Purine nucleoside phosphorylase explained
purine-nucleoside phosphorylase |
Ec Number: | 2.4.2.1 |
Cas Number: | 9030-21-1 |
Go Code: | 0004731 |
Purine nucleoside phosphorylase, PNP, PNPase or inosine phosphorylase is an enzyme that in humans is encoded by the NP gene.[1] It catalyzes the chemical reaction
purine nucleoside + phosphate
purine + alpha-D-ribose 1-phosphate
Thus, the two substrates of this enzyme are a purine nucleoside and phosphate, whereas its products are a purine and alpha-D-ribose 1-phosphate.
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 phosphate. Note: adenosine is first metabolized to inosine via the enzyme adenosine deaminase.[2]
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.
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
This protein may use the morpheein model of allosteric regulation.[3]
Clinical significance
PNPase, together with adenosine deaminase (ADA), serves a key role in purine catabolism, referred to as the salvage pathway. Mutations in ADA lead to an accumulation of (d)ATP, which inhibits ribonucleotide reductase, leading to a deficiency in (d)CTPs and (d)TTPs, 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.
See also
Further reading
- Markert ML . Purine nucleoside phosphorylase deficiency . Immunodeficiency Reviews . 3 . 1 . 45–81 . 1991 . 1931007 .
- Borgers M, Verhaegen H, De Brabander M, De Cree J, De Cock W, Thoné F, Geuens G . Purine nucleoside phosphorylase in chronic lymphocytic leukemia (CLL) . Blood . 52 . 5 . 886–95 . Nov 1978 . 100152 . 10.1182/blood.V52.5.886.886. free .
- Aust MR, Andrews LG, Barrett MJ, Norby-Slycord CJ, Markert ML . Molecular analysis of mutations in a patient with purine nucleoside phosphorylase deficiency . American Journal of Human Genetics . 51 . 4 . 763–72 . Oct 1992 . 1384322 . 1682776 .
- Andrews LG, Markert ML . Exon skipping in purine nucleoside phosphorylase mRNA processing leading to severe immunodeficiency . The Journal of Biological Chemistry . 267 . 11 . 7834–8 . Apr 1992 . 10.1016/S0021-9258(18)42589-6 . 1560016 . free .
- Jonsson JJ, Williams SR, McIvor RS . Sequence and functional characterization of the human purine nucleoside phosphorylase promoter . Nucleic Acids Research . 19 . 18 . 5015–20 . Sep 1991 . 1923769 . 328804 . 10.1093/nar/19.18.5015 .
- Ealick SE, Rule SA, Carter DC, Greenhough TJ, Babu YS, Cook WJ, Habash J, Helliwell JR, Stoeckler JD, Parks RE . Three-dimensional structure of human erythrocytic purine nucleoside phosphorylase at 3.2 A resolution . The Journal of Biological Chemistry . 265 . 3 . 1812–20 . Jan 1990 . 2104852 . 10.2210/pdb2pnp/pdb.
- Williams SR, Gekeler V, McIvor RS, Martin DW . A human purine nucleoside phosphorylase deficiency caused by a single base change . The Journal of Biological Chemistry . 262 . 5 . 2332–8 . Feb 1987 . 10.1016/S0021-9258(18)61658-8 . 3029074 . free .
- Williams SR, Goddard JM, Martin DW . Human purine nucleoside phosphorylase cDNA sequence and genomic clone characterization . Nucleic Acids Research . 12 . 14 . 5779–87 . Jul 1984 . 6087295 . 320030 . 10.1093/nar/12.14.5779 .
- Pannicke U, Tuchschmid P, Friedrich W, Bartram CR, Schwarz K . Two novel missense and frameshift mutations in exons 5 and 6 of the purine nucleoside phosphorylase (PNP) gene in a severe combined immunodeficiency (SCID) patient . Human Genetics . 98 . 6 . 706–9 . Dec 1996 . 8931706 . 10.1007/s004390050290 . 5657916 .
- Markert ML, Finkel BD, McLaughlin TM, Watson TJ, Collard HR, McMahon CP, Andrews LG, Barrett MJ, Ward FE . Mutations in purine nucleoside phosphorylase deficiency . Human Mutation . 9 . 2 . 118–21 . 1997 . 9067751 . 10.1002/(SICI)1098-1004(1997)9:2<118::AID-HUMU3>3.0.CO;2-5 . 46243170 . free .
- Erion MD, Takabayashi K, Smith HB, Kessi J, Wagner S, Hönger S, Shames SL, Ealick SE . Purine nucleoside phosphorylase. 1. Structure-function studies . Biochemistry . 36 . 39 . 11725–34 . Sep 1997 . 9305962 . 10.1021/bi961969w .
- Erion MD, Stoeckler JD, Guida WC, Walter RL, Ealick SE . Purine nucleoside phosphorylase. 2. Catalytic mechanism . Biochemistry . 36 . 39 . 11735–48 . Sep 1997 . 9305963 . 10.1021/bi961970v .
- Stoeckler JD, Poirot AF, Smith RM, Parks RE, Ealick SE, Takabayashi K, Erion MD . Purine nucleoside phosphorylase. 3. Reversal of purine base specificity by site-directed mutagenesis . Biochemistry . 36 . 39 . 11749–56 . Sep 1997 . 9305964 . 10.1021/bi961971n .
- Sasaki Y, Iseki M, Yamaguchi S, Kurosawa Y, Yamamoto T, Moriwaki Y, Kenri T, Sasaki T, Yamashita R . Direct evidence of autosomal recessive inheritance of Arg24 to termination codon in purine nucleoside phosphorylase gene in a family with a severe combined immunodeficiency patient . Human Genetics . 103 . 1 . 81–5 . Jul 1998 . 9737781 . 10.1007/s004390050787 . 8373698 .
- Sheppard TL, Ordoukhanian P, Joyce GF . A DNA enzyme with N-glycosylase activity . Proceedings of the National Academy of Sciences of the United States of America . 97 . 14 . 7802–7 . Jul 2000 . 10884411 . 16625 . 10.1073/pnas.97.14.7802 . 2000PNAS...97.7802S . free .
- Dalal I, Grunebaum E, Cohen A, Roifman CM . Two novel mutations in a purine nucleoside phosphorylase (PNP)-deficient patient . Clinical Genetics . 59 . 6 . 430–7 . Jun 2001 . 11453975 . 10.1034/j.1399-0004.2001.590608.x . 24624559 .
- Ivings L, Pennington SR, Jenkins R, Weiss JL, Burgoyne RD . Identification of Ca2+-dependent binding partners for the neuronal calcium sensor protein neurocalcin delta: interaction with actin, clathrin and tubulin . The Biochemical Journal . 363 . Pt 3 . 599–608 . May 2002 . 11964161 . 1222513 . 10.1042/0264-6021:3630599 .
- Maria Falkenberg. Falkenberg M, Gaspari M, Rantanen A, Trifunovic A, Larsson NG, Gustafsson CM . Mitochondrial transcription factors B1 and B2 activate transcription of human mtDNA . Nature Genetics . 31 . 3 . 289–94 . Jul 2002 . 12068295 . 10.1038/ng909 . 11164308 .
- Stoychev G, Kierdaszuk B, Shugar D . Xanthosine and xanthine. Substrate properties with purine nucleoside phosphorylases, and relevance to other enzyme systems . European Journal of Biochemistry . 269 . 16 . 4048–57 . Aug 2002 . 12180982 . 10.1046/j.1432-1033.2002.03097.x . free .
- Agarwal RP, Parks RE . 1969 . Purine nucleoside phosphorylase from human erythrocytes. IV Crystallization and some properties . J. Biol. Chem. . 244 . 644 - 7 . 5768862 . 4 . 10.1016/S0021-9258(18)94403-0 . free .
- Boyer, P.D., Lardy, H. and Myrback, K. (Eds.), The Enzymes, 2nd ed., vol. 5, Academic Press, New York, 1961, p. 237-255.
- HEPPEL LA, HILMOE RJ . 1952 . [Phosphorolysis and hydrolysis of purine ribosides by enzymes from yeast.] . J. Biol. Chem. . 198 . 683 - 94 . 12999785 . 2 . 10.1016/S0021-9258(18)55525-3 . free .
- Kalckar HM . 1947 . The enzymatic synthesis of purine ribosides . J. Biol. Chem. . 167 . 2 . 477 - 486 . 10.1016/S0021-9258(17)31000-1 . 20285042. free .
- Saunders PP, Wilson BA, Saunders GF . 1969 . Purification and comparative properties of a pyrimidine nucleoside phosphorylase from Bacillus stearothermophilus . J. Biol. Chem. . 244 . 3691 - 7 . 4978445 . 13 . 10.1016/S0021-9258(18)83424-X . free .
- Tsuboi KK, Hudson PB. 1957 . Enzymes of the human erythrocyte. I. Purine nucleoside phosphorylase; isolation procedure . J. Biol. Chem. . 224 . 2 . 879 - 887 . 10.1016/S0021-9258(18)64980-4 . 13405917. free .
External links
Notes and References
- Web site: Entrez Gene: NP nucleoside phosphorylase.
- Kaplan USMLE Biochemistry Review
- Selwood T, Jaffe EK . Dynamic dissociating homo-oligomers and the control of protein function . Archives of Biochemistry and Biophysics . 519 . 2 . 131–43 . Mar 2012 . 22182754 . 3298769 . 10.1016/j.abb.2011.11.020 .