biochemistry-protein metabolism

1. TYROSINE METABOLISM AND ITS
DISORDERS
BY,P.JAYASHRI VIDYA
PHARM D FIRST YEAR

2. PHENYLALANINE AND TYROSINE
 Both phenylalanine and tyrosine are structurally related aromatic amino
acids.tyrosine is a nonessential amino acid and phenylalanine is a essential amino
acid.
 Ingestion of tyrosine reduces the dietary requirement of phenyalanine .this
phenomenon is called as sparring action of phenylalanine on tyrosine.
Functions:
 Tyrosine is involved in synthesizing a variety of biologically important compounds
like.Epinephrine,Nor-epinephrine,Thyroid hormones and Melanin.
 The metabolites of phenylalanine and tyrosine serves as aprecussors for the
synthesis of glucose and fat.so,they are called as glucogenic and ketogenic
hormones.

3. CONVERSION OF PHENYLALANINE TO
TYROSINE

4.  Phenylalanine is hydroxylated to produce tyrosine . this reaction requires biopterin
. the active form of biopterin is H4-biopterin.in this reaction the
tetrahydrobiopterin is oxidised to dihydrobiopterin . tetrahydrobiopterin is then
regenerated by an NADP dependent dihydrobiopterin reductase.
 In the conversion of phenylalanine to tyrosine the reaction involves a
incorporation of molecular oxygen at the para position of phenylalanine and other
atom is reduced to water.

6. DEGRADATION OF TYROSINE
1. As the phenylalanine is converted to tyrosine,tyrosine undergoes transamination to give p-hydroxyl
phenyl pyruvate and it is catalysed by the enzyme tyrosine transaminase.
2. P-hydroxyl phenypyruvate is a copper containing enzyme.it catalyses oxidative decarboxylation and
hydroxylation of phenyl ring to produce homogentisate. This reaction involves a shift of the hydroxyl
group from para position to mrta position nd incorporates a new hydroxyl group at the para position
for this it requires as orbic acid.
3. Homogentisate oxidase cleaves the benzene ring of homogentisate to form 4-maleyl
acetoacetate.molecular oxygen is required for the to break the aromatic ring.
4. Maleyl acetoacetate undergoes isomerisation to form 4-fumaryl acetoacetate catalysed by 4-maleyl
acetoacetate dehydrogenase.
5. Fumaryl acetoacetate undergeoes hydrolysis to liberate fumarate and acetoacetate and is catalysed by
fumaryl acetoacetase enzyme.
6. Fumarate is an intermediate of citric acid cycle and ptrecussor of gluconeogenesis. Acetoacetate is a
ketone bodyfrom which fat can be synthesized.

8. SYNTHESIS OF MELANIN
 Melanin is the pigment of hair,skin and eye.the synthesis of melanin occurs in melanosomes present in
melanocytes
 Tyrosine hydroxylates tyrosine to 3,4-dihydroxy phenylalanine.
 The next reaction is catalysed by tyrosinase in which DOPA is converted to dopaquinone.
 then in a couple of reactions it will form leudopachrome followed by 5,6 dihydroxy indole.
 The oxidation of 5,6 dihydroxy indole forms 5,6-quinone and is catalysed by the enzyme tyrosinase.
 Melanochromes formed from indole quinone on polymerization converted to black melanin.
 Cysteine condenses with dopaquinone results in the synthesis of red melanin.
 The presence of moles on the body represents severe hyperpigmentation due to hyperactivity of
melanocytes.

10. Synthesis of thyroid hormones.
 Thyroid hormones thyroxine and triiodothyronine are
synthesized from tyrosine residues of thyroglobulin and
activated iodine.
 Iodination of tyrosine ring occurs to producemono and di
iodo tyrosine from which tri iodothyroine and tetraiodo
thyroxine are synthesized.

12. SYNTHESIS OF CATECHOLAMINES.
 Tyrosine is first hydroxylated to 3,4 dihydroxy phenylalanine by tyrosine hydroxylase.this enzyme catalyses
the rate limiting step and requires tetrahydrobiopterin as a coenzyme.
 DOPA undergoes PLP-dependent decarboxylation to give dopamine and it is hydroxylated to produce
norepinephrine,
 Methylation of norepinephrine by S-adenosyl methionine gives epinephrine.
 Function of catecholamines:-
 Nor epinephrine and epinephrine regulate carbohydrate and lipid metabolisms
 They stimulate degradation of TAG and glycogen.
 They cause incease in blood pressure.
 Dopamine and norepinephrine seres as a neurotransmitter.

13. Disorders of tyrosine metabolism

14. PHENYLKETONURIA
 It is the most common metabolic disorder in amino acid metabolism.
 It is due to the deficieny of phenylalanine hydroxylase enzyme.
 This enzyme deficiency impairs the synthesis of tetrahydrobiopterin required for the ation of phenylalanine
hydroxylase.
 Due to the disturbances in routine metabolism,phenylalanine diverted to aiternate pathways resulting in
excess production of phenylpyruvate,phenyl acetate,and phenyllactate.
 Phenylacetate gives mousy odour to urine.
 Clinical manifestations:-
 Mental retardation,failure to walk,failure of growth.
 Accumulation of phenylalanime in brain impairs the transport metabolism
 The synthesis of serotonin is insufficient.
 Defect of myelin formation.

15.  Effect of pigmentation:-
 Accumulation of phenylalanine inhibits tyrosinase and impairs melanin formation.this result in
hypopigmentation.
 Phenylpyruvate in the urine can be detected by ferric chloride test.
 Treatment:-
 Selecting foods with low phenylalanine content.
 In some seriously affected patients treatment includes administration of 5-hydroxytryptophan and DOPA
to restore the synthesis.
 PKU patients with tetrahydrobiopterin deficiency require trtrahydrobiopterin supplementation.

16. TYROSINEMIA TYPE--II
 Known as richner hanharts syndrome due to the defect of enzyme tyrosine
transaminase.
 It is characterized by skin and eye leisions rarely mental retardation.
 NEONATAL TYROSINEMIA
 The absence of enzyme p-hydroxyphenyl pyruvate dioxygenase causes
neonatal tyrosinemia

17. ALKAPTONURIA
 Enzyme defect:- the defective enzyme in alkaptonuria is homogentisate oxidase accumulates in
tissues and blood and is excreted in urine.homogentisate oxidase on standing gets oxidised to
corresponding quinones which polymerize to give black or brown colour. For this reason urine
resembles coke in colour.
 Diagnosis:-the urine gives positive test with ferric chloride and silver nitrate. This is due to the strong
activity of homogentisate.
 Treatment:-consumption of protein diet with low phenylalanine content is recommended.

19. TYROSINEMIA TYPE--1
 Deficiency of enzyme fumaryl acetoacetate hydroxylase or maleyl acetoacetate
isomerase.
 It is rare ,it causes liver failure,rickets,renal tubular dysfunction and
polyneuropathy.
 In acute tyrosinosis the infant exhibits diarrhea,vomiting,and cabbage like
odourand death may occur within one year .

20. ALBINISM
 It is an inborn error due to lack of synthesis of pigment melanin,
 It is an autosomal recessive disorder
 Causes:-Deficiency of enzyme tyrosinase.
 Decrease in melanosomes of melanocytes.
 Impairment in melanin polymerization.
 Presence of inhibitors of tyrosinase.
 Lack of protein matrix in melanosomes.
 Clinical manifestations:-
 They are sensitive to light
 Increased suseptability to skin cancer
 Photophobia,lack of pigment in eyes.

21. HYPOPIGMENTATION
 Vitiligo and Leukoderma are important localised hypopigmentation.
 Vitiligo is an acquired progressive diseasewith loss of pigmentation around mouth,nose,eyes and
nipples. Leukoderma the lack of pigmentation usually begins with hands and then spreads.
 Piebaldism is a disorder
 it is characterized by scattered normal pigmented and hypopigmented macules and patches on
forehead.
 Localized hyperpigmentation due to hyperactivity of melanocytes results in the formation of
moles.