Purine nucleoside phosphorylase

Nomenclature

This enzyme belongs to the family of glycosyltransferases, specifically the pentosyltransferases. The systematic name of this enzyme class is purine-nucleoside:phosphate ribosyltransferase.

Other names in common use include:

• inosine phosphorylase
• PNPase
• PUNPI
• PUNPII
• inosine-guanosine phosphorylase
• nucleotide phosphatase
• purine deoxynucleoside phosphorylase
• purine deoxyribonucleoside phosphorylase
• purine nucleoside phosphorylase
• purine ribonucleoside phosphorylas

This enzyme participates in 3 metabolic pathways: purine metabolism, pyrimidine metabolism, and nicotinate and nicotinamide metabolism.

Function

Purine nucleoside phosphorylase is an enzyme involved in purine metabolism. PNP metabolizes inosine into hypoxanthine and guanosine into guanine, in each case creating ribose-1-phosphate. In humans, adenosine is first metabolized to inosine via the enzyme adenosine deaminase.

Nucleoside phosphorylase is an enzyme which cleaves a nucleoside by phosphorylating the ribose to produce a nucleobase and ribose-1-phosphate. It is one enzyme of the nucleotide salvage pathways. These pathways allow the cell to produce nucleotide monophosphates when the de novo synthesis pathway has been interrupted or is non-existent (as is the case in the brain). Often the de novo pathway is interrupted as a result of chemotherapy drugs such as methotrexate or aminopterin.

All salvage pathway enzymes require a high energy phosphate donor such as ATP or PRPP. For pyrimidine nucleosides:

• Thymidine can be phosphorylated by thymidine kinase.
• Uridine can be phosphorylated by uridine kinase.
• Cytidine can be phosphorylated by cytidine kinase.
• Deoxycytidine can be phosphorylated by deoxycytidine kinase.

Adenosine uses the enzyme adenosine kinase, which is a very important enzyme in the cell. Attempts are being made to develop an inhibitor for the enzyme for use in cancer chemotherapy.

Enzyme regulation

PNP protein may use the morpheein model of allosteric regulation.

Clinical significance

Purine nucleoside phosphorylase, together with adenosine deaminase (ADA), serves a key role in purine catabolism. Mutations in ADA lead to an accumulation of dATP, which inhibits ribonucleotide reductase, leading to a deficiency in dCTP and dTTP, which, in turn, induces apoptosis in T-lymphocytes and B-lymphocytes, leading to severe combined immunodeficiency (SCID).

PNP-deficient patients will have an immunodeficiency problem. It affects only T-cells; B-cells are unaffected by the deficiency.

References

References

1. (January 2004). "Structures of human purine nucleoside phosphorylase complexed with inosine and ddI". Biochemical and Biophysical Research Communications.
2. "Entrez Gene: NP nucleoside phosphorylase".
3. Kaplan USMLE Biochemistry Review
4. (March 2012). "Dynamic dissociating homo-oligomers and the control of protein function". Archives of Biochemistry and Biophysics.
5. (August 1987). "Mutations in the human adenosine deaminase gene that affect protein structure and RNA splicing". Proceedings of the National Academy of Sciences of the United States of America.