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 ($H_4 ext{BP}$).- Enzyme: Phenylalanine hydroxylase (a monooxygenase) requiring iron ions ($Fe^{2+}$).
- Products: Tyrosine, water, and dihydrobiopterin ($H_2 ext{BP}$).- Enzyme: Phenylalanine hydroxylase (monooxygenase), requiring iron ions ($Fe^{2+}$).
- Products: Tyrosine, water, and dihydrobiopterin ($H_2 ext{BP}$).
The resulting tyrosine is a conditionally essential amino acid because animal cells cannot independently synthesize the aromatic ring. During the reaction, the coenzyme is oxidized to $H_2 ext{BP}$, and its regeneration requires the enzyme dihydropteridine reductase, which utilizes $NADPH+H^+$.
Major Pathways of Tyrosine Utilization
The further fate of tyrosine depends on the tissue type:
- In the liver (energy metabolism). Tyrosine loses its amino group (via tyrosine aminotransferase + vitamin $B_6$), turning into $p$-hydroxyphenylpyruvate. After a series of complex reactions involving cleavage of the aromatic ring by dioxygenases, fumarate (enters the Krebs cycle or gluconeogenesis) 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. Serves as a precursor for thyroid hormones—iodothyronines.
- In nervous tissue and the adrenal medulla. Used for catecholamine synthesis.
Synthesis of Catecholamines
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: inhibited by the end product (norepinephrine) and activated by phosphorylation (cAMP-dependent protein kinase) or cortisol.
Steps of synthesis:
- Tyrosine → DOPA. Enzyme: tyrosine hydroxylase ($H_4 ext{BP}$, $O_2$, $Fe^{2+}$).
- DOPA → Dopamine. Enzyme: DOPA decarboxylase (cofactor: pyridoxal phosphate). $CO_2$ is released.
- Dopamine → Norepinephrine. Enzyme: dopamine $eta$-hydroxylase (cofactors: vitamin C, copper, $O_2$).
- Norepinephrine → Epinephrine. Enzyme: phenylethanolamine $N$-methyltransferase. The methyl group donor is S-adenosylmethionine (SAM).
Hereditary Enzymopathies
Disorders of amino acid metabolism lead to severe conditions:
- Phenylketonuria (PKU). Caused by a deficiency of phenylalanine hydroxylase (classical form) or impaired $H_4 ext{BP}$ metabolism (malignant variant). Phenylalanine is shunted into an alternative pathway producing toxic phenylpyruvate and phenyllactate, causing brain damage and seizures.
- Alkaptonuria. Deficiency of homogentisate 1,2-dioxygenase. Manifests as urine darkening upon air exposure and pigment deposition in cartilage (ochronosis).
- Tyrosinemia Type I. Deficiency of fumarylacetoacetate hydrolase, leading to severe liver and kidney damage.
- Albinism. Blockade of tyrosinase in melanocytes, leaving skin, hair, and irises devoid of melanin pigment.