Amino Acid Catabolism

Overview

Three possible fates
- enter citric acid cycle
- form ketone bodies
- substrates for gluconeogenesis
Urea cycle
- function
  - degrade excess amino acids and safely remove nitrogen
    - surplus amino acids cannot be stored
  - produce urea
- pathway
  - aspartate and carbamoyl phosphate provide nitrogens
    - carbamoyl phosphate synthesized from NH₄⁺ + HCO₃^– + 2 ATP via carbamoyl phosphate synthetase I
      - rate determining step of pathway
      - requires N-acetylglutamate which regulates the cycle
        only produced when excess amino acids are present
  - nitrogen added from systemic pool via alanine cycle
  - one turn of the cycle:
    - aspartate + NH₃ + CO₂ + 3 ATP → urea (containing 2N)+ fumarate + 2 ADP + P_i + AMP + PP_i + 3 H₂0
  - connected to citric acid cycle
    - via aspartate-argininosuccinate shunt
      - fumarate of urea cycle → malate of citric acid cycle
      - oxaloacetate of citric acid cycle → aspartate of urea cycle
- location
  - cellularly
    - formation of carbamoyl phosphate occurs in the mitochondrial matrix
    - addition of aspartate and removal of fumarate and urea occurs in the cytoplasm
  - systemic
    - liver and kidney
- deficiencies
  - common presentation
    - hyperammonemia + ↑ [glutamine]_blood + ↓ blood urea nitrogen (BUN)
    - onset shortly after birth (< 1-3 day)
    - hyperammonemia intoxication presents with
      - cerebral edema, vomiting, hyperventilation, lethargy, blurring vision
      - α-ketoglutarate consumed
        stops TCA cycle
  - carbamoyl phosphate synthase I creates carbamoyl phosphate
    - AR inheritance pattern
    - orotic aciduria absent
  - ornithine transcarbamoylase forms citrulline from carbamoyl phosphate
    - XR inheritance pattern
    - most common urea cycle disorder
    - orotic aciduria because excess carbamoyl phosphate is shunted into the UMP synthetic pathway in which orotic acid is an intermediate.
  - treatment
    - low protein diet
    - benzoate or phenylbutyrate
      - chelate nitrogen by becoming aminated
Ammonia transport
- function
  - safely move nitrogenous wastes from tissues to kidney and intestine in the form of glutamine
- pathway
  - ammonia loaded via glutamine synthetase
    - NH₃ + glutamate → glutamine
    - occurs in nearly all tissues
  - ammonia unloaded via glutaminase
    - glutamine → NH₃ + glutamate
    - specific to kidneys and intestine (and low concentration in liver)
      - induced by acidosis
Glucose-alanine cycle
- function
  - transport pyruvate from muscle to liver for gluconeogenesis
- pathway
  - involves reversible aminotransferase reactions
    - alanine aminotransferase (ALT)
      - glutamate + pyruvate → α-ketoglutarate + alanine
        in muscle
      - α-ketoglutarate + alanine → glutamate + pyruvate
        in liver
      - requires vitamin B₆
    - aspartate aminotransferase (AST)
      - glutamate + oxaloacetate → α-ketoglutarate + aspartate
        in liver
- relationship between amino acids and α-keto acids
  - alanine – NH₃ = pyruvate
  - aspartate – NH₃= oxaloacetate
  - glutamate – NH₃ = α-ketoglutarate
Defects in specific amino acid catabolism
- all are part of newborn screening program
- phenylketonuria (PKU)
  - inability to break down phenylalanine
    - deficient in phenylalanine hydroxylase
    - ↓ tetrahydrobiopterin cofactor
  - presentation
    - ↑ phenylalanine, ↓ tyrosine
      - requires tyrosine supplementation
    - mental retardation
    - microcephaly
    - musty/mousy odor to sweat and urine
  - restriction of phenylalanine in the diet
    - though cannot eliminate as it essential for protein synthesis
    - very strict adherence to diet during pregnancy for a mother with PKU
    - avoid aspartame
- maple syrup urine disease
  - inability to breakdown branched-chain amino acids (Val, Leu, Ile)
    - deficient in branched-chain ketoacid dehydrogenase
  - presentation
    - infantile onset
      - normal for first week
      - progressive onset of symptoms
    - lethargy
    - weight loss
    - hyper/hypotonia
    - mental retardation
    - urine smells of maple syrup
    - death if dietary intake of Val, Leu, Ile is not restricted
- alkaptonuria
  - inability to breakdown homogentisic acid (breakdown product of tyrosine and phenylalanine)
    - deficient in homogentisate oxidase
  - presentation
    - arthritis
      - accumulates over years in the cartilage (ochronosis)
      - onset prior to third decade
    - urine that darkens upon sitting in air
    - dark coloration of the sclera
- Hartnup’s disease
  - deficiency of neutral amino acid transporter
    - leads to ↓ tryptophan absorption
  - presentation
    - pellagra
    - result of niacin deficiency (niacin produced from tryptophan)
- homocystinuria
  - inability to breakdown homocystinuria (methionine degradation pathway)
    - causes
      - cystathionine synthase deficiency
      - ↓ affinity of cystathionine synthase for pyridoxal phosphate (B₆)
      - homocysteine methyltransferase deficiency
      - deficiency in folate, B₆ or B₁₂ in the diet can produce elevated levels of homocysteine
  - presentation
    - vessel damage
      - DVT
      - atherosclerosis
      - MI before 2nd decade of life
    - similar to Marfan’s
      - mental retardation
      - lens dislocations
        downward
        as opposed to upward in Marfan syndrome
      - tall with long extremities
    - ↑ homocysteine in the urine
  - treatment varies by cause
    - cystathionine synthase deficiency
      - ↓ intake of Met, ↑ intake of Cys, B₁₂ and folate
    - ↓ affinity of cystathionine synthase for pyridoxal phosphate
      - ↑ intake of B₆
- propionyl-CoA carboxylase/methylmalonyl-CoA deficiency
  - inability to handle Val, Met, Ile, Thr
  - part of propionic acid pathway
  - presentation
    - ketoacidosis
    - propionyl-CoA carboxylase deficiency has ↑ propionic acid, methyl citrate, hydroxypropionic acid
    - methylmalonyl-CoA mutase deficiency has ↑ methylmalonic acid
treat by restricting Val, Met, Ile, Thr in the diet

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