Purine-nucleoside phosphorylase

Purine-nucleoside phosphorylase (PNP) is an enzyme that plays a crucial role in the metabolism of purines in the human body. PNP catalyzes the reversible phosphorolysis of purine nucleosides to produce purine bases and ribose 1-phosphate. This enzyme is essential for the salvage pathway that recycles purines for the synthesis of nucleic acids, which are vital for cell growth and division.

Function

PNP is involved in the breakdown of purine nucleosides, such as inosine and guanosine, into their respective bases, hypoxanthine and guanine, and ribose 1-phosphate. This process is critical for the maintenance of adequate levels of purine bases for DNA and RNA synthesis, especially in cells that divide rapidly, such as those of the immune system.

Structure

The enzyme is a homotrimer, meaning it consists of three identical subunits. Each subunit contains a binding site for both the purine nucleoside and phosphate. The active sites are located in the clefts between the subunits, facilitating the catalytic process.

Clinical Significance

Mutations in the gene encoding PNP can lead to a rare, inherited metabolic disorder known as Purine nucleoside phosphorylase deficiency. This condition results in a severe defect in the purine salvage pathway, leading to immunodeficiency due to the accumulation of toxic metabolites that affect lymphocyte viability and function. Patients with this disorder typically present with recurrent infections, autoimmune disorders, and neurological symptoms.

Treatment

There is no cure for PNP deficiency, but treatment focuses on managing symptoms and preventing infections. Bone marrow transplantation has been used successfully in some cases to restore a functional immune system.

Research

Research into PNP has also focused on its potential as a target for chemotherapy drugs. Inhibitors of PNP can increase the levels of toxic purine metabolites selectively in cancer cells, leading to their death while sparing normal cells. This approach has shown promise in the treatment of certain types of leukemia and lymphoma.