Phenylalanine and tyrosine metabolism
Phenylalanine is an essential aromatic amino acid, as human cells are unable to synthesize the aromatic ring. The main pathway of its metabolism is hydroxylation to form tyrosine. The reaction is catalyzed by phenylalanine hydroxylase, whose cofactor is tetrahydrobiopterin (H4-biopterin). During the reaction, H4-biopterin is oxidized to H2-biopterin and then reduced by dihydropteridine reductase using NADPH (analogously to the reduction of H4-folate).
Tyrosine is a conditionally essential amino acid: its synthesis is possible only from phenylalanine. Tyrosine catabolism occurs predominantly in the liver, leading to the formation of fumarate and acetoacetate, which enter the general catabolic pathways (gluconeogenesis, ketogenesis, or oxidation to CO₂ and H₂O). The key step is the cleavage of the homogentisic acid ring by the enzyme homogentisate 1,2-dioxygenase; vitamin C is required for this process.
Synthesis of catecholamines and other tyrosine derivatives
In the adrenal glands and nervous tissue, catecholamines are synthesized from tyrosine: dopamine → norepinephrine → epinephrine. The key regulatory enzyme is tyrosine hydroxylase, which converts tyrosine to DOPA (3,4-dihydroxyphenylalanine); subsequently, DOPA decarboxylase (with pyridoxal phosphate as a coenzyme) forms dopamine.
Regulation of tyrosine hydroxylase:
- inhibition by phosphorylation and by the end product — epinephrine;
- induction by cortisol.
Other pathways of tyrosine utilization:
- in the thyroid gland — synthesis of iodothyronines (T3, T4);
- in melanocytes — synthesis of melanin from DOPA with the participation of tyrosinase.
Phenylketonuria
Normally, when phenylalanine hydroxylase activity is sufficient, the alternative catabolic pathway (conversion of phenylalanine to phenylpyruvate, then to phenyllactate and phenylacetate conjugated with glutamine and excreted in the urine) is minimally expressed. When the primary pathway is defective, this shunt is sharply activated, leading to phenylketonuria (PKU).
Forms of PKU:
- classic — defect in phenylalanine hydroxylase itself;
- variant (atypical) — impairment of H4-biopterin metabolism (defect in synthesis or dihydropteridine reductase).
Clinical manifestations are associated with the toxic effects of phenylalanine, phenylpyruvate, and phenylacetate on brain cells, as well as competitive impairment of the transport of tyrosine and tryptophan across the blood-brain barrier. This leads to neurotransmitter deficiency and severe intellectual disability in the absence of treatment.
Disorders of tyrosine catabolism
Alkaptonuria — a hereditary defect in homogentisate 1,2-dioxygenase. Homogentisic acid accumulates and is excreted in the urine, where it is oxidized by atmospheric oxygen to form dark pigments — alkaptons. Urine darkens upon exposure to air ("black urine"); alkaptons deposit in cartilage and joints, causing ochronosis and arthropathy.
Albinism — a defect in the enzyme tyrosinase in melanocytes, leading to reduced or absent melanin synthesis. It is characterized by the absence of pigmentation in the skin, hair, and irises, reduced visual acuity, and photophobia.
Parkinson's disease and disorders of dopaminergic transmission
Parkinsonism develops with a deficiency of dopamine in the substantia nigra due to decreased activity of tyrosine hydroxylase or DOPA decarboxylase. The classic triad of symptoms includes:
- akinesia — poverty of movement;
- rigidity — increased muscle tone;
- resting tremor.
Treatment is carried out not with dopamine (it does not cross the blood-brain barrier), but with its precursor — L-DOPA. Additionally, inhibitors of dopamine inactivation are used — MAO inhibitors (deprenyl, nialamide). Conversely, dopamine hypersecretion is considered one of the mechanisms of schizophrenia.
Biogenic amines: synthesis
Biogenic amines are formed by decarboxylation of amino acids involving pyridoxal phosphate (vitamin B6). B6 deficiency impairs their synthesis.
- GABA (-aminobutyric acid) — from glutamate under the action of glutamate decarboxylase; the main inhibitory neurotransmitter of the CNS.
- Serotonin — from tryptophan via 5-hydroxytryptophan (5-HTP) with the participation of tryptophan hydroxylase (cofactor H4-biopterin) and decarboxylase. It regulates smooth muscle tone, peristalsis, vascular tone, temperature, respiration, mood, and allergic reactions.
- Histamine — from histidine (a conditionally essential amino acid synthesized from glutamate); formed in mast cells, it is a mediator of inflammation and allergy and stimulates HCl secretion in the stomach.
- Acetylcholine — from serine: decarboxylation yields ethanolamine, which is methylated (methyl donor — S-adenosylmethionine, SAM) to choline; choline acetyltransferase attaches acetyl-CoA. Deficiency leads to muscle weakness.
- Dopamine, norepinephrine, epinephrine — from tyrosine (see above).
Inactivation of biogenic amines
There are several inactivation pathways:
- Transamination — characteristic only of GABA; through a series of reactions, GABA is converted into succinate, which enters the citric acid cycle.
- Methylation involving SAM — for histamine, epinephrine, norepinephrine; the products (e.g., metanephrine) are inactive. Mnemonic: SAM (three letters), HEN (histamine, epinephrine, norepinephrine — three letters).
- Oxidative deamination by the enzyme monoamine oxidase (MAO), with FAD as a cofactor; characteristic of dopamine, norepinephrine, serotonin, GABA. An aldehyde is formed, which is converted by aldehyde oxidase into the corresponding organic acid, excreted in the urine as an ammonium salt.
Key points
- Phenylalanine hydroxylase with the cofactor H4-biopterin converts phenylalanine into tyrosine — the main metabolic reaction.
- PKU can be classic (enzyme defect) and variant (biopterin metabolism disorder); phenylpyruvate, phenyllactate, and phenylacetate are toxic.
- Alkaptonuria — a defect in homogentisate 1,2-dioxygenase; albinism — a defect in tyrosinase.
- Synthesis of catecholamines: tyrosine → DOPA → dopamine → norepinephrine → epinephrine; the key enzyme is tyrosine hydroxylase.
- Parkinson's disease is caused by dopamine deficiency; treatment includes L-DOPA and MAO inhibitors.
- All biogenic amines are formed by decarboxylation of amino acids with the coenzyme pyridoxal phosphate.
- GABA is an inhibitory neurotransmitter, synthesized from glutamate, and inactivated by transamination.
- Inactivation of biogenic amines: MAO (dopamine, NE, serotonin, GABA), SAM methylation (histamine, epinephrine, norepinephrine).