trans

264 INTRACELLULAR SIGNALING
ATPase domain
Cyclase domain
PfGCa
PfGCb
FIGURE 11.6 (See also Color Plate 8) Structural organization of the bifunctional genes encoding guanylyl cyclase
in P. falciparum. PfGCa is uninterrupted by introns, but there are 13 (shown in white) in PfGCb and all but one of
these are in the ATPase domain.
genes, one encoding a P-type ATPase and the
second encoding a cyclase. There are at least
two other examples in Plasmodium of bifunctional
proteins that occur as distinct molecules
in other organisms; dihydrofolate reductase–
thymidylate synthase and dihydropteroate
synthetase–pyrophosphokinase. The fusion
event that gave rise to the bifunctional proteins
with GC activity almost certainly occurred
in a common ancestor of Plasmodium, Paramecium
and Tetrahymena, in agreement with
the classification of the ciliates with the apicomplexans
and dinoflagellates in the Alveolata. In
Plasmodium, this initial fusion event appears
to have been followed by gene duplication to
create two copies that then diverged to become
PfGCa and PfGCb. Although it cannot be
excluded that the progenitor gene contained
introns, their absence from the Paramecium
and Tetrahymena genes suggests that the most
likely explanation for their presence in PfGCb
is that they have been added over time. Why
they are found in only one of the Plasmodium
genes, and why they are predominantly
restricted to the ATPase domain, is a puzzle.
Other enzymatic components of the cyclic
nucleotide signaling pathways in Plasmodium
have been less well characterized. Two putative
ACs have been identified in the genome
database and G-protein-independent AC
activity, distinct from that of red blood cells,
has been detected in P. falciparum asexual
blood stages. Putative homologs of both the
catalytic and regulatory subunits of PKA have
also been identified. Interestingly, the antimalarial
drug halofantrine is a potent and
specific inhibitor of the catalytic subunit of
mammalian PKA. The possibility that interaction
between halofantrine and the parasite
PKA contributes to anti-malarial activity should
be worth investigating. Sequences corresponding
to P. falciparum phosphodiesterases and
a cGMP-dependent protein kinase (PKG)
can also be found in the database. With the
completion of a fully annotated P. falciparum
genome sequence in the near future, it can
be confidently expected that the entire repertoire
of proteins involved in cyclic nucleotidemediated
signaling will be available. This
should provide a framework for the detailed
functional dissection of these signal transduction
pathways.
Cyclic nucleotide signaling and
differentiation of the malaria
parasite
Cyclic nucleotides have been implicated in the
triggering of differentiation in Plasmodium,
although limited progress has been made in
dissecting the precise mechanisms involved.
For example, addition of membrane-permeable
analogs of cAMP to cultures of P. falciparum
that contain a high proportion of asexual
BIOCHEMISTRY AND CELL BIOLOGY: PROTOZOA