5. Tyrosine metabolism SHOWING ITS METABOLISTES

METABOLISM OFTYROSINE AND IT DERIVATIVES AND ITS VARIOUS BIOHEMICAL FUNCTIONS

1. INBORN ERRORS OF AMINO ACIDS METABOLISM TYROSINE METABOLISM NEUROSCIENCE MODULE 18.2.25

2. Inborn Errors of aa Metabolism Caused by enzyme loss or deficiency due to gene loss or gene mutation Enzyme + Substrate Product Cofactors Excess Deficient

3. Tyrosine Tyrosine is formed from phenylalanine by enzyme phenyl alanine hydroxylase . Tyrosine, like cysteine , is formed from an essential amino acid and is, therefore, non essential in the presence of adequate dietary phenylalanine. One atom of molecular oxygen becomes the hydroxyl group of tyrosine, and the other atom is reduced to water. +O 2 tetrahydro-biopterin PA hydroxylase

4. Degradation of Phenylalanine to Tyrosine The reaction requires molecular oxygen and the coenzyme tetra hydrobiopterin (BH4), which can be synthesized from guanosine triphosphate (GTP) by the body. During the reaction, BH4 is oxidized to dihydro - biopterin (BH2). BH4 is regenerated from BH2 by NADH-requiring dihydro pteridine reductase .

5. Tyrosine is a precursor for synthesis of melanins and of epinephrine and norepinephrine. High [phenylalanine] inhibits Tyrosine Hydroxylase, on the pathway for synthesis of the pigment melanin from tyrosine. Individuals with phenylketonuria have light skin & hair color.

6. Degradation of TYROSINE & Aromatic Amino Acids

7. Degradation of TYROSINE & Aromatic Amino Acids Molecular oxygen is used to break an aromatic ring . homogentisate oxidase fumarylacetoacetase

8. Homogentisate Oxidase Deficiency ( Alcaptonuria ), Alkaptonuria is a rare metabolic condition involving a deficiency in homogentisic acid oxidase , resulting in the accumulation of homo­gentisic acid. The condition has three characteristic symptoms: 1.homogentisic aciduria (the patient’s urine contains elevated levels of homogentisic acid, which is oxidized to a dark pigment on standing (Accumulation of homogentisic acid in the blood causes its excretion in urine, after which it gradually darkens upon exposure to air ),

9. 2. large joint arthritis, and 3. black ochronotic pigmentation of cartilage and collagenous tissue (The dark pigment also accumulates over years in the cartilage ( ochronosis ) and may be seen in the sclera of the eye, in ear cartilage) . Patients with alkaptonuria are usually asymptomatic until about age 40. Dark staining of the diapers sometimes can indicate the disease in infants, but usually no symptoms are present until later in life.

10. INBORN ERRORS OF AMINO ACIDS METABOLISM Alcaptonuria - inherited disorder of the tyrosine metabolism caused by the absence of homogentisate oxidase . homogentisate is accumulated and excreted in the urine turns a black color upon exposure to air In children: urine in diaper may darken In adults: darkening of the ear dark spots on the on the sclera and cornea arthritis

11. Alcaptonuria Aortic valve stenosis in alcaptonuria Accumulation of oxidized homogentisic acid pigment in connective tissue ( ochronosis )

12. Characteristics of Alkaptonuria Homogentisic aciduria : elevated homogentisic acid in urine which is oxidized to dark pigment over time Black pigmentation of cartilage, tissue Usually asymptomatic until adulthood Arthritis of the spine is a complication of alkaptonuria ochronosis Treatment is targeted to managing the symptoms.

13. Arthritis of the spine is a complication of alkaptonuria ochronosis

14. Treatment of alkaptonuria Restricted intake of tyrosine and phenylalanine reduces homogentisic acid and dark pigmentation

15. Symptoms of albinism: inhibition of production or lack of melanin in skin, hair, eyes increased sensitivity to sunlight increased risk of skin cancer development sun burns photophobia decrease of vision acuity strabismus, nystagmus

16. Albinism A disease of tyrosine metabolism Tyrosine is involved in melanin production Melanin is a pigment of hair, skin, eyes Due to tyrosinase deficiency Melanin is absent in albino patients Hair and skin appear white Vision defects, photophobia

17. A deficiency of the enzyme fumarylacetoacetase leads to an accumulation of the novel and extremely toxic compound succinylacetone

18. Albinism Albinism refers to a group of conditions in which a defect in tyrosine metabolism results in a deficiency in the production of melanin. These defects result in the partial or full absence of pigment from the skin, hair, and eyes. Albinism appears in different forms, and Albinism

19. Modes of inheritance it may be inherited by one of several modes: autosomal recessive (primary mode), autosomal dominant, or X-linked. Complete albinism (also called tyrosinase -negative oculocutaneous albinism) results from a deficiency of copper-requiring tyrosinase , causing a total absence of pigment from the hair, eyes, and skin It is the most severe form of the condition. In addition to hypopigmentation, affected individuals have vision defects and pho­tophobia (sunlight hurts their eyes). They are at increased risk for skin cancer.

20. Voet Biochemistry 3e © 2004 John Wiley & Sons, Inc. Melanin biosynthesis from tyrosine: Deficiency of tyrosinase leads to albinisim Page 1002 Tyrosinase Melanin

21. A deficiency of the enzyme fumarylacetoacetase leads to an accumulation of the novel and extremely toxic compound succinylacetone

22. Tyrosinemia is an extremely rare but treatable hereditary d isorder. When the body cannot break down tyrosine, high levels build up in the blood and form a toxic substance (known as succinylacetone ) in the liver, kidneys, and central nervous system. This means that if tyrosinemia isn't treated, it may cause liver and kidney damage and brain-related problems, such as problems with learning.

23. Types of tyrosinemia There are three types of tyrosinemia . The type a child has depends on which enzyme they are lacking. Children with tyrosinemia type 1 (HT-1) are deficient in an enzyme called fumarylacetoacetate hydrolase. If not recognized and treated right away, the condition could be fatal for a child at an early age. However, with treatment, tyrosine levels in the blood can be managed. Dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1).

24. Tyrosinaemia type 1 A deficiency of the enzyme fumarylacetoacetase leads to an accumulation of the novel and extremely toxic compound succinylacetone . This is detected by urine organic acid analysis. Tyrosine concentrations in body fluids are also elevated but can be variable. Affected children typically present with severe liver disease and renal Fanconi syndrome. The drug nitisinone inhibits an enzyme higher in the pathway, 4 hydroxyphenylpyruvate dioxygenase . This prevents the synthesis of succinylacetone and dramatically improves prognosis. Patients continue to need dietary therapy to prevent tyrosine accumulation.

25. Albinism – genetically determined lack or deficit of enzyme tyrosinase Tyrosinase in melanocytes oxidases tyrosine to DOPA and DOPA-chinone tyrosinase Phenylalanine Tyrosine Tyroxine Melanin DOPA Dopamine Norepinephrine Epinephrine