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HERBERT ZIMMERMANN Y COLS. AN. R. ACAD. NAC. FARM.

formation. These differences in catalytic properties differentially
affect the scavenging or the production of agonists for P2 receptors
by individual enzymes or combinations of these.

E-NPPs

The three nucleotide-hydrolyzing members of the E-NPP family,
NPP1 to NPP3, hydrolyze 5’-monodiester bonds in nucleotides
and their derivatives, resulting in the release of 5’-nucleoside
monophosphates. E-NPPs are members of the alkaline phosphatase
superfamily and their catalytic core structure reveals close similarity
to the superfamily of phospho-/sulfo-coordinating metalloenzymes
comprising alkaline phosphatases, phosphoglycerate mutases, and
arylsulfatases (69, 70). All three enzymes share a typical modular
structure. NPP1 and NPP3 are type II transmembrane glycoproteins
that also occur in soluble form whereas NPP2 is secreted. The
enzymes have a broad tissue distribution (42, 43). NPP1 was
originally discovered at the surface of lymphocytes as plasma cell
differentiation antigen (PC-1). Physiological substrates of these
enzymes include ATP, NAD+, nucleotide sugars and dinucleoside
polyphosphates (42, 43, 71). ATP is an inhibitor of diadenosine
polyphosphate hydrolysis (72). In several tissues investigated,
diadenosine polyphosphates are hydrolyzed considerably more slowly
than ATP, implicating a prolonged extracellular half-life of these
nucleotides (73). Nucleotide hydrolysis by NPPs has a very alkaline
pH optimum (8.5 - 9.0), comparable to that of alkaline phosphatases.
In addition to its nucleotidase activity, the splice variant of NPP2,
autotaxin, also exerts lysophospholipase D activity (74). The four
additional and non-nucleotide-hydrolyzing members of the E-NPP
family NPP4 to NPP7 are shortened at the N terminus, with
presumptive inverse membrane topography. Of these, NPP6 and
NPP7 exhibit lysophospholipase-C or choline glycerophosphodiester
phosphodiesterase activity (43).

NPP1 to NPP3 hydrolyze ligands of nucleotide receptors. In the
case of nucleoside triphosphates, hydrolysis typically proceeds
directly to the nucleoside monophosphate with the formation of PPi
(Table 1). This circumvents activation of receptors for nucleoside

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