Enzyme Defects and Their Consequences

Mutations may result in the synthesis of a defective enzyme with reduced activity or in a reduced amount of a normal enzyme. In either case, the consequence is a metabolic block.

 1. Accumulation of the substrate, depending on the site of block, may be accompanied by accumulation of one or both intermediates. Moreover, an increased concentration of intermediate 2 may stimulate the minor pathway and thus lead to an excess of M1 and M2.

Under these conditions, tissue injury may result if the precursor, the intermediates, or the products of alternative minor pathways are toxic in high concentrations. For example, in galactosemia, the deficiency of galactose-1-phosphate uridyltransferase leads to the accumulation of galactose and consequent tissue damage. In phenylketonuria, a deficiency of phenylalanine hydroxylase results in the accumulation of phenylalanine. Excessive accumulation of complex substrates within the lysosomes as a result of deficiency of degradative enzymes is responsible for a group of diseases generally referred to as lysosomal storage diseases.

2. An enzyme defect can lead to a metabolic block and a decreased amount of end product that may be necessary for normal function. For example, a deficiency of melanin may result from lack of tyrosinase, which is necessary for the biosynthesis of melanin from its precursor, tyrosine. This results in the clinical condition called albinism.

If the end product is a feedback inhibitor of the enzymes involved in the early reactions, the deficiency of the end product may permit overproduction of intermediates and their catabolic products, some of which may be injurious at high concentrations. A prime example of a disease with such an underlying mechanism is the Lesch-Nyhan syndrome.

3. Failure to inactivate a tissue-damaging substrate is best exemplified by ?1-antitrypsin (?1-AT) deficiency. Patients who have an inherited deficiency of serum ?1-AT are unable to inactivate neutrophil elastase in their lungs. Unchecked activity of this protease leads to destruction of elastin in the walls of lung alveoli, leading eventually to pulmonary emphysema

Pathogenesis

 Mutations may result in the synthesis of a defective enzyme with reduced activity or in a reduced amount of a normal enzyme. In either case, the consequence is a metabolic block.

 Accumulation of the substrate, depending on the site of block, may be accompanied by accumulation of one or both intermediates. Moreover, an increased concentration of intermediate 2 may stimulate the minor pathway and thus lead to an excess of M1 and M2.

 Under these conditions, tissue injury may result if the precursor, the intermediates, or the products of alternative minor pathways are toxic in high concentrations.

In galactosemia, the deficiency of galactose-1-phosphate uridyltransferase leads to the accumulation of galactose and consequent tissue damage. In phenylketonuria, a deficiency of phenylalanine hydroxylase results in the accumulation of phenylalanine.

 Excessive accumulation of complex substrates within the lysosomes as a result of deficiency of degradative enzymes is responsible for a group of diseases generally referred to as lysosomal storage diseases.

 An enzyme defect can lead to a metabolic block and a decreased amount of end product that may be necessary for normal function.

For example, a deficiency of melanin may result from lack of tyrosinase, which is necessary for the biosynthesis of melanin from its precursor, tyrosine. This results in the clinical condition called albinism.

If the end product is a feedback inhibitor of the enzymes involved in the early reactions , the deficiency of the end product may permit overproduction of intermediates and their catabolic products, some of which may be injurious at high concentrations.

A prime example of a disease with such an underlying mechanism is the Lesch-Nyhan syndrome.

 Failure to inactivate a tissue-damaging substrate is best exemplified by ?1-antitrypsin (?1-AT) deficiency. Patients who have an inherited deficiency of serum ?1-AT are unable to inactivate neutrophil elastase in their lungs.

Unchecked activity of this protease leads to destruction of elastin in the walls of lung alveoli, leading eventually to pulmonary emphysema.

See also

 Genetic diseases

• metabolic genetic diseases