Amino acids forming pyruvate are convertible to acetyl-CoA. In addition to this, 5 amino acids form acetyl-CoA directly, without first forming pyruvate.
Phenylalanine (an essential amino acid) is converted to tyrosine by phenylalanine hydroxylase; tetrahydropteridine, NADPH and O, are required. The reaction is not reversible.
The catabolism of phenylalanine and tyrosine may be discussed under the following heads:
1. Formation of fumarate and acetoacetate.
2. Formation of melanin.
3. Conversion to epinephrine.
4. Conversion to thyroxine.
1. Formation of fumarate and acetoacetate:
1. Tyrosine is trans-aminated to β-hydroxyphenyl-pyruvate by tyrosine-α-ketoglutarate transaminase, an enzyme of mammalian liver tissue, as shown in Fig. 20.30.
2. P-hydroxyphenylpyruvate hydroxylase, a copper metalloprotein with properties similar to those of tyrosinase, converts P-hydroxyphenylpyruvate to homogentisic acid. Ascorbic acid acts as a cofactor in this reaction.
3. By oxidative reaction catalyzed by homogentisate oxidase, an iron metalloprotein of mammalian liver, maleylacetoacetate, is formed by the rupture of the benzene ring of homogentisate. The reaction is inhibited by a chelating agent that binds iron.
4. Maleylacetoacetate is converted to fumarylacetoacetate by maleylacetoacetate cistrans isomerase, present in mammalian liver.
5. Fumarylacetoacetate on hydrolysis by fumarylacetoacetate hydrolase forms fumarate and acetoacetate. Acetoacetate can be converted to acetyl-CoA and acetate by β-ketothiolase.
2. Formation of melanin:
1. Melanin, the black pigment present in the skin, hair and retina of the eye, is formed from phenylalanine and tyrosine in the specialised cells (melanoblasts) present in the skin. The pathway of melanin formation is given (Fig. 20.31).
2. Tyrosine is oxidized to dihydroxyphenylalanine (DOPA) catalyzed by tyrosinase in presence of ascorbic acid as cofactor.
3. DOPA is converted into dopaquinone which is further converted into 5:6 di-hydroxyindole-2-carboxylic acid. This is oxidized to di-hydroxyindole which polymerises spontaneously to melanin.
3. Conversion to Epinephrine:
1. Phenylalanine is converted into tyrosine which is further converted into 3:4-dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase with tetrahydropterdine as cofactor.
2. DOPA is decarboxylated to dopamine by a decarboxylase which is present in many tissues including adrenal medulla with pyridoxal phosphate as cofactor.
3. The hydroxylation of dopamine is carried out by dopamine β-hydroxylase to form norepinephrine in the presence of ascorbic acid and molecular oxygen.
4. The methylation from methionine converts norepinephrine to epinephrine.
The sequence of reactions are given in Fig. 20.32.
4. Conversion to thyroxine:
The synthesis of thyroxine takes place in the thyroid gland:
1. Phenylalanine is converted to tyrosine which, on iodination, forms monoiodotyrosine. This, on iodination, forms diiodotyrosine.
2. Coupling of 2 mols of diiodotyrosine yields thyroxine.
3. Coupling of 1 mol of monoiodotyrosine and 1 mol of diiodotyrosine produces triodothyronine.
The steps are shown:
1. Formation of tyramine.
2. Formation of tyrosine-o-sulphate.
1. Formation of tyramine:
Tyramine is produced by the bacterial decomposition involving decarboxylation of tyrosine by decarboxylase present in bacteria.
2. Formation of tyrosine-o-sulphate:
This is present in fibrinogen. Two peptides are liberated during the conversion of fibrinogen into fibrin. One of the peptides contain tyrosine-o-sulphate.
The carbon atoms of the side chain and of the aromatic ring of tryptophan may be completely degraded to amphibolic intermediates. This proceeds via kynurenine-anthranilate pathway. This pathway is important for degradation of tryptophan as well as niacin formation from tryptophan.
The catabolism of tryptophan may be discussed under the following pathways:
1. Kynurenine-anthranilate pathway.
2. Serotonin pathway.
3. Minor pathways.
1. Kynurenine-Anthranilate Pathway:
1. Tryptophan oxygenase (Tryptophan pyrrolase) cleaves the indole ring of tryptophan with the incorporation of 2 atoms of molecular oxygen forming N- formylkynurenine. The oxygenase enzyme is an iron porphyrin metalloprotein which is present in the liver of mammals, amphibians, birds and insects.
Four forms of hepatic tryptophan pyrrolase have been described: the active holoenzyme, the apoenzyme, third form is combined with hematin and the fourth form requires prolonged incubation. The chief inducing agents of tryptophan pyrrolase is adrenal corticosteroids, induction is blocked by puromycin. Tryptophan stabilizes the enzymes towards proteolytic degradation.
2. Kynurenine formylase of mammalian liver catalyzes the hydrolytic removal of the formyl group of N-formyl-kynurenine producing kynurenine.
3. Kynurenine on deamination produces 2-amino-3-hydroxy-benzoyl pyruvate which loses, water and then undergoes spontaneous ring closure forming kynurenic acid. This is not formed in the main pathway of tryptophan breakdown.
4. Kynurenine is hydroxylated by kynurenine hydroxylase with molecular oxygen in presence of NADPH to 3-hydroxy-kynurenine.
5. 3-hydroxyanthranilic acid is formed from 3-hydroxy kynurenin by the enzyme kynureninase which requires vitamin B4 (pyridoxal phosphate) as coenzyme. In the deficiency of vitamin B6, kynurenine derivatives reach the extrahepatic tissues where they are converted to xanthurenic acid. This is found in the urine of human, monkeys and rats when there is dietary deficiency of vitamin B6. Excess tryptophan feeding can induce excretion of xanthurenic acid if vitamin B6 deficiency exists.
The kidney can produce xanthurenic acid derivatives from kynurenine. In the deficiency of vitamin B6, the synthesis of pyridine nucleotides (NAD and NADP) in the tissues is impaired owing to the non-conversion of tryptophan to nicotinic acid. 60 mg of tryptophan produces 1 mg of nicotinic acid.
6. 3-hydroxyanthranilic acid is then converted to 2-acroleyl-3-aminofumaric acid by the specific oxidase- 2-acroleyl-3- aminofumaric acid is dehydrated to quinolinic acid which, on decarboxylation produces nicotinic acid.
7. Riboflavin is also necessary for the formation of 3-hydroxy-kinurenine. In riboflavin deficiency, anthranilic acid and 5-hydroxy-anthranilic acid are excreted. In febrile state, man often excretes 3-hydroxykynurenine.
8. 2-acroleyl-3-aminofumaric acid is decarboxylated to form 2-aminomuconic acid-6-semi-aldehyde which on deamination and oxidation produces oxalocrotonic acid. This, on reduction, forms α- ketoadipic acid which ultimately forms acetoacetyl-CoA.
The sequence of reactions is shown (Fig. 20.35).
In the deficiency of riboflavin:
2. Serotonin Pathway:
Tryptophan on hydroxylation in the liver forms 5-hydroxytryptophan which, on decarboxylation, produces 5-hydroxytryptamine (serotonin), a stimulant of the central nervous system and also a vasoconstrictor. Serotonin is stored in platelets. It also occurs in intestinal mucosa where it promotes peristalsis. Serotonin is broken down by oxidative deamination to 5-hydroxyindoleacetic acid which is excreted in the urine.
The sequence of reaction is given in Fig. 20. 36.
Serotonin on acetylation and methylation produces N-acetyl-5-methoxytryptamine (the hormone melatonin). Serotonin deficiency produces depressant effect. Drugs like Ipronizide which inhibit the enzyme mono-amine oxidase (MAO), prolong serotonin action on the brain and produce a psychic stimulation due to increased cerebral activity in carcinoid, serotonin-producing tumor cells of the abdominal cavity produce a high concentration of serotonin N-acetyl-serotonin glucuronide; and 5-hydroxyindoleaceturate are present in the urine of patients with carcinoid. The enhanced conversion of tryptophan to serotonin reduces niacin synthesis producing symptoms of pellagra in patients with carcinoid.
1. Ten forms of human oculocutaneous albinism are differentiated on the basis of their clinical, biochemical, ultra-structural and genetic characteristics exhibiting decreased pigmentation of the skin and eye.
A few are mentioned:
A. Tyrosine hydroxylase-negative albinos:
(i) They lack all visual pigment.
(ii) Hair bulbs from these patients fail to convert added tyrosine to pigment.
(iii) The melanocytes contain un-pigmented melanosomes.
B. Tyrosine hydroxylase-positive albinos:
(i) They have some visible pigment and white-yellow to light tan hair.
(ii) Their hair bulb melanocytes may contain highly pigmented melanosomes, which convert tyrosine to black melanin in vitro.
C. Ocular albinism:
(i) This occurs as an autosomal recessive and as an X-linked trait.
(ii) The melanocytes of X-linked and heterozygous ocular albinos contain macro-melanosomes.
(iii) The retinas of females heterozygous for X-linked ocular albinism exhibit a mosaic pattern of pigment distribution due to random X-chromosome in- activation.
2. This disease is involved in the defects of absorption of neutral amino acids.
3. Tryptophan metabolism is diverted to serotonin after the administration of the drug isoniazid and tryptophan absorption is also impaired in hartnup disease.
3. Minor Pathways:
Minor pathways include:
1. Formation of kynurenic acid.
2. Formation of tryptamine.
3. Formation of indoleacetic acid.
1. Formation of kynurenic acid:
Mentioned in the kynurenic-anthranilate pathway (Fig. 20.35)
2. Formation of tryptamine:
Small quantities of tryptophan arc converted into tryptamine by tryptophan decarboxylase present in bacteria in large intestine.
3. Formation of indoleacetic acid:
Oxidative deamination converts tryptophan to indolepyruvic acid which, in turn, is oxidized to indoleacetic acid. Indoleacetic acid is further converted to indole, skatole and indoxyl by intestinal bacteria. The reactions are shown in Fig. 20.38.