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Aromatic amino acids
- 1. Aromatic Amino Acids Dr. K. Santha, Rajah Muthiah Medical College, Annamalai University
- 2. Aromatic Amino Acids • phenylalanine is an essential aromatic amino acid • Tyrosine is synthesised from phenylalanine and catabolized to fumarate and acetoacetate. • Tyrosine is both glucogenic and ketogenic. • Tyrosine is the precursor for the synthesis of catecholamines, thyroid hormones and melanin. • The need for phenylalanine is minimal if adequate amount of tyrosine is supplied.
- 3. Overall the reaction is considered a mixed function oxidation, because one O atom of O2 is reduced to water while the other is incorporated into the amino acid product. CH2 CH COO NH3 + CH2 CH COO NH3 + HO phenylalanine tyrosine O2 + tetrahydrobiopterin H2O + dihydrobiopterin Phenylalanine Hydroxylase
- 4. Phenylalanine and Tyrosine CH2CHCO2 - NH3 + CH2CHCO2 - NH3 + HO HN N N H N H H2N O H H CHCHCH3 HO OH HN N N H NH2N O CHCHCH3 HO OH Phenylalanine (Essential) Tyrosine (Non-essential) Phenylalanine-4- Monooxygenase (Phenylalanine hydroxylase) O2 H2O + + NADPH + H+ NADP+ Tetrahydrobiopterin (BH4) Dihydrobiopterin
- 5. Transaminase Phenylalanine Phenylpyruvate (Phenylketone) Phenylalanine Deficient in Hydroxylase Phenylketonuria Tyrosine Melanins Multiple Reactions Fumarate + Acetoacetate
- 6. • Deficiency of Phenylalanine hydroxylase • Agitation, tremors,Seizures, mental retardation, brain damage, hypopigmentation, mousy body odour Phenylketonuria CH2CCO2 - O Phenylal anine Tyrosine Transamination Phenylpyruvate (urine)
- 10. • Phenylalanine accumulate in blood • Phenylpyruvate, phenyl lactate, phenyl acetate are excreted in urine. • Diagnosis : Ferric chloride test • Guthrie test – Bacillus subtilis cannot grow in medium devoid of phenyl alanine. • Early detection is important. • Treatment consists of limiting phenylalanine intake adequate to support growth. Tyrosine must be supplied in the diet .
- 13. CH2CHCO2 - NH3 + HO CH2CHCO2 - NH3 + HO HO CH2CH2NH2 HO HO CHCH2NH2 HO HO OH CHCH2NHCH3 HO HO OH Tyr hydroxylase O2 Tyrosine Dihydroxyphenylalanine (DOPA) Dopamine DOPA decarboxylase CO2 Dopamine hydroxylase Norepinephrine Catechol Epinephrine (Adrenaline) SAM S-Adenosyl- homocysteine Methyl transferase DOPA, dopamine, norepinephrine,and epinephrine
- 14. • Dopamine is a neurotransmitter in the substantia nigra, extrapyramidal tract and striatal tract. • In parkinsonism, dopamine content of the brain is reduced. • As dopamine will not enter the brain cells, the precursor L-Dopa is used as a drug in parkinsonism. • Alpha methyl dopa will inhibit dopa decarboxylase and prevent the production of epinephrine. So it is an antihypertensive drug.
- 15. Degradation of adrenaline • The half life of adrenaline is 2-5 minutes. • Epinephrine is catabolised in tissues by catechol- o- methyltransferase to metanephrine. • Monoamine oxidase then oxidatively deamintes metanephrine to Homovanillic acid (HVA) or vanillylmandelic acid ( VMA ) • Homovanillic acid is the main urinary metabolite of Dopa and Dopamine
- 16. Melanin • Melanin is a pigment of skin, hair and eyes. • The synthesis of melanin occurs in the melanosomes present in the melanocytes the pigment forming cells. • Only one enzyme namely tyrosinase, a copper cotaining oxygenase is involved in the formation of melanin.
- 17. Melanin Formation CH2CHCO2 - NH3 O O + CH2CHCO2 - NH3 + HO HO Highly colored polymeric intermediates Melanin (Black polymer) Tyr hydroxylase DOPA Dopaquinone CH2CHCO2 - NH3 + HO Tyrosine Tyrosinase O2
- 18. • Another pathway • Cysteine condenses with dopaquinone and results in the synthesis of red melanin. • Skin colour of the individual is determined by the relative concentration of black and red melanin. • Localised absence or degeneration of melaocytes results in the formation of white patches on the skin referred to as leucoderma • Albinism is an inborn error with generalised lack of melanin synthesis.
- 19. • In the adrenal gland, tyrosine is converted to levodopa by the enzyme tyrosine hydroxylase (TH). TH is also the rate-limiting enzyme involved in the synthesis of the catecholamine hormones - dopamine, norepinephrine and epinephrine. • The thyroid hormones triiodothyronine (T3) and thyroxine (T4) in the colloid of the thyroid also are derived from tyrosine. • Tyrosine is also the precursor of the pigment melanin.
- 20. Alkaptonuria • black urine disease • Inherited as an autosomal recessive trait due to deficiency of homogentisate dioxygenase • It is compatible with normal life. • Oxidation of homogentisic acid produces benzoquinone acetate which polymrizes to black coloured alkaptone bodies which are deposited in the connective tissues - nose, ear catilages – greyish discoloration called Ochronosis joint cavities to produce arthritis in adulthood.
- 21. Urine turns dark on standing because of oxidation products of homogentisate. Diagnosis is by finding elevated urinary levels of homogentisic acid (> 4 to 8 g/24 h). Ferric chloride test, Benedicts test will be positive. ascorbic acid 1 g once/day may diminish pigment deposition by increasing renal excretion of homogentisic acid.
- 22. • Tyrosinemia type III (Transient tyrosinemia of the newborn): Transient immaturity of metabolic enzymes p- hydroxyphenylpyruvic acid dioxygenase • elevated plasma tyrosine levels (usually in premature infants, particularly those receiving high-protein diets) • Most patients are asymptomatic, but some demonstrate lethargy and poor feeding.
- 23. • Albinism • Autosomal recessive • Absence of tyrosinase - defective synthesis of melanin. • Fundus is hypopigmented - photophobia, nystagmus, and decresed visual acuity. Skin and hair white • Sensitive to UV rays - Presence of naevi and melanomas in skin
- 24. Patient with oculocutaneous albinism, showing blond hair & white eyebrows and lashes
- 25. • Tyrosinemia type I: • autosomal recessive trait • deficiency of fumarylacetoacetate hydroxylase • Symptoms occur in 6 months of life with acute liver failure, failure to thrive, rickets hypoglycemia and cabbage like odour. • Diagnosis - by elevated plasma levels of tyrosine and methionine • Tyrosine and methionine restricted diet.
- 26. • Tyrosinemia type II: Richner Hanhart syndrome autosomal recessive disorder caused by tyrosine transaminase deficiency. • Accumulation of tyrosine causes keratosis, painful corneal lesions and photophobia. • Mental retardation. • Diagnosis is by elevation of tyrosine in plasma, increased tyrosine and tyramine in urine, and by measurement of decreased enzyme activity in liver biopsy. • restriction of dietary phenylalanine and tyrosine.