferase. (Methyl acceptors: norepinephrine, guanidoacetate, ethanolamine and N- acetyl serotonin). - Polyamines synthesis. - Cysteine synthesis and its derivatives.


Slide24: Catabolism: Into pyruvate by one of 3 ways: Desulfhydrase (- NH3 & - H2S) Oxidation  Cysteine sulfinic acid TA sulfite+ pyruvate TA  desulfation  thiosulfate & pyruvate Functions: GSH Taurine Cystine Decarboxylated  thioethanolamine (4’-phosphopantheine) Non-Essential Glucogenic AA


Slide25: Methionine degradation and Re-synthesis Serine Propionyl CoA Trans-Methylation Reductase


Homocysteinuria: Homocysteinuria


Hyper-homocysteinemia: Hyper-homocysteinemia


Slide29: CH3-THF Methionine SAM SAH methyl transferase CH3- Homocysteine BHMT Betaine DMG MS THF B12 CH2-THF MTHFR Synthase cystathionine cysteine B6 B6 Folate cycle Trans-sulfuration pathway Methionine cycle Lyase


Slide31: Cystinuria Aminoacidopathy (Not a metabolic disorder) Caused by: Defective renal re- absorption of dibasic amino acid ROCK Clinically: Cystine precipitation  Renal cystine stones Loss of AA  Loss of thrive Treatment: - Alkalinization of urine - Plenty of fluids


Alanine Metabolism: Alanine Metabolism Synthesis: By trans-amination of pyruvate Catabolism By trans-amination or oxidative deamination to pyruvate Function


Threonine Metabolism: Threonine Metabolism Essential Glucogenic AA Catabolism Transamination into α-Ketobutyrate  Succinyl CoA Function OH group shares in phosphorylation / de- phosphorylation regulatory process


Arginine Metabolism: Arginine Metabolism Semi-Essential Glucogenic AA (Essential on demand, but not on nitrogen equilibrium) Catabolism


Arginine functions: Arginine functions Nitric Oxide Guanidine donor to Glycine  Creatine synthesis Polyamines (Growth factors) via Ornithine. Gives positive charges to basic proteins e.g. histones of DNA


Lysine Metabolism: Lysine Metabolism Essential basic amino acid Mixed glucogenic and ketogenic amino acid Component of basic proteins e.g. histones of DNA Undergoes hydroxylation when it is incorporated in collagen with help of Ascorbic acid as cofactor. Link with some functioning molecules via έ-amino group (e.g. Biotin).


Slide38: Proline Metabolism Glucogenic AA Interconverts with glutamate semi-aldehyde. Undergoes hydroxylation in presence of Vitamin C to be incorporated into collagen along with Lysine, otherwise impaired hydroxylation will result in weak and fragile tissues.


Slide39: Aspartate Metabolism Glucogenic AA Gives aspargine. Incorporated in purine & pyramidine synthesis. It is acidic AA  Negative charges to proteins it is contained.


Slide41: Glutamate Synthesis via GDH (Reductive amination) Synthesis via ALT or AST (Transaminases) Synthesis from R or P with glutamate semi- aldehyde as an intermediate. Synthesis from H by cleavage of its catabolic intermediate N- Formimino glutamate.


Slide42: Glutamate dehdrogenase (Reductive amination) Oxidation of glutamate semi- aldehyde


Slide43: In the pathway of histidine degradation, N-formiminoglutamate is converted to glutamate by transfer of the formimino group to THF, yielding N5-formimino-THF.


Slide44: Proline from Glutamate


Slide45: Glucogenic AA by transamination or oxidative deamination


Slide46: Ornithine, Proline & Arginine synthesis via glutamate semi- aldehyde. Glutamine synthesis. Glutamate biologically active compounds As dicarboxylic acid Negative charges to protein it contains GABA (γ - aminobutyric acid) synthesis. GSH synthesis.


GABA Formation: GABA Formation GABA is an important inhibitory neurotransmitter in the brain Drugs (e.g., benzodiazepines) that enhance the effects of GABA are useful in treating epilepsy


Amino Acids Formed From a-Ketoglutarate: Amino Acids Formed From a-Ketoglutarate Transamination or Glutamate dehydrogenase a-Keto- glutarate Glutamate Glutamine Glutamine synthase 4 Steps Proline Ornithine 5 Steps Arginine Urea Cycle Guanidino group


Slide49: Histidine Metabolism Urocanic Semi-Essential AA Glucogenic AA Basic AA basic proteins (important role in iron binding in globin of hemoglobin) Histamine Carnosine ( H +Alanine) Ergothionine (methylated product , Antioxidant)


Histamine Formation: Histamine Formation Histidine Histamine Histidine decarboxylase CO2 Histamine: Synthesized in and released by mast cells Mediator of allergic response: vasodilatation, broncho-constriction (H1 receptors) H1 blockers: Diphenhydramine (Benadryl) Loratidine (Claritin) Stimulates secretion of gastric acid (H2 receptors) H2 blockers: Cimetidine (Tagamet); Ranitidine (Zantac)


Slide51: Tryptophan Metabolism


Tryptophan Metabolism: Serotonin Formation: Tryptophan Metabolism: Serotonin Formation Tryptophan (Trp) Indole ring Hydroxylase O2 5-Hydroxy- tryptophan Decarboxylase CO2 5-Hydroxy- tryptamine (5-HT); Serotonin


Serotonin: Serotonin Serotonin formed in: Brain (neurotransmitter; regulation of sleep, mood, appetite) Platelets (platelet aggregation, vasoconstriction) Smooth muscle (contraction) Argentaffin cells of GIT Increase ms. tone Tumor of argentaffin cell  Increased Serotonin Drugs affecting serotonin actions used to treat: Depression Serotonin-selective reuptake inhibitors (SSRI) Migraine Schizophrenia Chemotherapy-induced emesis Some hallucinogens (e.g., LSD) act as serotonin agonists


Serotonin Metabolism: 5-HIAA: Serotonin Metabolism: 5-HIAA Serotonin MAO Dehydrogenase 5-Hydroxyindole acetic acid (5-HIAA) (Urine) Carcinoid tumors: Malignant GI tumor type (Argentaffin cell) Excretion of large amounts of 5-HIAA


Serotonin Metabolism: Melatonin: Serotonin Metabolism: Melatonin 2 Steps 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 N- Acetylation Methylation


Tryptophan Metabolism:Biosynthesis of Nicotinic Acid: Tryptophan Metabolism: Biosynthesis of Nicotinic Acid Tryptophan Nicotinic acid (Niacin) Several steps Nicotinamide adenine dinucleotide (NAD)


Slide58: Tryptophan derivatives


Phenylalanine and Tyrosine: Phenylalanine and Tyrosine Phenylalanine (Essential) Tyrosine (Non-essential) Phenylalanine-4- Monooxygenase (Phenylalanine hydroxylase) O2 H2O + + NADPH + H+ NADP+ Tetrahydrobiopterin Dihydrobiopterin


Catecholamine Biosynthesis: Catecholamine Biosynthesis Tyr hydroxylase O2 Tyrosine Dihydroxyphenylalanine (DOPA) Dopamine DOPA decarboxylase CO2 Dopamine hydroxylase Norepinephrine Catechol Epinephrine (Adrenaline) SAM S-Adenosyl- homocysteine Methyl transferase DOPA, dopamine, norepinephrine, and epinephrine are all neurotransmitters


Homogentisic Acid Formation: Homogentisic Acid Formation Transamination Tyrosine p-Hydroxyphenyl- pyruvate Homogentisate p-Hydroxyphenyl- pyruvate dioxygenase (ascorbate-dep.) O2 CO2 Homogentisate dioxygenase O2 Cleavage of aromatic ring Fumarate + acetoacetate Deficient in alkaptonuria


Melanin Formation: Melanin Formation Highly colored polymeric intermediates Melanin (Black polymer) Tyr hydroxylase DOPA Dopaquinone Tyrosine Tyrosinase Melanin formed in skin (melanocytes), eyes, and hair In skin, protects against sunlight Albinism: genetic deficiency of tyrosinase O2


Slide64: Phenylketonuria (PKU) Most common inborn error in amino acid metabolism High phe can cause neurologic damage Unusual compounds: phenyl-pyruvate; phenyl- lactate; phenylacetate Brain toxicity: reduced uptake of other aromatic amino acids Tyrosine deficiency may lead to hypopigmentation


Slide65: Alkaptonuria First defect to which inborn error of metabolism applied – Sir Archibald Garrod in early 1900’s Homogentisate oxidase defect  increased Homogentisate  Oxidized  Quinones (Deep Brown) Deposited in cartilage and elsewhere  polymerization (black) Ocular ochronosis in alkaptonuric patient Polymerized homogentisate in ear cartilage


Slide66: Albinism Genetic disease Classical defect is tyrosinase (tyrosine hydroxylase) Formation of little or no skin pigment  sun sensitivity Affected Ocular chronoid cells  Photophobia.


Slide67: MAPLE SYRUP URINE DISEASE Most common BCAA disorder (1/185,000) in North America Defective BC ketoacid decarboxylation ( DH ) Similar to PDH with 3 enzyme activities Thiamine deficiency can produce same result Keto acids that accumulate smell like burnt sugar (maple syrup) BCAA also accumulate and increased in blood. Mental retardation & convulsions & death of untreated cases. Diagnosis - Microflurometric assay: using Leucine DH - Tandem mass spectrophotometer: measure both BCAA & Keto acids. - Guthrie Bacterial inhibition test


Slide69: Hartnup Disease Genetic disease Failure of membrane transport of tryptophan Pellagra is developed in presence of adequate intake of Try. & Niacin.


Slide70: 1ry Hyperoxaluria & Glycinuria 1ry Hyperoxaluria Failure of transamination product of glycine (Glyoxalate) to re- aminate into glycine  hyperoxaluria. Glycinaemia is due to defective cleavage system  non- ketotic hyperglycinemia. Glycinuria (Failure of re-absorption)  oxidation in situ  oxalate stone.