Updated: 8/25/2018

Amino Acid Catabolism

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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 + 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

       

 
 

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Questions (13)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Volume  
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Urine  
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2
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(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?
Review Topic

QID: 106624
1

Hereditary defect of renal amino acid transporter

10%

(2/20)

2

Cystathionine synthase deficiency

65%

(13/20)

3

Decreased in phenylalanine hydroxylase

15%

(3/20)

4

Deficiency of homogentisic acid oxidase

10%

(2/20)

5

Inability to degrade branched chain amino acids

0%

(0/20)

M1

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(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? Review Topic

QID: 107085
1

Phenylalanine

41%

(40/98)

2

Valine

45%

(44/98)

3

Tyrosine

5%

(5/98)

4

Methionine

3%

(3/98)

5

Threonine

1%

(1/98)

M1

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(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? Review Topic

QID: 106623
FIGURES:
1

Phenylalanine hydroxylase

4%

(5/140)

2

Branched-chain ketoacid dehydrogenase

6%

(8/140)

3

Homogentisate oxidase

76%

(107/140)

4

Cystathionine synthase

5%

(7/140)

5

Methylmalonyl-CoA mutase

5%

(7/140)

M1

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PREFERRED RESPONSE 3

(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? Review Topic

QID: 106630
1

Methionine

49%

(100/206)

2

Valine

6%

(12/206)

3

Threonine

5%

(11/206)

4

Isoleucine

10%

(21/206)

5

Phenylalanine

28%

(57/206)

M1

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(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? Review Topic

QID: 106628
1

NH3 + HCO3- + 2 ATP --> carbamoyl phosphate + 2 ADP + Pi

54%

(60/112)

2

Carbamoyl phosphate + ornithine --> citrulline+ Pi

26%

(29/112)

3

Citrulline + aspartate + ATP --> arginosuccinate + AMP + PPi

11%

(12/112)

4

Argininosuccinate --> Arginine + fumarate

4%

(4/112)

5

Arginine + H20 --> ornithine + urea

4%

(5/112)

M1

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(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? Review Topic

QID: 106292
1

Uridine monophosphate

14%

(3/22)

2

Citrulline

82%

(18/22)

3

Homocysteine

0%

(0/22)

4

Phenylalanine

0%

(0/22)

5

Fructose-1-phosphate

5%

(1/22)

M1

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(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? Review Topic

QID: 100092
1

Leucine

7%

(18/263)

2

Aspartame

2%

(6/263)

3

Tyrosine

86%

(225/263)

4

Niacin

3%

(8/263)

5

Homogentisic Acid

2%

(4/263)

M1

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PREFERRED RESPONSE 3
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