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