questions 12

Amino Acid Catabolism

Topic updated on 11/21/17 7:20am

  • 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 + Pi + AMP + PPi + 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 a less severe form of homocystinuria
      • 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




Qbank (7 Questions)

(M1.BC.1) A 20-year-old male presents with confusion, asterixis, and odd behavior. Very early in the morning, his mother found him urinating on the floor of his bedroom. A detailed history taken from the mother revealed that he has been a vegetarian his entire life but decided to "bulk up" by working out and consuming whey protein several times a day. A blood test revealed increased levels of ammonia and orotic acid but a decreased BUN. The patient began hemodialysis and was given oral sodium benzoate and phenylbutyrate, which improved his condition. Gene therapy of the enzyme producing which product would correct his condition? Topic Review Topic

1. Uridine monophosphate
2. Citrulline
3. Homocysteine
4. Phenylalanine
5. Fructose-1-phosphate

(M1.BC.27) You are counseling a mother whose newborn has just screened positive for a deficit of phenylalanine hydroxylase enzyme. You inform her that her child will require dietary supplementation of which of the following? Topic Review Topic

1. Leucine
2. Aspartame
3. Tyrosine
4. Niacin
5. Homogentisic Acid

(M1.BC.74) A 25-year-old male presents to the orthopedic surgeon after several years of complaining of elbow pain, which he claims may be due to playing tennis everyday. The orthopedic surgeon explains that arthoplasty may be useful in treating his condition. Upon performing surgery, the surgeon notes the following in Figure A. Which of the following enzymes is deficient in this male? Topic Review Topic
FIGURES: A          

1. Phenylalanine hydroxylase
2. Branched-chain ketoacid dehydrogenase
3. Homogentisate oxidase
4. Cystathionine synthase
5. Methylmalonyl-CoA mutase

(M1.BC.74) A 3-year-old boy is seen in clinic. He was born at home without perinatal care. He was apparently normal at birth, but later developed failure to thrive and developmental delay. He also has a history of cataracts. His older brother had a myocardial infarction at the age of 18 and is rather lanky and tall in appearance. Laboratory testing of his urine showed an increase in the level of an amino acid. What is the most likely mechanism responsible for this boy's pathology?
Topic Review Topic

1. Hereditary defect of renal amino acid transporter
2. Cystathionine synthase deficiency
3. Decreased in phenylalanine hydroxylase
4. Deficiency of homogentisic acid oxidase
5. Inability to degrade branched chain amino acids

(M1.BC.74) During the normal catabolism of protein, urea and ammonia are produced as waste products. If these waste products are not cleared by the liver and kidneys, hyperammonemia can occur, leading to confusion and delirium. Fortunately, a healthy liver can clear these waste products via the urea cycle. Which of the following reactions is the rate limiting step in this cycle? Topic Review Topic

1. NH3 + HCO3- + 2 ATP --> carbamoyl phosphate + 2 ADP + Pi
2. Carbamoyl phosphate + ornithine --> citrulline+ Pi
3. Citrulline + aspartate + ATP --> arginosuccinate + AMP + PPi
4. Argininosuccinate --> Arginine + fumarate
5. Arginine + H20 --> ornithine + urea

(M1.BC.74) You have isolated cells from a patient with an unknown disorder and would like to locate the defect in this patient. When radiolabeled propionate is added to the mitochondria, no radiolabeled carbon dioxide is detected. However, when radiolabeled methylmalonic acid is added, radiolabeled carbon dioxide is detected from these cells. Which of the following amino acids can be fully metabolized by this patient? Topic Review Topic

1. Methionine
2. Valine
3. Threonine
4. Isoleucine
5. Phenylalanine

(M1.BC.204) On a medical trip to Nicaragua, you observe a sweet odor in the cerumen of 12-hour female newborn. Within 48 hours, the newborn develops ketonuria, poor feeding, and a sweet odor is also noticed in the urine. By 96 hours, the newborn is extremely lethargic and opisthotonus is observed. In order to prevent a coma and subsequent death, which of the following amino acids should be withheld from this newborn's diet? Topic Review Topic

1. Phenylalanine
2. Valine
3. Tyrosine
4. Methionine
5. Threonine

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Pathophysiology of alkaptonuria
A video describing the experience of some patients with alkaptonuria
good overview

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