Main pathway: conversion to tyrosine
Up to 80% of dietary phenylalanine not used for tissue protein synthesis undergoes hydroxylation.
- Substrates: Phenylalanine, oxygen ($O_2$), and the coenzyme tetrahydrobiopterin ($H_4BP$).
- Enzyme: Phenylalanine hydroxylase (monooxygenase), which requires iron ions ($Fe^{2+}$).
- Products: Tyrosine, water, and dihydrobiopterin ($H_2BP$).
The resulting tyrosine is a conditionally essential amino acid because animal cells cannot synthesize the aromatic ring on their own. During the reaction, the coenzyme is oxidized to $H_2BP$, and its reduction requires the enzyme dihydropteridine reductase, which utilizes $NADPH+H^+$.
Main pathways of tyrosine utilization
The subsequent fate of tyrosine depends on the type of tissue in which it is located:
- In the liver (energy metabolism). Tyrosine loses its amino group (enzyme tyrosine aminotransferase + vitamin $B_6$), converting into p-hydroxyphenylpyruvate. Following a series of complex reactions involving the cleavage of the aromatic ring by dioxygenases, fumarate (enters the Krebs cycle or goes toward glucose synthesis) and acetoacetate (a ketone body) are formed.
- In melanocytes (pigmentation). With the participation of the enzyme tyrosinase and copper ions ($Cu^+$), tyrosine is oxidized to DOPA and then converted into melanin pigments.
- In the thyroid gland. It serves as a precursor for thyroid hormones—iodothyronines.
- In nervous tissue and the adrenal glands. It is used for the synthesis of catecholamines.
Catecholamine synthesis
Synthesis occurs in nerve terminals and the adrenal medulla.
The rate-limiting step is the first reaction — the formation of DOPA from tyrosine. It is catalyzed by tyrosine hydroxylase, which is tightly regulated: it is inhibited by the end product (norepinephrine) and activated by phosphorylation (cAMP-dependent protein kinase) or cortisol.
Stages of synthesis:
- Tyrosine → DOPA. Enzyme: tyrosine hydroxylase ($H_4BP$, $O_2$, $Fe^{2+}$).
- DOPA → Dopamine. Enzyme: DOPA decarboxylase (cofactor: pyridoxal phosphate). $CO_2$ is released.
- Dopamine → Norepinephrine. Enzyme: dopamine beta-hydroxylase (cofactors: vitamin C, copper, $O_2$).
- Norepinephrine → Epinephrine. Enzyme: phenylethanolamine N-methyltransferase. The methyl group donor is S-adenosylmethionine (SAM).
Hereditary enzymopathies
Disorders in the metabolism of these amino acids lead to severe diseases:
- Phenylketonuria (PKU). Arises from a deficiency of phenylalanine hydroxylase (classic form) or impaired $H_4BP$ metabolism (variant form). Phenylalanine is shunted into an alternative pathway, producing toxic phenylpyruvate and phenyllactate. This causes brain damage and seizures.
- Alkaptonuria. Homogentisate 1,2-dioxygenase deficiency. Manifests as urine darkening upon air exposure and pigment deposition in cartilage (ochronosis).
- Tyrosinosis (Tyrosinemia type I). Fumarylacetoacetate hydrolase deficiency, leading to severe liver and kidney damage.
- Albinism. Blockade of tyrosinase in melanocytes, leaving the skin, hair, and iris devoid of melanin pigment.
Briefly: answers to topical questions
Which specific thyroid hormones are synthesized from tyrosine?
Thyroid hormones of the iodothyronine group are synthesized from tyrosine in the thyroid gland. The following active hormones are formed within the thyroglobulin protein:
- Thyroxine ($T_4$ or tetraiodothyronine) — formed by the condensation of two molecules of diiodotyrosine (DIT).
- Triiodothyronine ($T_3$) — formed by the condensation of monoiodotyrosine (MIT) and diiodotyrosine (DIT).
The synthesis process involves the iodination of tyrosine residues mediated by the enzyme thyroid peroxidase. Only the free hormone fraction in plasma is active, with $T_3$ providing the main clinical effect.
Which intermediate metabolites are formed on the pathway from p-hydroxyphenylpyruvate to fumarate?
Along the catabolic pathway of tyrosine from p-hydroxyphenylpyruvate to fumarate, the following intermediate metabolites are formed sequentially:
- Homogentisic acid — formed by the action of the enzyme p-hydroxyphenylpyruvate dioxygenase.
- Maleylacetoacetate — the result of aromatic ring cleavage by homogentisate dioxygenase.
- Fumarylacetoacetate — the product of maleylacetoacetate isomerization.
During the final reaction, fumarylacetoacetate undergoes hydrolysis to yield fumarate and acetoacetate.
Which toxic phenylalanine derivatives accumulate in phenylketonuria?
In phenylketonuria, due to the blockade of the main metabolic pathway, phenylalanine itself and the metabolites of its alternative pathway—toxic derivatives (phenylketones)—accumulate:
- Phenylpyruvate (phenylpyruvic acid) — the primary product of phenylalanine transamination.
- Phenyllactate — the reduction product of phenylpyruvate.
- Phenylacetate — the decarboxylation product.
- Phenylacetoacetic acid.
- Phenylacetylglutamine — formed by the conjugation of phenylacetate with glutamine.
High concentrations of these substances exert toxic effects on brain cells, impairing central nervous system development.
To memorize the catecholamine synthesis pathway, use the mnemonic: «Tyrosine Produces Dopamine, Norepinephrine, Epinephrine».
Class and exam questions
Why are phenylalanine and tyrosine called glucoketogenic?
During their degradation in the liver, fumarate is formed, which can be used for glucose synthesis, alongside acetoacetate, a typical ketone body.
What is the danger of tetrahydrobiopterin coenzyme deficiency?
It is required for the activity of hydroxylases. Its deficiency disrupts the metabolism of not only phenylalanine, but also tyrosine and tryptophan, blocking the synthesis of catecholamines and serotonin in the brain (malignant PKU).
What happens in alkaptonuria?
Due to a genetic defect in homogentisate dioxygenase, aromatic ring cleavage is interrupted. The acid accumulates in the body, polymerizes in tissues, and turns urine dark upon exposure to air.
What else to study on this topic
- Mechanisms of tetrahydrobiopterin regeneration by dihydropteridine reductase
- Specificity of dioxygenase enzymes in aromatic ring cleavage
- Alternative metabolic pathways in classic phenylketonuria
- The role of S-adenosylmethionine in norepinephrine methylation
- Allosteric and covalent regulation of tyrosine hydroxylase
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