METABOLISMO DE AMINOÁCIDOS

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1 DEZ 2015 METABOLISMO DE AMINOÁCIDOS Licenciatura em Ciências da Saúde (Ano ) Isabel Tavares de Almeida Faculdade de Farmácia da ULisboa

2 PROTEIN DEGRADATION - DIGESTION

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4 AMINO ACID STRUCTURE 2-, alpha-, or α-amino acids Side-chain Generic Formula

5 The term "amino acid" is used to refer specifically to the 22 proteinogenic ("proteinbuilding") amino acids, which combine into peptide chains ("polypeptides") to form the building-blocks of a vast array of proteins.

6 Standard Amino Acid (abbreviations) Properties Amino Acid 3-Letter [114] 1-Letter [114] Side-chain polarity [114] Side-chain charge (ph 7.4) [114] Absorbanceλ ma x(nm) [116] Alanine Ala A nonpolar neutral Arginine Arg R basic polar positive Asparagine Asn N polar neutral Aspartic acid Asp D acidic polar negative Cysteine Cys C nonpolar neutral 250 Glutamic acid Glu E acidic polar negative Glutamine Gln Q polar neutral Glycine Gly G nonpolar neutral Histidine His H basic polar positive(10%)neutral(90%) 211 Isoleucine Ile I nonpolar neutral Leucine Leu L nonpolar neutral Lysine Lys K basic polar positive Methionine Met M nonpolar neutral Phenylalanine Phe F nonpolar neutral 257, 206, 188 Proline Pro P nonpolar neutral Serine Ser S polar neutral Threonine Thr T polar neutral Tryptophan Trp W nonpolar neutral 280, 219 Tyrosine Tyr Y polar neutral 274, 222, 193 Valine Val V nonpolar neutral

7 Standard Amino Acid Classification (1)

8 The Standard Amino Acids The mass of the peptide or protein is the sum of the residue masses plus the mass of water

9 Standard Amino Acid Classification (2) Essential Amino Acids Arginine* Histidine* Isoleucine Leucine Lysine Methionine Phenlyalanine Threonine Tryptophan Valine Serine Nonessential Amino Acids Alanine Asparagine Aspartic acid Citrulline Cysteine Glutamic acid Glycine Proline Tyrosine *for children In the form of proteins, amino acids comprise the second-largest component (water is the largest) of human muscles, cells and other tissues.

10 Amino Acids Fate Amino acids are not only the components of proteins, but also precursors to various compounds including neurotransmitters, hormones and porphyrins furthermore have an important role in the energy metabolism. When the body's energy sources are low, it begins to degrade proteins for use as an alternative energy source. The oxidative degradation of amino acids produces 10-15% of total metabolic energy in animals Amino acids are degraded to compounds that can be metabolized to CO 2 and H 2 O, or used in gluconeogenesis or in fatty acid synthesis

11 INTRACELLULAR PROTEIN DEGRADATION The two main routes of intracellular protein degradation are the lysosomes and the proteasomes. a Lysosomes are cytoplasmic, membrane-bound vesicles that enclose proteases and hydrolytic enzymes. They degrade extracellular and transmembrane proteins that are taken up by endocytosis the process by which the cellular plasma membrane invaginates and breaks off internally to transport materials into the cell and participate in autophagocytosis by fusing with phagosomes. b Proteasomes are primarily involved in degrading intracellular proteins. These might be targeted by phosphorylation following activation of signalling pathways, or recognized because they are misfolded. The proteins are targeted for degradation by their ubiquitin tag. The proteasome is an abundant multi-enzyme complex that provides the main pathway for degradation of intracellular proteins in eukaryotic cells.

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18 TRANSPORTE ENTRE TECIDOS

19 TRANSAMINAÇÃO

20 Aminoácido e cetoácido correspondente

21 Fosfato de Piridoxal

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23 Aminotrransferase

24 Transaminação GPT ALAT GOT ASAT

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26 Desaminação Oxidativa

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28 Glutaminase

29 Transporte entre tecidos

30 HYPERAMMONIEMIA Definition: NH3> 100 μmol/l in newborns (R.V. 80) NH3 > 50μmol/l in children or adults (R.V. 70) Origin of NH3: Nitrogen protein catabolism

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32 The urea cycle and associated pathways. GDH, glutamate dehydrogenase; GLS, glutaminase; OAT, ornithine aminotransferase; OMP, orotidine monophosphate; P5CR, pyrroline-5-carboxylate reductase; P5CS, Δ1-pyrroline-5- carboxylate synthetase; UMP, uridine monophosphate.

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38 ENZYMES AND TRANSPORTERS INVOLVED IN HYPERAMMONEMIA 1- UREA CYCLE DISORDERS: N-acetylglutamate synthase (NAGS) Carbamylphosphate synthetase (CPS1) Ornithine carbamoyltranférase (OTC) Argininosuccinate syntase (citrullemia type I) (ASS) Argininosuccinate lyase (argininosuccinic aciduria) (ASL) Arginase (ARG) 2- TRANSPORTER DEFICIENCY: HHH Syndrome Citrin (citrullinemia type II) Lysinuric protein intolerance

39 CITRIN DEFICIENCY CITRIN DEFICIENCY Gene SLC25A13

40 HHH SYNDROME Compartmentalization of the biochemical pathways involved in HHH syndrome due to deficiency of the mitochondrial ornithine transporter SLC25A15 (ORNT1), leading to abnormal accumulation of the metabolites marked in black rectangles

41 Lysinuric Protein intolerance Gene SLC7A7) Defective cationic amino acid transport at the basolateral membrane of epithelial cells in the kidney and intestine

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43 Fármacos usados no tratamento da hiperamoniémia

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45 Hyperammonemia : A nonspecific marker of inadequate nitrogen detoxification The hallmark for most UCDs Differential diagnosis: Plasma amino acid Blood or plasma acylcarnitines Urinary organic acids Urinary orotic acid Carbamylglutamate test

46 POTENTIAL TRIGGERS OF HYPERAMMONEMIC CRISES IN UCD PATIENTS Infections Fever Vomiting Gastrointestinal or internal bleeding Decreased energy or protein intake (e.g. fasting pre surgery, major weight loss in neonates) Catabolism and involution of the uterus during the postpartum period (mostly OTC females) Chemotherapy, high-dose glucocorticoids Prolonged or intense physical exercise Surgery under general anesthesia Unusual protein load (e.g. parenteral nutrition) Drugs: Mainly valproate and L-asparaginase/pegaspargase. topiramate, carbamazepine, phenobarbitone, phenytoine, primidone, furosemide, hydrochlorothiazide and salicylates have also been associated with hyperammonemic decompensation.

47 Hyperammonemia : A nonspecific marker of inadequate nitrogen detoxification The hallmark for most UCDs Differential diagnosis: Plasma amino acid Blood or plasma acylcarnitines Urinary organic acids Urinary orotic acid Carbamylglutamate tes Enzymatic assays Molecular diagnosis

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