Question

1
Question

• What is NTBC, how does it function, and what does
  it prevent?

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Tyrosinemia

• Carolyn Jablonowski

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Tyrosinemia

• Inborn error in the degradation of the amino acid
  tyrosine.
• Hereditary autosomally recessive.
• Three types (type I, type II, type III).

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Tyrosine and Phenylalanine

• Tyrosine Phenylalanine
• Structures made by Carolyn Jablonowski

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http//upload.wikimedia.org/wikipedia/commons/thum
b/a/a4/Autorecessive.jpg/180px-Autorecessive.jpg
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Types of Tyrosinemia

• Type I deficiency of the enzyme
  fumarylacetoacetate hydrolase (FAH).
• Type II deficiency of the enzyme tyrosine
  aminotransferase (TAT).
• Type III deficiency of the enzyme
  4-hydroxyphenylpyruvate dioxygenase (HPPD).

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Type I Tyrosinemia

• Most common type of tyrosinemia.
• Caused by a mutation in the FAH gene that encodes
  for the FAH enzyme.
• Autosomally recessive
• Can be either chronic or acute.
• Acute infancy
• Chronic later in life

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FAH gene

• Chromosome 15
• Contains 14 exons and extends 35kb long
• 34 mutations associated with HT1
• All effect normal activity of FAH.

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Symptoms of Type I Tyrosinemia

• Failture to gain wieight or grow
• Diarrhea and vomiting
• Jaundice of skin and eyes
• Cabbage-like odor
• Increased tendency to bleed (esp. nosebleeds)
• Can lead to kidney and liver failure
• Liver cirrhosis and/or hepatocellular carcinoma
  (chronic).

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Fumarylacetoacetate Hydrolase

• FAH is the last in the series of five enzymes
  needed to catabolize tyrosine.
• Metalloenzyme
• Catalyzes the hydrolysis of 4-fumarylacetoacetate
  to fumarate acetoacetate.
• Deficiency of FAH results in accumulation of
  succinylacetone, maleylacetoacetone, and
  fumarylacetoacetate.

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FAH Catalyzed Reaction
http//umbbd.msi.umn.edu/tyr/tyr_map.html
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HT1
http//www.newbornscreening.info/Parents/aminoacid
disorders/Images/tyrosinemia_type1.gif
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http//www.childrenshospital.org/newenglandconsort
ium/NBS/descriptions/images/tyro3.gif
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Type II Tyrosinemia

• Caused by a mutation in the TAT gene that encodes
  for the hepatic (liver) TAT enzyme.
• Autosomally recessive
• Rare
• Also known as Richner-Hanhard syndrome

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TAT gene

• Codes for tyr aminotransferase
• 10.9kb long
• Makes 454-AA protein weighing 50.4kDa.
• 12 exons
• 13 mutations associated with HT2.

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Symptoms of Type II Tyrosinemia

• Elevated serum and plasma tyrosine levels also.
• Lesions of skin and eyes
• Due to clumping of cellular tyrosine crystals.
• Excessive tearing and abnormal sensitivity to
  light (photophobia).
• Mental retardation (caused by elevated blood
  tyrosine levels)
• Symptoms often begin in early childhood.

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Tyrosine Aminotransferase

• TAT is the enzyme involved in the first of a
  series of five reactions of tyrosine degradation.
• In cytosol
• Pyridoxal 5-phosphate (PLP) dependent enzyme
• Transaminates tyrosine and
• a-ketogluterate into p-hydrophenylpyruvate and
  glutamate.
• Narrow substrate specificity

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TAT Catalyzed Reaction
http//umbbd.msi.umn.edu/tyr/tyr_map.html
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http//www.childrenshospital.org/newenglandconsort
ium/NBS/descriptions/images/tyro3.gif
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Type III Tyrosinemia

• Caused by a mutation in the HPPD gene that
  encodes for the enzyme HPPD.
• Rare, autosomally recessive
• Deficiency of 4-hydroxyphenylpyruvate dioxygenase
  (HPPD).

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HPPD gene

• Located on 12q24-qter
• 14 exons
• HT3 and Hawkinsinura both affect this gene.

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Symptoms of Type III Tyrosinemia

• Mild mental retardation
• Seizures
• Loss of balance and coordination (intermittent
  ataxia).
• High blood and urine concentrations of tyrosine
  and HPP

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4-Hydroxyphenylpyruvate Dioxygenase (HPPD)

• Second enzyme involved in tyrosine catabolism
  pathway.
• Non-heme iron oxygenase. Often forms dimers.
• Requires Fe(II), oxygen and a alpha-keto acid
  substrate (typically alpha-ketoglutarate).

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HPPD
http//www.uwm.edu/moran/images/HPPD.jpg
http//www.uwm.edu/moran/images/NTBC.jpg
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Reaction Catalyzed by HPPD
http//umbbd.msi.umn.edu/tyr/tyr_map.html
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http//www.childrenshospital.org/newenglandconsort
ium/NBS/descriptions/images/tyro3.gif
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http//www.uwm.edu/moran/images/Tyrcatab.gif
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Treatments

• Dietary restriction of tyrosine and
  phenylalanine. (aim is below 500 µmol/L)
• Treatement with NTBC (2-(2-nitro-4-trifluoro-methy
  lbenzoyl)-1,3-cyclohexanedione) to block
  metabolism.
• Pro- Inhibitor of HPPD. NTBC structurally
  similar to HPPD
• Pro- Protects patients from fatal, end stages of
  disease
• Con- However, increases plasma tyrosine levels
  and requires several follow-ups.
• Liver transplant (popular in 1980s)

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Inhibition of HPPD
http//www.uwm.edu/moran/images/Inhibitors.gif
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Summary

• Tyrosinemia is an error in tyrosine catabolism.
• Three types of tyrosinemia (I, II, and III)
• Each is affect by a deficiency of a separate
  enzyme
• HT1 FAH
• HT2 TAT
• HT3 HPPD
• Treatments liver transplant, dietary
  restriction, inhibitors (NTBC)

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More information

• http//umbbd.msi.umn.edu/tyr/tyr_map.html