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Phenylalanine and Tyrosine Metabolism Disorders

Q: What coenzymes are required for phenylalanine hydroxylase activity?

Tetrahydrobiopterin is required as a coenzyme for phenylalanine hydroxylase activity. This compound participates in the reaction as follows: Tetrahydrobiopterin acts as a hydrogen donor during substrate hydroxylation, becoming oxidized to dihydrobiopterin.Cofactor — iron ions are also required for enzyme function. Subsequently, to restore the active form of the cofactor, a coupled reaction takes place where dihydrobiopterin is reduced back to tetrahydrobiopterin with the participation of the enzyme dihydropteridine reductase and NADPH.

Q: What forms of phenylketonuria exist besides classical PKU?

In addition to classical phenylketonuria, variant and atypical forms of this disease are distinguished. Variant form — biopterin-responsive hyperphenylalaninemia. It arises from mutations in genes controlling the metabolism of the coenzyme tetrahydrobiopterin. Its clinical course is characterized as malignant phenylketonuria with severe neurological impairments.Atypical form — occurs in 3–10% of cases and is caused by a deficiency of other enzymes, such as dihydropteridine reductase. In this form, neurotransmitter synthesis is disrupted, and neurological impairments develop even with normal phenylalanine levels, which is why it cannot be treated by dietary therapy alone.

Q: Why does urine acquire a "musty" odor in phenylketonuria?

The odor is caused by the excretion of phenylacetate—a toxic byproduct of phenylalanine metabolism that forms due to the blockade of its normal conversion pathway into tyrosine.

Q: Which enzyme is deficient in alkaptonuria?

In alkaptonuria, the activity of the enzyme homogentisate 1,2-dioxygenase (homogentisic acid oxidase) is absent.

Q: What makes albinism dangerous besides the lack of pigmentation?

The absence of melanin leaves the skin unprotected against ultraviolet radiation, leading to burns and increasing the risk of skin cancer, and is also accompanied by decreased visual acuity and photophobia.

For medical students2 min readUpdated 2026-10-10

Hereditary enzyme defects involved in the metabolism of phenylalanine and tyrosine lead to severe enzymopathies. Due to the blockade of normal biochemical pathways, toxic metabolites accumulate in the body or a deficiency of vital biologically active substances, such as melanin, occurs.

PKU enzymePhenylalanine hydroxylase

PKU symptom"Musty" or "mousy" urine odor

Alkaptonuria pigmentAlkapton (dark/black pigment)

Albinism enzymeTyrosinase

Phenylketonuria (PKU)

Classical phenylketonuria is caused by a blockade of the enzyme phenylalanine hydroxylase, which normally converts phenylalanine to tyrosine in the presence of molecular oxygen and tetrahydrobiopterin ($BH_4$).

When this pathway is blocked, an alternative, pathological pathway is triggered—transamination. Phenylalanine interacts with $\alpha$-ketoglutarate to form phenylpyruvate (phenylpyruvic acid). Subsequently, phenylpyruvate is transformed into:

Phenyllactate;
Phenylacetate (this is responsible for the characteristic "musty" or "mousy" odor of the urine);
Phenylacetylglutamine.

These substances, known as phenylketons, are toxic. Their accumulation in the blood (normal phenylalanine is < 2 mg/dL, in PKU it can reach 34 mg/dL) and tissues leads to severe toxic damage to the central nervous system.

Alkaptonuria

This condition is associated with impaired tyrosine catabolism in the liver. The cause is an autosomal recessive gene mutation (most commonly a missense mutation) leading to a deficiency of the enzyme homogentisate 1,2-dioxygenase.

Normally, this enzyme cleaves homogentisic acid (2,5-dihydroxyphenylacetic acid) to form maleylacetoacetate, which is then converted into fumarate and acetoacetate. In the absence of the enzyme, homogentisic acid accumulates and is excreted in the urine.

Clinical features of alkaptonuria:

"Black urine": homogentisic acid in the urine is oxidized in the air, turning into dark pigments (alkaptons). This is often noticed by darkened diapers in infants.
Ochronosis: deposition of dark pigment in cartilage and joints.
Development of arthritis due to joint tissue damage.

Albinism

Unlike PKU and alkaptonuria, albinism is caused by a disruption in pigment synthesis. The primary cause is a hereditary defect of the enzyme tyrosinase in melanocytes.

Tyrosinase is responsible for converting tyrosine into DOPA, which is the precursor of dark pigments—melanins. Due to the absence of melanin, characteristic symptoms develop:

Absence of skin and hair pigmentation (albus — white);
Visual disturbances and photophobia;
High risk of sunburns and skin cancer with prolonged sun exposure.

Frequently asked questions

What coenzymes are required for phenylalanine hydroxylase activity?

Tetrahydrobiopterin is required as a coenzyme for phenylalanine hydroxylase activity. This compound participates in the reaction as follows:

Tetrahydrobiopterin acts as a hydrogen donor during substrate hydroxylation, becoming oxidized to dihydrobiopterin.
Cofactor — iron ions are also required for enzyme function.

Subsequently, to restore the active form of the cofactor, a coupled reaction takes place where dihydrobiopterin is reduced back to tetrahydrobiopterin with the participation of the enzyme dihydropteridine reductase and NADPH.

What forms of phenylketonuria exist besides classical PKU?

In addition to classical phenylketonuria, variant and atypical forms of this disease are distinguished.

Variant form — biopterin-responsive hyperphenylalaninemia. It arises from mutations in genes controlling the metabolism of the coenzyme tetrahydrobiopterin. Its clinical course is characterized as malignant phenylketonuria with severe neurological impairments.
Atypical form — occurs in 3–10% of cases and is caused by a deficiency of other enzymes, such as dihydropteridine reductase. In this form, neurotransmitter synthesis is disrupted, and neurological impairments develop even with normal phenylalanine levels, which is why it cannot be treated by dietary therapy alone.

Why does urine acquire a "musty" odor in phenylketonuria?

The odor is caused by the excretion of phenylacetate—a toxic byproduct of phenylalanine metabolism that forms due to the blockade of its normal conversion pathway into tyrosine.

Which enzyme is deficient in alkaptonuria?