Prostatic Acid Phosphatase Is an Ectonucleotidase and Suppresses Pain by Generating Adenosine

Zylka, Mark J.; Sowa, Nathaniel A.; Taylor-Blake, Bonnie; A., Twomey, Margaret; Herrala, Annakaisa; Võikar, Vootele; Vihko, Pirkko

doi:10.1016/j.neuron.2008.08.024

Cited by 156 publications

(330 citation statements)

References 74 publications

Supporting

Mentioning

306

Contrasting

Unclassified

Order By: Relevance

“…This may have implications in inflammatory conditions where extracellular pH is reduced. By dephosphorylating extracellular AMP to adenosine and activating A1-adenosine receptors, the membranebound form of PAP (TM-PAP) is thought to exert antinociceptive effects in the dorsal spinal cord [19][20][21]. Similarly, mammalian tartrate-resistant acid phosphatase (TRAP) hydrolyzes a wide range of phosphate monoesters and anhydrides including nucleotides such as ATP, ADP, and (to a minor extent) AMP [22].…”

Section: Additional Nucleotide-metabolizing Enzymesmentioning

confidence: 99%

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

872

922

View full text Add to dashboard Cite

Ecto-nucleotidases play a pivotal role in purinergic signal transmission. They hydrolyze extracellular nucleotides and thus can control their availability at purinergic P2 receptors. They generate extracellular nucleosides for cellular reuptake and salvage via nucleoside transporters of the plasma membrane. The extracellular adenosine formed acts as an agonist of purinergic P1 receptors. They also can produce and hydrolyze extracellular inorganic pyrophosphate that is of major relevance in the control of bone mineralization. This review discusses and compares four major groups of ectonucleotidases: the ecto-nucleoside triphosphate diphosphohydrolases, ecto-5′-nucleotidase, ecto-nucleotide pyrophosphatase/phosphodiesterases, and alkaline phosphatases. Only recently and based on crystal structures, detailed information regarding the spatial structures and catalytic mechanisms has become available for members of these four ecto-nucleotidase families. This permits detailed predictions of their catalytic mechanisms and a comparison between the individual enzyme groups. The review focuses on the principal biochemical, cell biological, catalytic, and structural properties of the enzymes and provides brief reference to tissue distribution, and physiological and pathophysiological functions.

show abstract

Section: Additional Nucleotide-metabolizing Enzymesmentioning

confidence: 99%

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

872

922

View full text Add to dashboard Cite

show abstract

“…In PAP knockout mice (PAP −/− ), the enzyme histochemical staining in the nociceptice circuit had entirely disappeared. The heterologously expressed TM-PAP hydrolyzed AMP (to adenosine) and to a minor extent ADP but not ATP [6]. In the soma of small-diameter neurons of dorsal root ganglia TM-PAP is the predominant ecto-5′-nucleotidase and the secretory form is hardly detectable.…”

mentioning

confidence: 99%

“…Moreover, enzyme histochemistry at the ultrastructural level had demonstrated an association of FRAP specifically with the plasma membranes of synaptic glomeruli of the rat dorsal horn substantia gelatinosa [9]. Whilst previous studies had already recognized considerable overlap in the properties of PAP and FRAP/TMPase [8], Zylka et al [6] demonstrate identity of TM-PAP and FRAP/TMPase. In PAP knockout mice (PAP −/− ), the enzyme histochemical staining in the nociceptice circuit had entirely disappeared.…”

mentioning

confidence: 99%

“…Thus, the only two ectonucleotidases considered to form extracellular adenosine from AMP were ecto-5′-nucleotidase and the ALPs (Fig. 1).In a recent study, Zylka et al demonstrate that prostatic acid phosphatase (PAP, EC 3.1.3.2) functions as an additional ectonucleotidase capable of producing adenosine from extracellular AMP [6]. This followed the demonstration of a membrane-bound splice variant (Trans Membrane-PAP, TM-PAP) of the soluble and secreted prostate-specific enzyme PAP by Quintero et al [7].…”

mentioning

confidence: 99%

“…Zylka et al [6] add a surprising new twist to the story. It had been known for 50 years that many small-diameter neurons of the dorsal root ganglia express a histochemically identifiable acid phosphatase (AP).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Prostatic acid phosphatase, a neglected ectonucleotidase

Zimmermann

2009

Purinergic Signalling

View full text Add to dashboard Cite

Two recent papers reveal that the soluble and secreted prostatic acid phosphatase, an enzyme that has long served as a diagnostic marker for prostate cancer, has a membrane-bound splice variant. This enzyme exhibits ecto-5′-nucleotidase activity, is widely distributed, and implicated in the formation of chronic pain. While prostatic acid phosphatase hydrolyzes phosphomonoesters other than 5′-nucleoside monophosphates these novel data suggest that, in addition to ecto-5′-nucleotidase and the alkaline phosphatases, prostatic acid phosphatase must be taken into account in future studies on extracellular adenosine production.Keywords Ecto-5′-nucleotidase . Prostatic acid phosphatase . Alkaline phosphatase . Pain Controlling the availability of extracellular nucleotides or of adenosine is a major means of modulating the activity of purinergic receptors (P2 nucleotide receptors and P1 adenosine receptors [1]). Work of the past two decades resulted in the molecular and functional characterization of apparently all types of ectonucleotidases, including the ectonucleoside triphosphate diphosphohydrolase (E-NTPDase), ectonucleotide pyrophosphatase/ phosphodiesterase (E-NPP), and alkaline phosphatase (ALP) protein families, the soluble calcium-activated nucleotidase (SCAN) [2] and ecto-5′-nucleotidase. In addition evidence has been provided for cell-surfacelocated mitochondrial F 1 F o ATP synthase/F 1 ATPase and for ATPase activity associated with the neural cell adhesion molecule (NCAM) and the sarcolemmal α-sarcoglycan. Additional enzymes such as ectonucleoside diphosphate kinase and ectoadenylate kinase are capable of interconverting extracellular nucleotides [3][4][5].The cell-surface-located members of the E-NTPDase family NTPDase1-3 and NTPDase8 hydrolyze extracellular nucleoside triphosphates and to varying extent nucleoside diphosphates. In contrast, NTPDase5 and NTPDase6, two largely intracellularly located nucleotidases that can be shed and released into the extracellular medium, hydrolyze only select nucleoside diphosphates. Similarly, the nucleoside diphosphate-hydrolyzing human ectonucleotiase SCAN is cleaved and released from cells. Physiological substrates of the three nucleotide-hydrolyzing members of the E-NPP family (NPP1-3) include ATP, NAD + , nucleotide sugars and dinucleoside polyphosphates. None of these enzymes can hydrolyze nucleoside monophosphates. In contrast, alkaline phosphatases degrade nucleoside 5′-tri-, -di-, and -monophosphates and thus produce the nucleoside as final hydrolysis product. Ecto-5′-nucleotidase is peculiar as its substrate specificity (at least in mammals) is restricted to nucleoside monophosphates. Thus, the only two ectonucleotidases considered to form extracellular adenosine from AMP were ecto-5′-nucleotidase and the ALPs (Fig. 1).In a recent study, Zylka et al. demonstrate that prostatic acid phosphatase (PAP, EC 3.1.3.2) functions as an additional ectonucleotidase capable of producing adenosine from extracellular AMP [6]. This followed the demonstration of a m...

show abstract

Ectonucleotidase activity driven by acid ectophosphatase in luminal A MCF‐7 breast cancer cells

Lacerda‐Abreu,

Mendonça,

Nestal de Moraes

et al. 2024

Cell Biology International

View full text Add to dashboard Cite

Ectophosphatases catalyse the hydrolysis of phosphorylated molecules, such as phospho‐amino acids, in the extracellular environment. Nevertheless, the hydrolysis of nucleotides in the extracellular environment is typically catalysed by ectonucleotidases. Studies have shown that acid ectophosphatase, or transmembrane‐prostatic acid phosphatase (TM‐PAP), a membrane‐bound splice variant of prostatic acid phosphatase, has ecto‐5′‐nucleotidase activity. Furthermore, it was demonstrated that ectophosphatase cannot hydrolyse ATP, ADP, or AMP in triple‐negative breast cancer cells. In contrast to previous findings in MDA‐MB‐231 cells, the ectophosphatase studied in the present work displayed a remarkable capacity to hydrolyse AMP in luminal A breast cancer cells (MCF‐7). We showed that AMP dose‐dependently inhibited p‐nitrophenylphosphate (p‐NPP) hydrolysis. The p‐NPP and AMP hydrolysis showed similar biochemical behaviours, such as increased hydrolysis under acidic conditions and comparable inhibition by NiCl2, ammonium molybdate, and sodium orthovanadate. In addition, this ectophosphatase with ectonucleotidase activity was essential for the release of adenosine and inorganic phosphate from phosphorylated molecules available in the extracellular microenvironment. This is the first study to show that prostatic acid phosphatase on the membrane surface of breast cancer cells (MCF‐7) is correlated with cell adhesion and migration.

show abstract

Prostatic Acid Phosphatase Is an Ectonucleotidase and Suppresses Pain by Generating Adenosine

Cited by 156 publications

References 74 publications

Cellular function and molecular structure of ecto-nucleotidases

Cellular function and molecular structure of ecto-nucleotidases

Prostatic acid phosphatase, a neglected ectonucleotidase

Ectonucleotidase activity driven by acid ectophosphatase in luminal A MCF‐7 breast cancer cells

Contact Info

Product

Resources

About