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Purine nucleoside phosphorylase , PNP , PNPase or inosine phosphorylase (EC 2.4.2.1 ) is an enzyme that in humans is encoded by the NP gene .[2] It catalyzes the chemical reaction
purine nucleoside + phosphate
⇌
{\displaystyle \rightleftharpoons }
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
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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:
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
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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.[3]
One of the reaction catalyzed by purine nucleoside phosphorylase in purine metabolism
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
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This protein may use the morpheein model of allosteric regulation .[4]
Clinical significance
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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).[citation needed ]
PNP-deficient patients will have an immunodeficiency problem. It affects only T-cells; B-cells are unaffected by the deficiency.
See also
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References
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^ Kaplan USMLE Biochemistry Review
^ Selwood T, Jaffe EK (Mar 2012). "Dynamic dissociating homo-oligomers and the control of protein function" . Archives of Biochemistry and Biophysics . 519 (2 ): 131–43. doi :10.1016/j.abb.2011.11.020 . PMC 3298769 . PMID 22182754 .
Further reading
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Markert ML (1991). "Purine nucleoside phosphorylase deficiency". Immunodeficiency Reviews . 3 (1 ): 45–81. PMID 1931007 .
Borgers M, Verhaegen H, De Brabander M, De Cree J, De Cock W, Thoné F, Geuens G (Nov 1978). "Purine nucleoside phosphorylase in chronic lymphocytic leukemia (CLL)" . Blood . 52 (5 ): 886–95. doi :10.1182/blood.V52.5.886.886 . PMID 100152 .
Aust MR, Andrews LG, Barrett MJ, Norby-Slycord CJ, Markert ML (Oct 1992). "Molecular analysis of mutations in a patient with purine nucleoside phosphorylase deficiency" . American Journal of Human Genetics . 51 (4 ): 763–72. PMC 1682776 . PMID 1384322 .
Andrews LG, Markert ML (Apr 1992). "Exon skipping in purine nucleoside phosphorylase mRNA processing leading to severe immunodeficiency" . The Journal of Biological Chemistry . 267 (11 ): 7834–8. doi :10.1016/S0021-9258(18 )42589-6 . PMID 1560016 .
Jonsson JJ, Williams SR, McIvor RS (Sep 1991). "Sequence and functional characterization of the human purine nucleoside phosphorylase promoter" . Nucleic Acids Research . 19 (18 ): 5015–20. doi :10.1093/nar/19.18.5015 . PMC 328804 . PMID 1923769 .
Ealick SE, Rule SA, Carter DC, Greenhough TJ, Babu YS, Cook WJ, Habash J, Helliwell JR , Stoeckler JD, Parks RE (Jan 1990). "Three-dimensional structure of human erythrocytic purine nucleoside phosphorylase at 3.2 A resolution". The Journal of Biological Chemistry . 265 (3 ): 1812–20. doi :10.2210/pdb2pnp/pdb . PMID 2104852 .
Williams SR, Gekeler V, McIvor RS, Martin DW (Feb 1987). "A human purine nucleoside phosphorylase deficiency caused by a single base change" . The Journal of Biological Chemistry . 262 (5 ): 2332–8. doi :10.1016/S0021-9258(18 )61658-8 . PMID 3029074 .
Williams SR, Goddard JM, Martin DW (Jul 1984). "Human purine nucleoside phosphorylase cDNA sequence and genomic clone characterization" . Nucleic Acids Research . 12 (14 ): 5779–87. doi :10.1093/nar/12.14.5779 . PMC 320030 . PMID 6087295 .
Pannicke U, Tuchschmid P, Friedrich W, Bartram CR, Schwarz K (Dec 1996). "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. doi :10.1007/s004390050290 . PMID 8931706 . S2CID 5657916 .
Markert ML, Finkel BD, McLaughlin TM, Watson TJ, Collard HR, McMahon CP, Andrews LG, Barrett MJ, Ward FE (1997). "Mutations in purine nucleoside phosphorylase deficiency" . Human Mutation . 9 (2 ): 118–21. doi :10.1002/(SICI)1098-1004(1997)9:2<118::AID-HUMU3>3.0.CO;2-5 . PMID 9067751 . S2CID 46243170 .
Erion MD, Takabayashi K, Smith HB, Kessi J, Wagner S, Hönger S, Shames SL, Ealick SE (Sep 1997). "Purine nucleoside phosphorylase. 1. Structure-function studies". Biochemistry . 36 (39 ): 11725–34. doi :10.1021/bi961969w . PMID 9305962 .
Erion MD, Stoeckler JD, Guida WC, Walter RL, Ealick SE (Sep 1997). "Purine nucleoside phosphorylase. 2. Catalytic mechanism". Biochemistry . 36 (39 ): 11735–48. doi :10.1021/bi961970v . PMID 9305963 .
Stoeckler JD, Poirot AF, Smith RM, Parks RE, Ealick SE, Takabayashi K, Erion MD (Sep 1997). "Purine nucleoside phosphorylase. 3. Reversal of purine base specificity by site-directed mutagenesis". Biochemistry . 36 (39 ): 11749–56. doi :10.1021/bi961971n . PMID 9305964 .
Sasaki Y, Iseki M, Yamaguchi S, Kurosawa Y, Yamamoto T, Moriwaki Y, Kenri T, Sasaki T, Yamashita R (Jul 1998). "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. doi :10.1007/s004390050787 . PMID 9737781 . S2CID 8373698 .
Sheppard TL, Ordoukhanian P, Joyce GF (Jul 2000). "A DNA enzyme with N-glycosylase activity" . Proceedings of the National Academy of Sciences of the United States of America . 97 (14 ): 7802–7. Bibcode :2000PNAS...97.7802S . doi :10.1073/pnas.97.14.7802 . PMC 16625 . PMID 10884411 .
Dalal I, Grunebaum E, Cohen A, Roifman CM (Jun 2001). "Two novel mutations in a purine nucleoside phosphorylase (PNP)-deficient patient". Clinical Genetics . 59 (6 ): 430–7. doi :10.1034/j.1399-0004.2001.590608.x . PMID 11453975 . S2CID 24624559 .
Ivings L, Pennington SR, Jenkins R, Weiss JL, Burgoyne RD (May 2002). "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. doi :10.1042/0264-6021:3630599 . PMC 1222513 . PMID 11964161 .
Falkenberg M , Gaspari M, Rantanen A, Trifunovic A, Larsson NG, Gustafsson CM (Jul 2002). "Mitochondrial transcription factors B1 and B2 activate transcription of human mtDNA". Nature Genetics . 31 (3 ): 289–94. doi :10.1038/ng909 . PMID 12068295 . S2CID 11164308 .
Stoychev G, Kierdaszuk B, Shugar D (Aug 2002). "Xanthosine and xanthine. Substrate properties with purine nucleoside phosphorylases, and relevance to other enzyme systems" . European Journal of Biochemistry . 269 (16 ): 4048–57. doi :10.1046/j.1432-1033.2002.03097.x . PMID 12180982 .
Agarwal RP, Parks RE (1969). "Purine nucleoside phosphorylase from human erythrocytes. IV Crystallization and some properties" . J. Biol. Chem . 244 (4 ): 644–7. doi :10.1016/S0021-9258(18 )94403-0 . PMID 5768862 .
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 (2 ): 683–94. doi :10.1016/S0021-9258(18 )55525-3 . PMID 12999785 .
Kalckar HM (1947). "The enzymatic synthesis of purine ribosides" . J. Biol. Chem . 167 (2 ): 477–486. doi :10.1016/S0021-9258(17 )31000-1 . PMID 20285042 .
Saunders PP, Wilson BA, Saunders GF (1969). "Purification and comparative properties of a pyrimidine nucleoside phosphorylase from Bacillus stearothermophilus" . J. Biol. Chem . 244 (13 ): 3691–7. doi :10.1016/S0021-9258(18 )83424-X . PMID 4978445 .
Tsuboi KK, Hudson PB (1957). "Enzymes of the human erythrocyte. I. Purine nucleoside phosphorylase; isolation procedure" . J. Biol. Chem . 224 (2 ): 879–887. doi :10.1016/S0021-9258(18 )64980-4 . PMID 13405917 .
External links
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PDB gallery
1m73 : Crystal structure of human PNP at 2.3A resolution
1pf7 : Crystal structure of human PNP complexed with Immucillin H
1pwy : Crystal structure of human PNP complexed with acyclovir
1rct : Crystal structure of human purine nucleoside phosphorylase complexed with inosine
1rfg : Crystal structure of human purine nucleoside phosphorylase complexed with guanosine
1rr6 : Structure of human purine nucleoside phosphorylase in complex with Immucillin-H and phosphate
1rsz : Structure of human purine nucleoside phosphorylase in complex with DADMe-Immucillin-H and sulfate
1rt9 : Structure of human purine nucleoside phosphorylase in complex with Immucillin-H and sulfate
1ula : Application of crystallographic and modeling methods in the design of purine nucleoside phosphorylase inhibitors
1ulb : Application of crystallographic and modeling methods in the design of purine nucleoside phosphorylase inhibitors
1v2h : Crystal structure of human PNP complexed with guanine
1v3q : Structure of human PNP complexed with DDI
1v41 : Crystal structure of human PNP complexed with 8-Azaguanine
1v45 : Crystal structure of human PNP complexed with 3-deoxyguanosine
1yry : Crystal structure of human PNP complexed with MESG
2a0w : Structure of human purine nucleoside phosphorylase H257G mutant
2a0x : Structure of human purine nucleoside phosphorylase H257F mutant
2a0y : Structure of human purine nucleoside phosphorylase H257D mutant
2oc4 : Crystal structure of human purine nucleoside phosphorylase mutant H257D with Imm-H
2oc9 : Crystal structure of human purine nucleoside phosphorylase mutant H257G with Imm-H
2on6 : Crystal structure of human purine nucleoside phosphorylase mutant H257F with Imm-H
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R e t r i e v e d f r o m " https://en.wikipedia.org/w/index.php?title=Purine_nucleoside_phosphorylase&oldid=1172359017 "
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