Purine nucleoside phosphorylase
Encyclopedia
Purine nucleoside phosphorylase also known as PNPase and inosine phosphorylase is an enzyme
that in humans is encoded by the NP gene
.
, inosine
into hypoxanthine
, and guanosine
into guanine
, in each case creating ribose phosphate.
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.
, 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.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that in humans is encoded by the NP gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Function
Purine nucleoside phosphorylase is an enzyme involved in purine metabolism. PNP metabolizes adenosine into adenineAdenine
Adenine is a nucleobase with a variety of roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate and the cofactors nicotinamide adenine dinucleotide and flavin adenine dinucleotide , and protein synthesis, as a chemical component of DNA...
, inosine
Inosine
Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring via a β-N9-glycosidic bond....
into hypoxanthine
Hypoxanthine
Hypoxanthine is a naturally occurring purine derivative. It is occasionally found as a constituent of nucleic acids where it is present in the anticodon of tRNA in the form of its nucleoside inosine. It has a tautomer known as 6-Hydroxypurine. Hypoxanthine is a necessary additive in certain cell,...
, and guanosine
Guanosine
Guanosine is a purine nucleoside comprising guanine attached to a ribose ring via a β-N9-glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate , cyclic guanosine monophosphate , guanosine diphosphate , and guanosine triphosphate...
into guanine
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
, in each case creating ribose phosphate.
Nucleoside phosphorylase is an enzyme which cleaves a nucleoside by phosphorylating
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
the ribose to produce a nucleobase
Nucleobase
Nucleobases are a group of nitrogen-based molecules that are required to form nucleotides, the basic building blocks of DNA and RNA. Nucleobases provide the molecular structure necessary for the hydrogen bonding of complementary DNA and RNA strands, and are key components in the formation of stable...
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
De novo synthesis
De novo synthesis refers to the synthesis of complex molecules from simple molecules such as sugars or amino acids, as opposed to their being recycled after partial degradation. For example, nucleotides are not needed in the diet as they can be constructed from small precursor molecules such as...
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
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
drugs such as methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
or aminopterin
Aminopterin
Aminopterin , a 4-amino analog of folic acid, is an antineoplastic drug with immunosuppressive properties used in chemotherapy. Aminopterin is a synthetic derivative of pterin. Aminopterin works as an enzyme inhibitor by competing for the folate binding site of the enzyme dihydrofolate reductase...
.
All salvage pathway enzymes require a high energy phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
donor such as ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
or PRPP.
- ThymidineThymidineThymidine is a chemical compound, more precisely a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine in double-stranded DNA...
can be phosphorylated by thymidine kinaseThymidine kinaseThymidine kinase is an enzyme, a phosphotransferase : 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, . It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2...
(TK). - UridineUridineUridine is a molecule that is formed when uracil is attached to a ribose ring via a β-N1-glycosidic bond.If uracil is attached to a deoxyribose ring, it is known as a deoxyuridine....
can be phosphorylated by uridine kinaseUridine kinaseIn enzymology, an uridine kinase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are ATP and uridine, whereas its two products are ADP and UMP....
(UK). - CytidineCytidineCytidine is a nucleoside molecule that is formed when cytosine is attached to a ribose ring via a β-N1-glycosidic bond...
can be phosphorylated by cytidine kinase (CK). - DeoxycytidineDeoxycytidineDeoxycytidine is a deoxyribonucleoside. It is like cytidine, but with one oxygen atom removed....
can be phosphorylated by deoxycytidine kinaseDeoxycytidine kinaseDeoxycytidine kinase, also known as DCK, is an enzyme which in humans is encoded by the DCK gene.DCK transfers phosphate to deoxycytidine.- Function :...
(DOK).
Adenosine uses the enzyme adenosine kinase
Adenosine kinase
In enzymology, an adenosine kinase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are ATP and adenosine, whereas its two products are ADP and AMP....
, which is a very important enzyme in the cell. Attempts are being made to develop an inhibitor for the enzyme for use in cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
chemotherapy.
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 reductaseRibonucleotide reductase
Ribonucleotide reductase is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides. Deoxyribonucleotides in turn are used in the synthesis of DNA. The reaction catalyzed by RNR is strictly conserved in all living organisms...
, leading to a deficiency in (d)CTPs and (d)TTPs, which, in turn, induces apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
in T-lymphocytes and B-lymphocytes, leading to severe combined immunodeficiency
Severe combined immunodeficiency
Severe combined immunodeficiency , is a genetic disorder in which both "arms" of the adaptive immune system are impaired due to a defect in one of several possible genes. SCID is a severe form of heritable immunodeficiency...
(SCID).
PNP-deficient patients will have an immunodeficiency problem. It affects only T-cells; B-cells are unaffected by the deficiency.
External links
- Human PNP at Cornell UniversityCornell UniversityCornell University is an Ivy League university located in Ithaca, New York, United States. It is a private land-grant university, receiving annual funding from the State of New York for certain educational missions...
- E. Coli PNP at Cornell UniversityCornell UniversityCornell University is an Ivy League university located in Ithaca, New York, United States. It is a private land-grant university, receiving annual funding from the State of New York for certain educational missions...