Nucleotide pyrophosphatase/phosphodiesterase

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Nucleotide pyrophosphatase/phosphodiesterase (NPP)
Nucleotide pyrophosphatase.png
The overall dimeric structure of NPP in Xanthomonas axonopodis pv. citri str. 306 (Xac). This enzyme relies on the catalytic ability of 2 Zn2+ atoms in the catalytic core, which are shown in white. [1]
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EC no. 3.6.1.9
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Nucleotide pyrophosphatase/phosphodiesterase (NPP) is a class of dimeric enzymes that catalyze the hydrolysis of phosphate diester bonds. NPP belongs to the alkaline phosphatase (AP) superfamily of enzymes. [2] Humans express seven known NPP isoforms, [3] some of which prefer nucleotide substrates, some of which prefer phospholipid substrates, and others of which prefer substrates that have not yet been determined. [4] In eukaryotes, most NPPs are located in the cell membrane and hydrolyze extracellular phosphate diesters to affect a wide variety of biological processes. [5] [6] Bacterial NPP is thought to localize to the periplasm. [1]

Contents

Net reaction scheme for Nucleotide Pyrophosphatase/Phosphodiesterase enzyme, showing a natural NTP substrate (ATP) and a chromophore-producing phosphodiester reagent used for activity assays (methyl para-nitrophenyl phosphate). NPPScheme.png
Net reaction scheme for Nucleotide Pyrophosphatase/Phosphodiesterase enzyme, showing a natural NTP substrate (ATP) and a chromophore-producing phosphodiester reagent used for activity assays (methyl para-nitrophenyl phosphate).

Structure

The catalytic site of NPP consists of a two-metal-ion (bimetallo) Zn2+ catalytic core. These Zn2+ catalytic components are thought to stabilize the transition state of the NPP phosphoryl transfer reaction. [7]

A closer view of the active site of Xac NPP, which is located on the surface of the subunit. The Zn atoms of the bimetallo catalytic site are shown by white spheres. Nucleotide pyrophosphatase close up.png
A closer view of the active site of Xac NPP, which is located on the surface of the subunit. The Zn atoms of the bimetallo catalytic site are shown by white spheres.
Schematic of Xac NPP active site in a transition state. Violet denotes the phosphodiester substrate. Red and blue curved arrows represent nucleophilic addition (AN) and elimination (DN) steps, respectively, of the phosphoryl transfer reaction. These two steps could occur in either order, and probably overlap. The active site's threonine nucleophile is regenerated via hydrolysis. Adapted from. NPPActiveSite.png
Schematic of Xac NPP active site in a transition state. Violet denotes the phosphodiester substrate. Red and blue curved arrows represent nucleophilic addition (AN) and elimination (DN) steps, respectively, of the phosphoryl transfer reaction. These two steps could occur in either order, and probably overlap. The active site's threonine nucleophile is regenerated via hydrolysis. Adapted from.

Mechanism

Overview

NPP catalyses the nucleophilic substitution of one ester bond on a phosphodiester substrate. It has a nucleoside binding pocket that excludes phospholipid substrates from the active site. [8] A threonine nucleophile has been identified through site-directed mutagenesis, [9] [10] [11] and the reaction inverts the stereochemistry of the phosphorus center. [12] The sequence of bond breakage and formation has yet to be resolved.

Ongoing Investigation

Three extreme possibilities have been proposed for the mechanism of NPP-catalyzed phosphoryl transfer. They are distinguished by the sequence in which bonds to phosphorus are made and broken. Though this phenomenon is subtle, it is important for understanding the physiological roles of AP superfamily enzymes, and also to molecular dynamic modeling.

Extreme mechanistic scenarios:

(a) A 2-dimensional reaction coordinate plot, also known as a More-O'Ferall-Jenck diagram, illustrating possible catalytic mechanisms for NPP. The x and y coordinates represent the reaction coordinates (i.e. progress) of the addition (AN) and elimination (DN) steps, respectively. To use the plot to visualize a potential energy surface, imagine energy of the system on an axis projecting out of the screen. The shape of the potential energy surface determines the actual mechanism of the enzyme, since the system will proceed from reactants to products along the lowest-energy path. (b) Schematics of the reaction intermediates and transition states produced by each hypothetical path plotted in (a). Note partial charges. NPP More-OFerall-Jenck.png
(a) A 2-dimensional reaction coordinate plot, also known as a More-O'Ferall-Jenck diagram, illustrating possible catalytic mechanisms for NPP. The x and y coordinates represent the reaction coordinates (i.e. progress) of the addition (AN) and elimination (DN) steps, respectively. To use the plot to visualize a potential energy surface, imagine energy of the system on an axis projecting out of the screen. The shape of the potential energy surface determines the actual mechanism of the enzyme, since the system will proceed from reactants to products along the lowest-energy path. (b) Schematics of the reaction intermediates and transition states produced by each hypothetical path plotted in (a). Note partial charges.

1) A two-step "dissociative" (elimination-addition or DN + AN) mechanism that proceeds via a trigonal metaphosphate intermediate. [13] This mechanism is represented by the red dashed lines in the figure at right.

2) A two-step "associative" (addition-elimination or AN + DN) mechanism that proceeds via a pentavalent phosphorane intermediate. [13] This is represented by the blue dashed lines in the figure at right.

3) A one-step fully synchronous mechanism analogous to SN2 substitution. Bond formation and breakage occur simultaneously and at the same rate. This is represented by the black dashed line in the figure at right.

The above three cases represent archetypes for the reaction mechanism, and the actual mechanism probably falls somewhere in between them. [13] [14] The red and blue dotted lines in Fig. 2a represent more realistic "concerted" mechanisms in which addition and elimination overlap, but are not fully synchronous. The difference in initial rates of the two steps implies different charge distribution in the transition state (TS).

When the addition step occurs more quickly than elimination (an ANDN mechanism), [13] more positive charge develops on the nucleophile, and the transition state is said to be "tight." [1] [14] Conversely, if elimination occurs more quickly than addition (DNAN), the transition state is considered "loose."

López-Canut et al. modeled substitution of a phosphodiester substrate using a hybrid quantum mechanics/molecular mechanics model. [14] Notably, the model predicted an ANDN concerted mechanism in aqueous solution, but a DNAN mechanism in the active site of Xac NPP.

Promiscuity

Although NPP primarily catalyzes phosphodiester hydrolysis, the enzyme will also catalyze the hydrolysis of phosphate monoesters, though to a much smaller extent. NPP preferentially hydrolyzes phosphate diesters over monoesters by factors of 102-106, depending on the identity of the diester substrate. This ability to catalyze a reaction with a secondary substrate is known as enzyme promiscuity, [1] and may have played a role in NPP's evolutionary history. [15]

NPP's promiscuity enables the enzyme to share substrates with alkaline phosphatase (AP), another member of the alkaline phosphate superfamily. Alkaline phosphatase primarily hydrolyzes phosphate monoester bonds, but it shows some promiscuity towards hydrolyzing phosphate diester bonds, making it a sort of opposite to NPP. The active sites of these two enzymes show marked similarities, namely in the presence of nearly superimposable Zn2+ bimetallo catalytic centers. In addition to the bimetallo core, AP also has an Mg2+ ion in its active site. [1]

Biological function

NPPs have been implicated in several biological processes, including bone mineralization, purine nucleotide and insulin signaling, and cell differentiation and motility. They are generally regulated at the transcriptional level. [12]

Mammalian Isoforms

Nucleotide pyrophosphatase/phosphodiesterase I

NPP1 helps scavenge extracellular nucleotides in order to meet the high purine and pyrimidine requirements of dividing cells. [12] In T-cells, it may scavenge NAD+ from nearby dead cells as a source of adenosine. [16]

The pyrophosphate produced by NPP1 in bone cells is thought to serve as both a phosphate source for calcium phosphate deposition and as an inhibitory modulator of calcification. [17] NPP1 appears to be important for maintaining pyrophosphate/phosphate balance. Overactivity of the enzyme is associated with chondrocalcinosis, while deficiency correlates to pathological calcification. [6]

NPP1 inhibits the insulin receptor in vitro. In 2005, overexpression of the isoform was implicated in insulin resistance in mice. [18] It has been linked to insulin resistance and Type 2 diabetes in humans. [12]

NPP2

NPP2, known in humans as autotaxin, acts primarily in cell motility pathways. With its active site functioning, NPP2 promotes cellular migration at picomolar concentrations. [12] Soluble splice variants of NPP2 are thought to be important to cancer metastasis, and also show angiogenic properties in tumors. [6]

NPP3

NPP3 is probably a major contributor to nucleotide metabolism in the intestine and liver. [12]

Intestinal NPP3 would be involved in hydrolyzing food-derived nucleotides. [19]

The liver releases ATP and ADP into the bile to regulate bile secretion. [20] It subsequently reclaims adenosine via a pathway that probably contains NPP3. [21]

Evolution

NPP belongs to the alkaline phosphatase superfamily, which is a group of evolutionarily related enzymes that catalyze phosphoryl and sulfuryl transfer reactions. This group includes phosphomonoesterases, phosphodiesterases, phosphoglycerate mutases, phosphophenomutases, and sulfatases. [22]

Related Research Articles

<span class="mw-page-title-main">Kinase</span> Enzyme catalyzing transfer of phosphate groups onto specific substrates

In biochemistry, a kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule. This transesterification produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group. These two processes, phosphorylation and dephosphorylation, occur four times during glycolysis.

<span class="mw-page-title-main">Cyclic nucleotide</span> Cyclic nucleic acid

A cyclic nucleotide (cNMP) is a single-phosphate nucleotide with a cyclic bond arrangement between the sugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a nitrogenous base, and a single phosphate group. As can be seen in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) images, the 'cyclic' portion consists of two bonds between the phosphate group and the 3' and 5' hydroxyl groups of the sugar, very often a ribose.

<span class="mw-page-title-main">Protein kinase A</span> Family of enzymes

In cell biology, protein kinase A (PKA) is a family of serine-threonine kinase whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase. PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. It should not be confused with 5'-AMP-activated protein kinase.

<span class="mw-page-title-main">Phosphodiester bond</span> –O– linkage between phosphoric acid and two other compounds

In chemistry, a phosphodiester bond occurs when exactly two of the hydroxyl groups in phosphoric acid react with hydroxyl groups on other molecules to form two ester bonds. The "bond" involves this linkage C−O−PO−2O−C. Discussion of phosphodiesters is dominated by their prevalence in DNA and RNA, but phosphodiesters occur in other biomolecules, e.g. acyl carrier proteins.

<span class="mw-page-title-main">Phosphoglucomutase</span>

Phosphoglucomutase is an enzyme that transfers a phosphate group on an α-D-glucose monomer from the 1 to the 6 position in the forward direction or the 6 to the 1 position in the reverse direction.

<span class="mw-page-title-main">Phosphatase</span> Enzyme which catalyzes the removal of a phosphate group from a molecule

In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid monoester into a phosphate ion and an alcohol. Because a phosphatase enzyme catalyzes the hydrolysis of its substrate, it is a subcategory of hydrolases. Phosphatase enzymes are essential to many biological functions, because phosphorylation and dephosphorylation serve diverse roles in cellular regulation and signaling. Whereas phosphatases remove phosphate groups from molecules, kinases catalyze the transfer of phosphate groups to molecules from ATP. Together, kinases and phosphatases direct a form of post-translational modification that is essential to the cell's regulatory network.

<span class="mw-page-title-main">Alkaline phosphatase</span> Homodimeric protein enzyme

The enzyme alkaline phosphatase has the physiological role of dephosphorylating compounds. The enzyme is found across a multitude of organisms, prokaryotes and eukaryotes alike, with the same general function but in different structural forms suitable to the environment they function in. Alkaline phosphatase is found in the periplasmic space of E. coli bacteria. This enzyme is heat stable and has its maximum activity at high pH. In humans, it is found in many forms depending on its origin within the body – it plays an integral role in metabolism within the liver and development within the skeleton. Due to its widespread prevalence in these areas, its concentration in the bloodstream is used by diagnosticians as a biomarker in helping determine diagnoses such as hepatitis or osteomalacia.

<span class="mw-page-title-main">Adenylate kinase</span> Class of enzymes

Adenylate kinase is a phosphotransferase enzyme that catalyzes the interconversion of the various adenosine phosphates. By constantly monitoring phosphate nucleotide levels inside the cell, ADK plays an important role in cellular energy homeostasis.

A regulatory enzyme is an enzyme in a biochemical pathway which, through its responses to the presence of certain other biomolecules, regulates the pathway activity. This is usually done for pathways whose products may be needed in different amounts at different times, such as hormone production. Regulatory enzymes exist at high concentrations so their activity can be increased or decreased with changes in substrate concentrations.

<span class="mw-page-title-main">AP endonuclease</span> Enzyme involved in DNA repair

Apurinic/apyrimidinic (AP) endonuclease is an enzyme that is involved in the DNA base excision repair pathway (BER). Its main role in the repair of damaged or mismatched nucleotides in DNA is to create a nick in the phosphodiester backbone of the AP site created when DNA glycosylase removes the damaged base.

<span class="mw-page-title-main">Cyclic nucleotide phosphodiesterase</span>

3′,5′-cyclic-nucleotide phosphodiesterases (EC 3.1.4.17) are a family of phosphodiesterases. Generally, these enzymes hydrolyze a nucleoside 3′,5′-cyclic phosphate to a nucleoside 5′-phosphate:

Transition state analogs, are chemical compounds with a chemical structure that resembles the transition state of a substrate molecule in an enzyme-catalyzed chemical reaction. Enzymes interact with a substrate by means of strain or distortions, moving the substrate towards the transition state. Transition state analogs can be used as inhibitors in enzyme-catalyzed reactions by blocking the active site of the enzyme. Theory suggests that enzyme inhibitors which resembled the transition state structure would bind more tightly to the enzyme than the actual substrate. Examples of drugs that are transition state analog inhibitors include flu medications such as the neuraminidase inhibitor oseltamivir and the HIV protease inhibitors saquinavir in the treatment of AIDS.

<i>para</i>-Nitrophenylphosphate Chemical compound

para-Nitrophenylphosphate (pNPP) is a non-proteinaceous chromogenic substrate for alkaline and acid phosphatases used in ELISA and conventional spectrophotometric assays. Phosphatases catalyze the hydrolysis of pNPP liberating inorganic phosphate and the conjugate base of para-nitrophenol (pNP). The resulting phenolate is yellow, with a maximal absorption at 405 nm. This property can be used to determine the activity of various phosphatases including alkaline phosphatase (AP) and protein tyrosine phosphatase (PTP).

<span class="mw-page-title-main">Autotaxin</span> Protein-coding gene in the species Homo sapiens

Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase family member 2, is an enzyme that in humans is encoded by the ENPP2 gene.

<span class="mw-page-title-main">Ectonucleotidase</span>

Ectonucleotidases consist of families of nucleotide metabolizing enzymes that are expressed on the plasma membrane and have externally oriented active sites. These enzymes metabolize nucleotides to nucleosides. The contribution of ectonucleotidases in the modulation of purinergic signaling depends on the availability and preference of substrates and on cell and tissue distribution.

<span class="mw-page-title-main">ADP-ribose diphosphatase</span>

ADP-ribose diphosphatase (EC 3.6.1.13) is an enzyme that catalyzes a hydrolysis reaction in which water nucleophilically attacks ADP-ribose to produce AMP and D-ribose 5-phosphate. Enzyme hydrolysis occurs by the breakage of a phosphoanhydride bond and is dependent on Mg2+ ions that are held in complex by the enzyme.

<span class="mw-page-title-main">Ectonucleotide pyrophosphatase/phosphodiesterase 1</span>

Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 is an enzyme that in humans is encoded by the ENPP1 gene.

<span class="mw-page-title-main">2',3'-Cyclic-nucleotide 3'-phosphodiesterase</span> Protein-coding gene in the species Homo sapiens

2′,3′-Cyclic-nucleotide 3'-phosphodiesterase is an enzyme that in humans is encoded by the CNP gene.

Somatomedin B is a serum factor of unknown function, is a small cysteine-rich peptide, derived proteolytically from the N-terminus of the cell-substrate adhesion protein vitronectin. Cys-rich somatomedin B-like domains are found in a number of proteins, including plasma-cell membrane glycoprotein and placental protein 11.

<span class="mw-page-title-main">RNA hydrolysis</span>

RNA hydrolysis is a reaction in which a phosphodiester bond in the sugar-phosphate backbone of RNA is broken, cleaving the RNA molecule. RNA is susceptible to this base-catalyzed hydrolysis because the ribose sugar in RNA has a hydroxyl group at the 2’ position. This feature makes RNA chemically unstable compared to DNA, which does not have this 2’ -OH group and thus is not susceptible to base-catalyzed hydrolysis.

References

  1. 1 2 3 4 5 6 7 Zalatan, JG; Fenn, TD; Brunger, AT; Herschlag, D (2006). "Structural and functional comparisons of nucleotide pyrophosphatase/phosphodiesterase and alkaline phosphatase: Implications for mechanism and evolution". Biochemistry. 45 (32): 9788–803. CiteSeerX   10.1.1.387.1378 . doi:10.1021/bi060847t. PMID   16893180.
  2. ↑ Enzyme Promiscuity, Evolution, and Phosphoryl Transfer. Herschlag Lab. Stanford University, Retrieved 1 March 2012.
  3. ↑ Terkeltaub, Robert (2006-06-01). "Physiologic and pathologic functions of the NPP nucleotide pyrophosphatase/phosphodiesterase family focusing on NPP1 in calcification". Purinergic Signalling. 2 (2): 371–377. doi:10.1007/s11302-005-5304-3. ISSN   1573-9538. PMC   2254483 . PMID   18404477.
  4. ↑ Pham, Truc Chi T.; Wanjala, Irene; Howard, Angela; Parrill, Abby L.; Baker, Daniel L. "Insights into the structure and function of lipid preferring Nucleotide PyrophosphotasePhosphodiesterase isoforms" 2011
  5. ↑ Stefan, Cristiana; Jansen, Silvia; Bollen, Mathieu (2005). "NPP-type ectophosphodiesterases: Unity in diversity". Trends in Biochemical Sciences. 30 (10): 542–50. doi:10.1016/j.tibs.2005.08.005. PMID   16125936.
  6. 1 2 3 Goding, James W.; Grobben, Bert; Slegers, Herman (2003). "Physiological and pathophysiological functions of the ecto-nucleotide pyrophosphatase/phosphodiesterase family" (PDF). Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1638 (1): 1–19. doi:10.1016/S0925-4439(03)00058-9. hdl: 10067/432350151162165141 . PMID   12757929.
  7. ↑ Bobyr, Elena; Lassila, Jonathan K.; Wiersma-Koch, Helen I.; Fenn, Timothy D.; Lee, Jason J.; Nikolic-Hughes, Ivana; Hodgson, Keith O.; Rees, Douglas C.; et al. (2012). "High-Resolution Analysis of Zn2+ Coordination in the alkaline phosphatase Superfamily by EXAFS and X-ray Crystallography". Journal of Molecular Biology. 415 (1): 102–17. doi:10.1016/j.jmb.2011.10.040. PMC   3249517 . PMID   22056344.
  8. ↑ Stefan, C.; Gijsbers, R.; Stalmans, W.; Bollen, M. (1999-05-06). "Differential regulation of the expression of nucleotide pyrophosphatases/phosphodiesterases in rat liver". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1450 (1): 45–52. doi: 10.1016/s0167-4889(99)00031-2 . ISSN   0006-3002. PMID   10231554.
  9. ↑ Belli, Sabina I.; Mercuri, Francesca A.; Sali, Adnan; Goding, James W. (1995-03-01). "Autophosphorylation of PC-1 (Alkaline Phosphodiesterase I/Nucleotide Pyrophosphatase) and Analysis of the Active Site". European Journal of Biochemistry. 228 (3): 669–676. doi:10.1111/j.1432-1033.1995.0669m.x. ISSN   1432-1033. PMID   7737162.
  10. ↑ Lee, Hoi Young; Clair, Timothy; Mulvaney, Peter T.; Woodhouse, Elisa C.; Aznavoorian, Sadie; Liotta, Lance A.; Stracke, Mary L. (1996-10-04). "Stimulation of Tumor Cell Motility Linked to Phosphodiesterase Catalytic Site of Autotaxin". Journal of Biological Chemistry. 271 (40): 24408–24412. doi: 10.1074/jbc.271.40.24408 . ISSN   0021-9258. PMID   8798697.
  11. ↑ Gijsbers, R.; Ceulemans, H.; Stalmans, W.; Bollen, M. (2001-01-12). "Structural and catalytic similarities between nucleotide pyrophosphatases/phosphodiesterases and alkaline phosphatases". The Journal of Biological Chemistry. 276 (2): 1361–1368. doi: 10.1074/jbc.M007552200 . ISSN   0021-9258. PMID   11027689.
  12. 1 2 3 4 5 6 Bollen, M.; Gijsbers, R.; Ceulemans, H.; Stalmans, W.; Stefan, C. (2000-01-01). "Nucleotide pyrophosphatases/phosphodiesterases on the move". Critical Reviews in Biochemistry and Molecular Biology. 35 (6): 393–432. doi:10.1080/10409230091169249. ISSN   1040-9238. PMID   11202013. S2CID   6461333.
  13. 1 2 3 4 Lassila, JK; Zalatan, JG; Herschlag, D (2011). "Biological phosphoryl-transfer reactions: Understanding mechanism and catalysis". Annual Review of Biochemistry. 80: 669–702. doi:10.1146/annurev-biochem-060409-092741. PMC   3418923 . PMID   21513457.
  14. 1 2 3 López-Canut, Violeta; Roca, Maite; Bertrán, Juan; Moliner, Vicent; Tuñón, Iñaki (2010-05-26). "Theoretical study of phosphodiester hydrolysis in nucleotide pyrophosphatase/phosphodiesterase. Environmental effects on the reaction mechanism". Journal of the American Chemical Society. 132 (20): 6955–6963. doi:10.1021/ja908391v. ISSN   1520-5126. PMID   20429564.
  15. ↑ O'Brien, Patrick J.; Herschlag, Daniel (1999-04-01). "Catalytic promiscuity and the evolution of new enzymatic activities". Chemistry & Biology. 6 (4): R91–R105. doi: 10.1016/S1074-5521(99)80033-7 . ISSN   1074-5521. PMID   10099128.
  16. ↑ Deterre, P.; Gelman, L.; Gary-Gouy, H.; Arrieumerlou, C.; Berthelier, V.; Tixier, J.-M.; Ktorza, S.; Goding, J.; Schmitt, C.; Bismuth, G. (1996). "Coordinated regulation in human T cells of nucleotide-hydrolyzing ecto-enzymatic activities, including CD38 and PC-1. Possible role in the recycling of nicotinamide adenine dinucleotide metabolites". The Journal of Immunology. 157 (4): 1381–8. doi: 10.4049/jimmunol.157.4.1381 . PMID   8759717. S2CID   20255979.
  17. ↑ Meyer, John L. (1984-05-15). "Can biological calcification occur in the presence of pyrophosphate?". Archives of Biochemistry and Biophysics. 231 (1): 1–8. doi:10.1016/0003-9861(84)90356-4. PMID   6326671.
  18. ↑ Dong, Hengjiang; Maddux, Betty A.; Altomonte, Jennifer; Meseck, Marcia; Accili, Domenico; Terkeltaub, Robert; Johnson, Kristen; Youngren, Jack F.; Goldfine, Ira D. (2005-02-01). "Increased Hepatic Levels of the Insulin Receptor Inhibitor, PC-1/NPP1, Induce Insulin Resistance and Glucose Intolerance". Diabetes. 54 (2): 367–372. doi: 10.2337/diabetes.54.2.367 . ISSN   0012-1797. PMID   15677494.
  19. ↑ Byrd, J. C.; Fearney, F. J.; Kim, Y. S. (1985). "Rat Intestinal Nucleotide-Sugar Pyrophosphatase". Journal of Biological Chemistry. doi: 10.1016/S0021-9258(17)39631-X .
  20. ↑ Schlenker T, Romac JM, Sharara AI, Roman RM, Kim SJ, LaRusso N, Liddle RA, Fitz JG (1997). "Regulation of biliary secretion through apical purinergic receptors in cultured rat cholangiocytes". American Journal of Physiology. Gastrointestinal and Liver Physiology. 273 (5): G1108-17. doi:10.1152/ajpgi.1997.273.5.G1108. PMID   9374709.
  21. ↑ Scott, L J; Delautier, D; Meerson, N R; Trugnan, G; Goding, J W; Maurice, M (1997-04-01). "Biochemical and molecular identification of distinct forms of alkaline phosphodiesterase I expressed on the apical and basolateral plasma membrane surfaces of rat hepatocytes". Hepatology. 25 (4): 995–1002. doi:10.1002/hep.510250434. ISSN   1527-3350. PMID   9096610. S2CID   40400771.
  22. ↑ LóPez-Canut, Violeta; Roca, Maite; Bertrán, Juan; Moliner, Vicent; Tuñón, Iñaki (2010). "Theoretical Study of Phosphodiester Hydrolysis in Nucleotide Pyrophosphatase/Phosphodiesterase. Environmental Effects on the Reaction Mechanism". Journal of the American Chemical Society. 132 (20): 6955–63. doi:10.1021/ja908391v. PMID   20429564.
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