PNP

Official Full Name

purine nucleoside phosphorylase

Organism

Homo sapiens

GeneID

4860

Background

This gene encodes an enzyme which reversibly catalyzes the phosphorolysis of purine nucleosides. The enzyme is trimeric, containing three identical subunits. Mutations which result in nucleoside phosphorylase deficiency result in defective T-cell (cell-mediated) immunity but can also affect B-cell immunity and antibody responses. Neurologic disorders may also be apparent in patients with immune defects. A known polymorphism at aa position 51 that does not affect enzyme activity has been described. A pseudogene has been identified on chromosome 2. [provided by RefSeq, Jul 2008]

Synonyms

NP; PUNP; PRO1837;

Bio Chemical Class

Pentosyltransferase

Protein Sequence

MENGYTYEDYKNTAEWLLSHTKHRPQVAIICGSGLGGLTDKLTQAQIFDYGEIPNFPRSTVPGHAGRLVFGFLNGRACVMMQGRFHMYEGYPLWKVTFPVRVFHLLGVDTLVVTNAAGGLNPKFEVGDIMLIRDHINLPGFSGQNPLRGPNDERFGDRFPAMSDAYDRTMRQRALSTWKQMGEQRELQEGTYVMVAGPSFETVAECRVLQKLGADAVGMSTVPEVIVARHCGLRVFGFSLITNKVIMDYESLEKANHEEVLAAGKQAAQKLEQFVSILMASIPLPDKAS

Open

Disease

Diabetes mellitus, Gout, Malignant haematopoietic neoplasm, Mycosis fungoides, Psoriasis, Rheumatoid arthritis

Approved Drug

Clinical Trial Drug

5 +

Discontinued Drug

1 +

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Detailed Information

The PNP (purine nucleoside phosphorylase) gene is located on human chromosome 14q11.2 and contains six exons, encoding a protein of 289 amino acids. This enzyme belongs to the nucleoside phosphorylase superfamily but specifically catalyzes the phosphorolysis of purine nucleosides. PNP exists as a homotrimer, with each monomer weighing approximately 32 kDa. The three subunits interact non-covalently to form a stable functional trimer. The active site lies at the subunit interface and contains key residues such as His257, Phe159, and Glu89, which are directly involved in substrate binding and catalysis. Crystal structure analysis has shown that the active pocket is highly conserved and recognizes purine bases (hypoxanthine and guanine) with high specificity, while displaying minimal affinity for pyrimidines.

Catalytic Mechanism and Substrate Specificity

The catalytic mechanism of PNP involves a concerted SN1-type nucleophilic substitution reaction, with inorganic phosphate serving as a co-substrate. PNP catalyzes the cleavage of the N-glycosidic bond of purine ribonucleosides (such as inosine and guanosine), producing free purine bases (hypoxanthine or guanine) and ribose-1-phosphate. Although reversible, under physiological conditions, the reaction proceeds mainly toward nucleoside degradation. PNP exhibits strict substrate specificity, with the highest activity toward 6-oxopurine nucleosides, such as inosine and deoxyinosine, while its activity toward adenosine is less than 1% of that for inosine. This specificity is physiologically significant for the purine salvage pathway. Notably, the PNP gene on chromosome 14 is functional, whereas a pseudogene exists on chromosome 2, providing useful information for genetic diagnosis.

Biological Function and Regulatory Mechanisms

PNP plays a central role in the purine salvage pathway and is widely expressed across tissues, though it exhibits the highest activity in lymphoid tissues, reflecting the strong dependence of lymphocytes on purine metabolism. The direction of the PNP-catalyzed reaction depends on substrate availability and cellular needs. In nucleoside degradation, inosine and guanosine are converted into purine bases and ribose-1-phosphate, which are further metabolized via uric acid excretion or the pentose phosphate pathway. Under conditions of low inorganic phosphate, PNP can catalyze the reverse reaction, forming nucleosides from bases and ribose-1-phosphate, thereby contributing to nucleotide synthesis.

Regulation of PNP activity occurs at multiple levels. Transcription factors such as SP1 and AP-1 modulate its gene expression, while post-translational regulation involves substrate availability, product feedback, and protein-protein interactions. PNP functionally couples with other purine metabolic enzymes such as hypoxanthine-guanine phosphoribosyltransferase (HGPRT), forming metabolite channeling complexes that enhance efficiency and minimize intermediate loss. Although predominantly cytoplasmic, PNP also localizes to the nucleus, where it may influence DNA repair and epigenetic regulation.

Role in Disease

Deficiency of PNP results in autosomal recessive severe combined immunodeficiency (SCID), characterized by near-complete loss of T cells, impaired B-cell function, and reduced natural killer (NK) cell activity. Clinical manifestations typically appear in infancy, including recurrent severe infections, growth retardation, and neurological abnormalities. Disease severity correlates with residual enzyme activity: complete deficiency often results in death before adolescence, while partial deficiency may present as milder or late-onset immunodeficiency.

The pathogenesis is primarily due to the toxic accumulation of deoxyguanosine metabolites. In the absence of PNP, deoxyguanosine is phosphorylated to dGTP, which accumulates to millimolar concentrations. Excess dGTP competitively inhibits ribonucleotide reductase, disturbs DNA synthesis, and interferes with DNA repair, ultimately activating p53-dependent apoptosis in developing T cells and causing selective T-cell depletion.

Beyond immunodeficiency, approximately one-third of patients display neurological abnormalities, including developmental delay, ataxia, spasticity, and motor neuron degeneration. Proposed mechanisms include dGTP-induced mitochondrial dysfunction, excitotoxicity via NMDA receptor activation, and neurotransmitter imbalance. Autoimmune manifestations, such as hemolytic anemia and thrombocytopenia, are also frequent, while cancer susceptibility is significantly increased, particularly for lymphoid malignancies.

Clinical Advances and Therapeutic Perspectives

Therapeutic approaches for PNP deficiency include enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and emerging gene therapy strategies. PEGylated recombinant PNP (PEG-PNP) has demonstrated long-lasting activity, lowering toxic metabolite levels and partially restoring immune function in clinical trials. HSCT remains the only curative option, with the best outcomes achieved when performed early, although neurological symptoms often persist despite successful transplantation. Gene therapy using autologous hematopoietic stem cells transduced with PNP cDNA has shown promising early results, with restoration of T-cell counts and reduction of toxic metabolites.

Figure 1. Structural and functional overview of purine nucleoside phosphorylase (PNP) as a therapeutic target in T-cell malignancies and immunological diseases. (Chen Y, et al., 2024)

Adjunctive small-molecule therapies, such as deoxycytidine analogs that inhibit deoxyguanosine phosphorylation, antioxidants, and neuroprotective agents, are under investigation. Future therapeutic advances will focus on improving central nervous system protection, developing brain-penetrant enzyme variants, and integrating newborn screening programs for early detection.

Reference

Zhang Y, Parker WB, Sorscher EJ, et al. PNP anticancer gene therapy. Curr Top Med Chem. 2005;5(13):1259-74.
Birder LA, Jackson EK. Purine nucleoside phosphorylase as a target to treat age-associated lower urinary tract dysfunction. Nat Rev Urol. 2022 Nov;19(11):681-687.
Chen Y, Li Y, Gao J, et al. Perspectives and challenges in developing small molecules targeting purine nucleoside phosphorylase. Eur J Med Chem. 2024 May 5;271:116437.

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