Prostatic acid phosphatase, a neglected ectonucleotidase

Abstract

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...

Pain-relieving prospects for adenosine receptors and ectonucleotidases

“…Several of these ENTPDs are expressed in the spinal cord [57]. Under acidic pH conditions, PAP and tartrate-resistant acid phosphatase (ACP5) can also hydrolyze ATP and ADP [58, 59]. Also, alkaline phosphatases hydrolyze ATP, ADP and AMP under neutral pH and alkaline conditions [60].…”

High-Throughput Screen Identifies Cyclic Nucleotide Analogs That Inhibit Prostatic Acid Phosphatase

“…14 Alkaline phosphatases and PAP have ectonucleotidase activity and utilize AMP as a substrate. 15 Given that pCPT-cAMP inhibited PAP but not ALP, pCPT-cAMP may prove useful for selectively inhibiting PAP in future physiological studies.…”

Emerging Roles of Human Prostatic Acid Phosphatase

“…Hence, there has been an urgent need for novel biomarkers to supplement PSA for detection and management of prostate cancer. Under these circumstances, there is now a renewed interest in PAP again because it has significantly higher correlation with prostate cancer progression (Zimmermann, 2009). The cancer-specific survival (CSS) study, which tested 193 patients’ serum, showed that, when PAP concentration is <1.5 U/L, 1.5-2.4 U/L and >2.5 U/L, the progression of prostate cancer is 93%, 87% and 75% (p=0.013), respectively.…”