3. Phenylalanine
• essential, aromatic amino acid.
• partly glucogenic and partly ketogenic.
• need for Phenylalanine becomes minimal, if adequate tyrosine is
supplied in the food.
Sparing action of Tyrosine on Phenylalanine.
5. • addition of a hydroxyl
group to the aromatic
ring, by phenylalanine
hydroxylase
• It needs NADPH and
Tetrahydrobiopterin as
co-enzymes.
• This is an irreversible
reaction, so Tyrosine
cannot replenish
Phenylalanine.
• Hence, Phenylalanine
is essential in food.
1= Phenylalanine
hydroxylase
6. Metabolism of Tyrosine
• aromatic amino acid.
• Synthesized from phenylalanine.
• non-essential amino acid.
• partly glucogenic and partly ketogenic.
7. Catabolism of Tyrosine
Step-1: Transamination
• Tyrosine is transaminated
to give para hydroxy
phenyl pyruvic acid by
Tyrosine Transaminase.
• Pyridoxal phosphate
dependent.
Step-2: Production of
homogentisic acid
• catalyzed by para
hydroxy phenyl pyruvate
hydroxylase which is a
copper containing
enzyme.
2= Tyrosine
transaminase
3= Para hydroxy
phenyl pyruvate
hydroxylase
8. Step 3: Cleavage of
aromatic ring
• Homogentisic acid
oxidase opens the ring.
• The product is 4-maleyl
aceto- acetate.
Step 4: Isomerization
• undergoes cis to trans
isomerisation to form
fumaryl acetoacetate by
an isomerase.
• isomerase requires
glutathione(GSH) as a
cofactor.
GSH
5= maleyl
acetoacetate
isomerase
4= homogentisic acid
oxidase
9. Step 5: Hydrolysis
• Fumaryl acetoacetate is then hydrolyzed to fumarate (glucogenic) and
acetoacetate(ketogenic) by a hydrolase.
• Hence phenyl alanine and tyrosine are partly glucogenic and partly
ketogenic.
6= fumaryl acetoacetate hydrolase
10. Specialised products of tyrosine
• Melanin
• Catecholamines(epinephrine, norepinephrine and dopamine)
• Thyroid hormones
11. Melanin: Melanin pigment gives
the black color to the skin,
hair, iris and retinal pigment
epithelium.
• It protects the skin by
absorbing UV rays and
prevents skin cancer
• hydroxylation of tyrosine by
tyrosinase which is a copper
containing enzyme.
• Converted to indolequinone
through a series of subsequent
non enzymatic reactions.
• Indolequinone is polymerized to
form melanin. 1= Tyrosinase ; 2 = Tyrosinase
12. Catecholamines
• epinephrine, nor-epinephrine and
dopamine.
• Synthesized in adrenal medulla and
sympathetic ganglion
• Tyrosine is first hydroxylated to
(DOPA) by Tyrosine Hydroxylase.
• Tyrosine Hydroxylase requires
tetrahydrobiopterine and NADPH.
• DOPA is decarboxylated to form
Dopamine by DOPA-decarboxylase.
Its a pyridoxal phosphate dependent
enzyme.
• Dopamine is an inhibitor of prolactin
secretion. It is also an important
neurotransmitter.
• In Parkinsonism, dopamine levels are
reduced in brain. L-dopa is used as a
drug as dopamine cannot enter BBB.
1= Tyrosine hydroxylase
2= DOPA decarboxylase
13. • Dopamine is further
hydroxylated to nor-
epinephrine
• Nor-epinephrine is
methylated by the enzyme
N-methyl transferase to
epinephrine.
• SAM is produced by adrenal
medulla and adrenergic
nerve endings and stored in
chromaffin granules.
3= Dopamine hydroxylase; 4= N-methyl
transferase; 5= catechol –o-methyl
transferase; 6= mono amine oxidase
14. VMA Estimation
• VMA excretion is increased in pheochromocytoma and
neuroblastoma.
• 24 hour urine is collected and analysed for VMA.
15. Homovanillic acid
• Main urinary metabolite of DOPA and dopamine.
• 24 hour urine
• Increased in neuroblastoma.
16. Actions of epinephrine
• increase the blood pressure.
• increases the rate and force of myocardial contraction.
• causes relaxation of smooth muscles of bronchi.
• anti-insulin in nature, i.e. increases glycogenolysis and stimulates
lipolysis.
• Adrenaline is released from adrenal medulla in response to flight,
fight, fright, exercise and hypoglycemia.
17. Thyroid Hormones
• Tyrosine residues in thyroglobulins are iodinated to form 3-mono-
iodo-tyrosine (MIT) and 3,5-di-iodo-tyrosine (DIT).
• These are coupled to give tri-iodo-thyronine (T3) and tetraiodo-
thyronine or thyroxine (T4).
Tyramine
• Tyrosine is decarboxylated to tyramine by intestinal bacteria.
• chocolate, cocoa, wine, dried fish, processed meat, buttermilk,
cheese, yeast, peanut.
• may precipitate an attack of migraine in susceptible individuals.
18. Inborn errors of metabolism
Phenylketonuria
• Due to deficiency of enzyme phenyl alanine hydroxylase.
• Autosomal recessive
• enzyme is not synthesized, or a non-functional enzyme is synthesized due to
genetic mutation(98% of cases)
• Incidence 1 in 20000
• 5 types of PKU described.
• Type I is the classical one and is due to phenylalanine hydroxylase deficiency.
• Types II and III are due to deficiency of dihydrobiopterin reductase.
• Type IV and V are due to the deficiency of the enzyme synthesizing biopterin.
20. Biochemical abnormalities
• Phenylalanine could not be converted to
tyrosine.
• So phenylalanine accumulates in blood.
• Hence alternate minor pathways are opened
• phenyl pyruvate, phenyl lactate and phenyl
acetate are excreted in urine.
21. Clinical Manifestations
• Classical PKU - child is mentally retarded with reduced IQ.
• Agitation, hyperactivity, tremors and convulsions because
phenylalanine interferes with neurotransmitter synthesis.
• child often has hypopigmentation, because of decreased level of
tyrosine.
• Phenyl acetic acid in sweat may lead to mousy body odor.
• If dietary restriction of phenylalanine is not done, children will
develop irreversible mental retardation. Therefore, early screening is
must.
22. Laboratory Diagnosis
• Blood phenylalanine: Normal level is 1 mg/dl ;
PKU : the level is >20 mg/dl.
Chromatography
Tandem mass spectrometry(quantitative determination, most
reliable).
• Guthrie test :
is a rapid screening test.
Bacillus subtilis need phenyl alanine as an essential growth factor and cannot grow in a
medium devoid of phenyl alanine.
Bacterial growth is proportional to the phenyl alanine content in the patient's blood.
• Ferric chloride test:
Urine phenyl ketones could be detected by adding ferric chloride to the urine.
blue-green color is a positive test (less reliable test).
• DNA probes are now available to diagnose biochemical defects.
23. Treatment
• Early detection and treatment is very important.
• Phenyl alanine restricted diet atleast for first 5 years (brain
development)
• Tyrosine becomes essential amino acid
• Food based on tapioca (cassava) has low phenyl alanine content. To
be taken atleast in the first decade of life; after which the child can
have a normal diet.
• Synthetic analogue of tetrahydrobiopterin
• Administration of concentrate of large neutral amino acids(LNAA)
24. Alkaptonuria
• autosomal recessive
• Due to deficiency of homogentisate oxidase.
• results in excretion of homogentisic acid in urine.
• Garrod’s tetrad: Alkaptonuria, albinism,pentosuria
and cystinuria.
• blackening of urine on standing.
• The homogentisic acid is oxidized by polyphenol
oxidase to benzoquinone acetate.
• It is then polymerized to black colored alkapton
bodies.
Polyphenol
oxidase
25. • Patient develops ochronosis in 3rd or 4th decade.
• Ochronosis = deposition of alkapton bodies in intervertebral discs,
cartilages of nose, pinna of ear,joints)
• Black pigments are deposited over the connective tissues including
joint cavities to produce arthritis.
26. Lab diagnosis:
• Urine becomes black on standing
• Blackening is accelerated on exposure to sunlight and oxygen.
• Ferric chloride test will be positive for urine.
• Benedict's test is strongly positive as homogentisic acid is a reducing
substance present in urine.
Treatment
• No specific treatment is required. Only symptomatic treatment
• protein intake with low phenylalanine level (less than 500 mg/day) is
recommended.
28. Albinism
• autosomal recessive.
• Tyrosinase is absent/deficient leading to defective synthesis of
melanin.
• Ocular fundus is hypopigmented and iris may be grey or red,
Associated photophobia, nystagmus and decreased visual acuity.
• Skin has low pigmentation, and is sensitive to UV rays.
• skin may show presence of melanomas.
• Hair may be white.
30. HYPERTYROSINEMIAS
Tyrosinemia Type I (Hepatorenal Tyrosinemia)
• also called as tyrosinosis.
• autosomal recessive
• deficiency of enzyme fumaryl aceto acetate hydrolase.
• Symptoms manifest by the first 6 months of life and death occurs
rapidly.
• Cabbage like odor, mild mental retardation, hypoglycemia and
eventual liver failure are seen.
• Urine contains tyrosine, parahydroxy phenyl pyruvic acid and hydroxy
phenyl lactic acid; and high serum tyrosine.
• Tyrosine and phenylalanine restricted diet is advised.
31. Tyrosinemia Type II (Oculocutaneous Tyrosinemia)
• Due to deficiency of tyrosine transaminase
• Mental retardation, keratosis of palmar surface, painful corneal
lesions and photophobia are seen.
• There is increased excretion of tyrosine and tyramine in urine.
• A diet low in protein is advised.
32. Neonatal tyrosinemia
• due to the absence of the enzyme para hydroxy phenyl pyruvate
hydroxylase.
• causes transient hypertyrosinemia in the new-born.
• Responds to administration of ascorbic acid and dietary protein
restriction.
33. Tryptophan
• Aromatic a.a. with an indole ring.
• Essential amino acid.
• Important Substances produced from Tryptophan
1. Alanine (glucogenic)
2. Acetoacetyl CoA (ketogenic)
3. Formyl group (One carbon unit)
4. Niacin and NAD+
5. Serotonin
6. Melatonin
34. Major pathway:
• Tryptophan forms N-formyl kynurenine with
the help of enzyme Trytophan
oxygenase/pyrrolase (heme containing
enzyme)
• Releases Alanine which is a glucogenic a.a.
• Forms acetoacetate which is ketogenic.
• Kynureninase is a PLP dependent enzyme
• Therefore, in vitamin B6 deficiency, the
pathway is blocked at this level.
• This leads to niacin deficiency and
manifestations of pellagra.
• accumulated kynurenine produces
xanthurenic acid and is excreted in
urine(greenish yellow colour) in Vit. B6
deficiency.
• The urine xanthurenic acid serves as a
marker of vitamin B6 deficiency.
35. • 3% of tryptophan is diverted to this pathway at the
level of 3-hydroxyl anthranilic acid, to form NAD+.
• The enzyme, QPRT (quinolinate phosphoribosyl
Transferase is the rate-limiting step.
• 60 mg of tryptophan will produce 1 mg of nicotinic
acid.
• Pellagra is common in people whose staple diet is
maize (deficient in tryptophan)
1= quinolinate phosphoribosyl
transferase (QPRT)
36. Serotonin
• Serotonin (5-hydroxy tryptamine) is
produced in the brain, mast cells,
platelets and gastrointestinal tract
mucosa.
• Tryptophan is first hydroxylated by
tryptophan hydroxylase.
• Then, 5-hydroxy tryptophan is
decarboxylated to 5-hydroxy
tryptamine (serotonin).
• Catalyzed by a PLP dependent
decarboxylase enzyme.
1= tryptophan hydroxylase 2= PLP dependent
aromatic amino acid decarboxylase
37. Functions of serotonin
• important neurotransmitter in brain.
• Serotonin is involved in mood, sleep, appetite and temperature
regulation.(important antidepressant)
• It increases gastrointestinal motility.
• Sensitivity to pain is reduced by serotonin.
• When a protein rich diet is taken, tryptophan being bulky is taken in brain cells
very slowly due to high traffic of other a.a. But when a carbohydrate rich diet
is taken, tryptophan easily enters the brain cells. When tryptophan is available
in brain in excess quantity, serotonin may be generated to induce sleep.
• That’s why protein rich food causes alertness and carbohydrate rich food
induces sleep.
38. Catabolism of Serotonin
• Monoamine oxidase (MAO) converts
serotonin to 5-hydroxy indole acetic acid
(HIAA).
• MAO inhibitors (e.g. iproniazid) will cause
mood elevation.
3= mono amino oxidase
39. Carcinoid tumors
• Argentaffin cells of the gastrointestinal tract produces Serotonin which is
necessary for GIT motility.
• These cells when grow malignant locally are known as argentaffinomas, or
carcinoid tumors.
• These tumors develop in small intestine or in the appendix.
• Clinical symptoms: flushing, sweating, intermittent diarrhea and fluctuating
hypertension.
• Normally, 1% tryptophan molecules are channelled to serotonin synthesis. But in
carcinoid syndrome, up to 60% is diverted to serotonin.
• Therefore, niacin deficiency (pellagra) may also be seen in carcinoid syndrome.
• Diagnosis : HIAA (5-Hydroxy indole acetic acid) excretion in Urine
40. Melatonin
• Serotonin is acetylated with the enzyme
acetylase.
• Further methylated with the help of S-
adenosyl methionine (SAM) to form
Melatonin.
• Pineal gland produces melatonin.
• Hormone of darkness
• Responsible for diurnal variations, sleep wake
cycles and the biological rhythms, mood
regulation
• Used as drug for treating many sleep
disorders.
4= acetylase 5= methyl transferase
41. • Intestinal bacterial putrefaction of tryptophan results in the
production of several indole compounds.
• These are mainly excreted in the feces and urine.
• The foul smell of feces and the natural color of urine is due to these
compounds.
42.
43. Hartnup's Disease
• Autosomal recessive disease.
• Caused by defective transport of neutral amino acids including tryptophan
across the renal tubular and intestinal mucosal epithelium.
• Absorption of these amino acids from GIT and renal tubules is impaired.
These neutral Amino acids are excreted in urine.
• deficiency of niacin derived from tryptophan leading to pellagra like
symptoms
• Dermatitis and neuropsychiatric manifestations.
• diagnosis is based on amino aciduria and increased excretion of indole
compounds
• Treatment: high protein diet with supplementation of niacin and minimum
exposure to sunlight.
44. Fate of Carbon Skeletons of Amino Acids
• During catabolism of amino acids, those which give rise to TCA cycle
intermediates can be made into glucose : glucogenic amino acids.
• Those amino acids which produce acetyl CoA are called ketogenic
amino acids
46. One carbon metabolism
• One-carbon (1C) groups donate carbon atoms for synthesis of
different types of compounds.
• THFA is the carrier of one carbon groups.
• Different one-carbon groups of the ‘one-carbon pool' of the body are:
1. Formyl group carried by N5–formyl–THFA and N10–formyl–THFA.
2. Formimino group carried by N5–formimino–THFA
3. Methenyl group carried by N5,N10–methenyl–THFA
4. Hydroxymethyl group carried by N10–hydroxymethyl THFA
5. Methylene group carried by N5,N10–methylene–THFA
6. Methyl group carried by N5–methyl–THFA and methyl cobalamin
47. Generation of One-Carbon Groups
One-carbon groups are contributed by following amino acids:
• Serine to glycine (Serine hydroxymethyl transferase) reaction is the
primary contributor for methylene THFA.
• Glycine cleavage system also produces methylene groups.
• Histidine contributes to N5-formimino THFA
• Tryptophan donates formyl-THFA.
• Choline and betaine are donors of hydroxyl methyl groups.
48.
49. Interconversion of One-Carbon Groups
• All one carbon units are
ultimately converted to
N5 methyl THFA. The
step involves Reductase
enzyme and is
irreversible.
53. Folate trap
• From methyl-THFA, the B12 co-
enzyme accepts the methyl group
to form methyl cobalamin.
• It then transfers the methyl group
to homocysteine to form
methionine.
• In B12 deficiency, deficiency of folic
acid is also observed as the
transfer of methyl group
from methyl-THFA does not
occur.
• THFA is not regenerated.
• This is called folate trap.
Editor's Notes
Tyrosinase is present in melanoblasts. DOPA produced by it is used for melanin synthesis.
Tyrosine hydroxylase is present in adrenal medulla. DOPA generated by it is used for catecholamine synthesis.