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    1. Question What is NTBC, how does it function, and what does it prevent?

    2. Tyrosinemia Carolyn Jablonowski

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

    4. Tyrosine and Phenylalanine Tyrosine Phenylalanine Structures made by Carolyn Jablonowski

    6. 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).

    7. 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

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

    9. 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).

    10. 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.

    11. FAH Catalyzed Reaction

    12. HT1

    14. 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”

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

    16. 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.

    17. 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

    18. TAT Catalyzed Reaction

    20. 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).

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

    22. 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

    23. 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).

    24. HPPD

    25. Reaction Catalyzed by HPPD

    28. Treatments Dietary restriction of tyrosine and phenylalanine. (aim is below 500 µmol/L) Treatement with NTBC (2-(2-nitro-4-trifluoro-methylbenzoyl)-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)

    29. Inhibition of HPPD

    30. 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)

    31. More information http://umbbd.msi.umn.edu/tyr/tyr_map.html

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