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METABOLISMO DE AMINOÁCIDOS
DEZ 2015
Isabel Tavares de Almeida Faculdade de Farmácia da ULisboa
Licenciatura em Ciências da Saúde (Ano 2015-2016)
PROTEIN DEGRADATION - DIGESTION
AMINO ACID STRUCTURE
Generic Formula
2-, alpha-, or α-amino acids
Side-chain
The term "amino acid" is used to refer specifically to the 22 proteinogenic ("protein-building") amino acids, which combine into peptide chains ("polypeptides") to form the building-blocks of a vast array of proteins.
Amino Acid 3-Letter[114] 1-Letter[114] Side-chain polarity[114] Side-chain charge (pH 7.4)[114] Absorbanceλma
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
Standard Amino Acid (abbreviations) Properties
Standard Amino Acid Classification (1)
The mass of the peptide or protein is the sum of the residue masses plus the mass of water
The Standard Amino Acids
Essential Amino Acids Nonessential Amino Acids
Arginine* Alanine
Histidine* Asparagine
Isoleucine Aspartic acid
Leucine Citrulline
Lysine Cysteine
Methionine Glutamic acid
Phenlyalanine Glycine
Threonine Proline
Tryptophan Tyrosine
Valine
Serine
*for children
In the form of proteins, amino acids comprise the second-largestcomponent (water is the largest) of human muscles, cells andother tissues.
Standard Amino Acid Classification (2)
When the body's energy sources are low, it begins to degrade proteins for use asan alternative energy source.
Amino acids are not only the components of proteins, but also precursors tovarious compounds including neurotransmitters, hormones and porphyrinsfurthermore have an important role in the energy metabolism.
The oxidative degradation of amino acids produces 10 - 15% of total metabolicenergy in animals
Amino acids are degraded to compounds that can be metabolized to CO2 and H2O, or used in gluconeogenesis or in fatty acid synthesis
Amino Acids Fate
The two main routes of intracellular protein degradation are the lysosomes and theproteasomes.
a | Lysosomes are cytoplasmic, membrane-bound vesicles that enclose proteases andhydrolytic enzymes. They degrade extracellular and transmembrane proteins that aretaken up by endocytosis — the process by which the cellular plasma membraneinvaginates and breaks off internally to transport materials into the cell — andparticipate in autophagocytosis by fusing with phagosomes.
b | Proteasomes are primarily involved in degrading intracellular proteins. Thesemight be targeted by phosphorylation following activation of signalling pathways, orrecognized because they are misfolded. The proteins are targeted for degradation bytheir ubiquitin tag.
The proteasome is an abundant multi-enzyme complex that provides the main pathway for degradation of intracellular proteins in eukaryotic cells.
INTRACELLULAR PROTEIN DEGRADATION
• TRANSPORTE ENTRE TECIDOS
TRANSAMINAÇÃO
Aminoácido e cetoácido correspondente
Fosfato de Piridoxal
Aminotrransferase
Transaminação
GPT
GOT
ALAT
ASAT
DesaminaçãoOxidativa
Glutaminase
Transporte entre tecidos
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
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.
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
CITRIN DEFICIENCY
CITRIN DEFICIENCYGene SLC25A13
Compartmentalization of the biochemical pathways involved in HHH syndrome due to deficiency of themitochondrial ornithine transporter SLC25A15 (ORNT1), leading to abnormal accumulation of themetabolites marked in black rectangles
HHH SYNDROME
Lysinuric Protein intolerance
Defective cationic amino acid transport at the basolateral membrane ofepithelial cells in the kidney and intestine
Gene SLC7A7)
Fármacos usados no tratamento da hiperamoniémia
Hyperammonemia : • A nonspecific marker of inadequate nitrogen detoxification
• The hallmark for most UCDs
• Plasma amino acid
• Blood or plasma acylcarnitines
• Urinary organic acids
• Urinary orotic acid
• Carbamylglutamate test
Differential diagnosis:
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 andsalicylates have also been associated with hyperammonemic decompensation.
Hyperammonemia : • A nonspecific marker of inadequate nitrogen detoxification
• The hallmark for most UCDs
• Plasma amino acid
• Blood or plasma acylcarnitines
• Urinary organic acids
• Urinary orotic acid
• Carbamylglutamate tes
Differential diagnosis:
• Enzymatic assays
• Molecular diagnosis