BIOCHEMISTRY - Textbook - Ostapchenko L. I. - 2012

Chapter 7. ENZYMOLOGY

7.8. Enzymopathies

A great number of diseases are caused by impaired cellular enzyme function, known as enzymopathies. They are classified into primary (hereditary) and secondary (acquired) enzymopathies. The latter, much like proteinopathies in general, presumably occur in all pathological conditions.

Primary enzymopathies are predominantly inherited in an autosomal recessive manner. Heterozygotes are typically free of phenotypic abnormalities. Primary enzymopathies are largely classified as Metabolic Disorders because they involve the disruption of specific metabolic pathways. The Pathogenesis of these disorders may follow one of several scenarios outlined below. Let us consider a generalized schematic of a metabolic pathway:

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Substance A is converted into product P through a sequence of enzymatic reactions. A hereditary deficiency of any enzyme, such as enzyme E₃, can lead to various disruptions in metabolic pathways:

Impaired synthesis of end products. A deficiency in the final product of a metabolic pathway (P) (in the absence of alternative synthesis pathways) can trigger the clinical symptoms characteristic of the given disorder:

Albinism serves as a classic example. This condition involves impaired synthesis of melanin pigments within melanocytes. These pigments are found in the Skin, Hair, iris, and retinal pigment epithelium, determining their coloration. Albinism manifests as hypopigmentation of the skin, fair hair, and a reddish hue of the iris due to visible underlying Blood Vessels. The manifestation of albinism is linked to a deficiency in tyrosinase (Tyrosine hydroxylase), one of the Key Enzymes catalyzing The pathway of melanin synthesis.

Accumulation of precursor substrates. Due to a deficiency of enzyme E₃, substance C—as well as preceding intermediates in many cases—will accumulate. The buildup of substrates preceding the defective enzyme is a key mechanism in The Development of numerous pathologies:

Alkaptonuria is an example of such a disorder, characterized by impaired oxidation of homogentisic acid in Tissues (this acid is an intermediate metabolite of tyrosine degradation). Affected individuals suffer from a deficiency in homogentisate 1,2-dioxygenase, the enzyme responsible for homogentisic acid oxidation, which drives the disease progression. Consequently, the concentration of homogentisic acid rises, leading to its increased excretion in urine. In the presence of oxygen, homogentisic acid converts into a dark-colored compound known as alkapton. As a result, the urine of such patients turns black upon exposure to air. Alkapton also accumulates in biological fluids and deposits in tissues, skin, tendons, and joints. Extensive deposition of alkapton in joints eventually impairs their mobility.

Combined impaired synthesis of end products and accumulation of precursor substrates. Certain disorders present clinical symptoms driven simultaneously by product deficiency and substrate accumulation.

For instance, individuals with von Gierke's disease (Glycogen storage disease type I) exhibit decreased blood glucose concentrations (hypoglycemia) during fasting periods between meals. This is caused by impaired hepatic glycogen breakdown and subsequent release of glucose into the bloodstream due to a deficiency in glucose-6-phosphatase. Simultaneously, these patients develop an enlarged Liver (hepatomegaly) as a result of excessive glycogen accumulation within the organ.