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

This skepticism was eventually overcome by the molecular
cloning, heterologous expression, analysis of membrane topology
and functional characterization of the molecular players involved.
The first ones were the nucleotide-hydrolyzing enzymes placental
alkaline phosphatase (30), ecto-nucleotide pyrophosphatase/
phosphodiesterase-1 (31) and ecto-5’-nucleotidase (32), followed by
the first adenosine (A2) receptor (33), the first P2Y receptors (34, 35)
and P2X receptors (36, 37) and finally the molecular identification
of the first mammalian member of the ecto-nucleoside triphosphate
diphosphohydrolase family NTPDase1 (CD39) (38, 39).

MULTIPLICITY OF ECTO-NUCLEOTIDASES

We now know that extracellular nucleoside triphosphates and -
diphosphates can be hydrolyzed by a variety of ecto-nucleotidases
belonging to three different enzyme families with several members
each (Figure 2, Table 1). These include the E-NTPDases (ecto-
nucleoside triphosphate diphosphohydrolases) (40, 41), the E-NPPs
(ecto-nucleotide pyrophosphatase/phosphodiesterases) (42-44)
and the alkaline phosphatases (45, 46). As for the adenosine and
nucleotide receptors (47), the identification and molecular cloning
of an increasing number of these enzymes required an adjustment
of nomenclature. Scientists at the Second International Workshop
on Ecto-ATPases proposed that all E-NTPDase family members
be termed as NTPDase proteins and all members of the E-NPP-
family as NPPs, classified in order of discovery and characterization
(40, 48). These enzymes vary considerably regarding substrate
preference and affinity, product formation, cation dependence
and pH optimum. Recently, an ecto-form of the mitochondrial
F1Fo ATP synthase/F1 ATPase has been implicated in extracellular
ATP synthesis or also hydrolysis. The subunit arrangement of
the ecto-form and its functional properties require further
characterization (49).

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