Amino Acid Metabolism

Digestion of Dietary Protein:

Stomach: HCl (denature) and Pepsin

Pancreas: Trypsin (carbonyl of arg and lys); Chymotrypsin (carbonyl of Trp, Tyr, Phe, Met, Leu); Elastase (carbonyl of Ala, Gly Ser); Carboxypeptidase A (amine side of Ala, Ile, Leu, Val); Carboxypeptidase B (amine side of Arg, lys)

Small Intestine: aminopeptidase (cleaves N-terminal residue of oligopeptides)

Nitrogen Removal from Amino Acids: make ammonia or aspartate to feed urea cycle.

Aminotransferase: a-amino acid + a-ketoglutarate à a-keto acid + glutamate

Glutamate + Oxaloacetate à Aspartate + a-ketoglutarate

Cofactor: pyridoxal phosphate/pyridoxamine phosphate

High serum AST and ALT indicate liver damage.

Oxidative Deamination: Glutamate dehydrogenase (mitochondria)

Glutamate + NAD⁺ (NADP⁺) à a-ketoglutarate +NADH (NADPH) + NH₃

Allosteric Regulators: ATP/GTP inhibit; ADP/GDP activate

Urea Cycle (liver):

Mitochondrial reactions:

Carbamoyl phosphate synthetase I:

CO2 + NH₄ + 2 ATP à carbamoyl phosphate (rate limiting)

Ornithine transcarbamoylase:

L-ornithine + carbamoyl phosphate à L-citrulline + Pi

Cytosol reactions:

L-citrulline + L-Aspartate + ATP à Argininosuccinate + AMP + PPi (argininosuccinate synthase)

Argininosuccinate à Fumarate + L-Arginine (argininosuccinate lyase)

L-Arginine à Urea + L-ornithine (arginase)

Overall:

Aspartate + NH3 + CO2 + 3 ATP à Urea + fumarate + 2 ADP + AMP + 2 Pi + PPi + 3 H2O

Urea is transported to kidneys for excretion

Metabolism of ammonia:

Sources: amino acids, glutamine (glutaminase), bacteria in intestine, from amines (catecholamine degradation), purine and pyrimidine catabolism

Transport of ammonia: urea and glutamine

Hyperammononemia: ammonia intoxication - tremors, slurring of speech, and blurring of vision, coma/death. Cause by cirrhosis of the liver or genetic deficiencies

Catabolism of Amino Acids

Ketogenic: formation of ketone bodies (leucine and lysine, exclusively)

Glucogenic: intermediates of citric acid cycle (see figure 22.3)

Essential vs. non-essential: PVT TIM HALL

Cofactors to remember: SAM, Biotin, Folic Acid (carriers of one-carbon units)

Biosynthesis of nonessential amino acids:

TCA cycle member + amino acid à a-keto acid + nonessential amino acid

Phenylalanine hydroxylase:

Phenylalanine + O₂ + coenzyme tetrahydrobiopterin à tyrosine + H2O + dihydrobiopterin

Metabolic defects in amino acid metabolism:

PKU = hyperphenylalaninemia caused by deficiency in phenylalanine hydroxylase or deficiency in coenzyme tetrahydrobiopterin. No tyrosine, no catecholamines

Conversion of Amino Acids to Specialized Products

Amino acids are precursors for porphyrins, neurotransmitters, hormones, purines, and pyrimidines

Porphyrins: biosynthesis of heme, important in coordinating iron.

Glycine + succinyl CoA à d-aminolevulinic acid (ALA) [d-aminolevulinic synthase]

Regulation by negative feedback (hemin)

Increased ALA synthase production via activation of P450s

d-aminolevulinic à porphobilinogen (d-aminolevulinic acid dehydrase, inhibited by lead)

Porphyrias: defects in heme synthesis. Erythropoietic or hepatic.

Degradation of Heme: Occurs in liver and spleen. Heme is converted to biliruben (requires NADPH). Transported in blood via bilirubin albumin complex to liver where it is conjugated and then excreted with bile.

Jaundice: yellow skin and sclerae cause by deposition of bilirubin. Hemolytic, obstructive, or hepatocellular jaundice.

Creatine: derivative Creatine phosphophate can donate phosphate group to ADP to form ATP in muscles. Synthesized from arginine and glycine precursors. Used as indicator of Kidney function.

Histamine: Synthesized from Histadine, used as neurotransmitter. Powerful vasodilator.

Serotonin: Neurotransmitter synthesized from tryptophan.

Catecholamines: Synthesized from tyrosine.

Melanin: Also synthesized from tyrosine.