Phenylketonuria (PKU)
Classic phenylketonuria occurs due to the blockage of the enzyme phenylalanine hydroxylase, which normally converts phenylalanine to tyrosine in the presence of oxygen and tetrahydrobiopterin ($BH_4$).
When this pathway is blocked, an alternative, pathological scenario is triggered — transamination. Phenylalanine interacts with $\alpha$-ketoglutarate to form phenylpyruvate (phenylpyruvic acid). Subsequently, phenylpyruvate is transformed into:
- Phenyllactate;
- Phenylacetate (this is what gives urine its characteristic «mousy» odor);
- Phenylacetylglutamine.
These substances, called phenylketones, 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 disease 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 defect in the enzyme homogentisate 1,2-dioxygenase.
Normally, this enzyme breaks down homogentisic acid (2,5-dihydroxyphenylacetic acid) to form maleylacetoacetate, which is then converted to fumarate and acetoacetate. In the absence of the enzyme, homogentisate accumulates and is excreted in the urine.
Clinical signs of alkaptonuria:
- «Black urine»: homogentisic acid in the urine is oxidized in the air, turning into black pigments (alkaptons). This is often noticed by the darkened diapers of infants.
- Ochronosis: deposition of dark pigment in cartilage and joints.
- Development of arthritis due to damage to joint tissues.
Albinism
Unlike PKU and alkaptonuria, albinism is caused by impaired pigment synthesis. The main cause is a hereditary defect of the enzyme tyrosinase in melanocytes.
Tyrosinase is responsible for converting tyrosine to DOPA, which is a precursor of dark pigments — melanins. Due to the lack of melanin, characteristic symptoms develop:
- Lack of skin and hair pigmentation (albus — white);
- Visual impairments and photophobia;
- High risk of sunburn and skin cancer with prolonged sun exposure.
Briefly: answers to topical questions
Which 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, being oxidized to dihydrobiopterin in the process.
- Cofactor — iron ions are also required for enzyme function.
Subsequently, to restore the active form of the coenzyme, 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 the classic one?
In addition to classic phenylketonuria, variant and atypical forms of this disease are distinguished.
- Variant form — biopterin-dependent hyperphenylalaninemia. It occurs due to mutations in genes controlling the metabolism of the coenzyme tetrahydrobiopterin. Its course is characterized as malignant phenylketonuria with severe neurological disorders.
- Atypical form — occurs in 3–10% of cases and is caused by a deficiency of other enzymes, for example, dihydropteridine reductase. In this form, neurotransmitter synthesis is impaired, and neurological disorders develop even at normal phenylalanine levels, which is why it cannot be cured by diet therapy alone.
Class and exam questions
Why does urine acquire a «mousy» odor in phenylketonuria?
The odor is caused by the excretion of phenylacetate, a secondary toxic product of phenylalanine metabolism that forms due to the blockage of its normal pathway of conversion into tyrosine.
Which enzyme is defective in alcaptonuria?
In alkaptonuria, the activity of the enzyme homogentisate 1,2-dioxygenase (homogentisate dioxygenase) is absent.
What makes albinism dangerous besides the lack of pigmentation?
The absence of melanin leaves the skin defenseless against ultraviolet radiation, which leads to burns and increases the risk of skin cancer, and is also accompanied by decreased visual acuity and photophobia.
What else to study on this topic
- Mechanism of the toxic effect of phenylketones on the central nervous system
- The role of tetrahydrobiopterin ($BH_4$) in amino acid metabolism
- Biosynthesis of melanins from DOPA
- Histidine metabolism and the formation of its biologically active derivatives
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