trans

REVERSIBLE PROTEIN PHOSPHORYLATION 265
erythrocytic parasites induces the development
of male and female gametocytes (gametocytogenesis),
an obligate step in the life cycle. In
apparent contradiction of this observation,
however, gametocyte producer and nonproducer
clones both have the same basal levels
of cAMP, although PKA activity in the nonproducer
clone was significantly lower. cGMP
has been implicated in exflagellation, a process
that occurs in the mosquito midgut when
eight flagellated male gametes erupt from
a single gametocyte-infected red blood cell.
Exflagellation is enhanced when either cGMP
analogs or phosphodiesterase inhibitors are
added to cultures of mature gametocytes.
Exflagellation can be triggered in vitro by
a decrease in temperature and a bicarbonate
ion-mediated increase in pH. Exflagellation
can also be induced at a non-permissive pH in
the absence of bicarbonate ions by a gametocyte-activating
factor which has now been
identified as xanthurenic acid, a product of
tryptophan metabolism. Significantly, addition
of xanthurenic acid to mature P. falciparum
gametocyte membrane preparations enhances
GC activity. These observations provide a link
between an external stimulator of exflagellation
and activation of a signal transduction
pathway associated with this essential developmental
process. Addition of xathurenic acid
to the recombinant catalytic domains of
PfGC, either individually or in combination,
had no significant stimulatory effect on GC
activity, suggesting that the mode of action
probably does not involve direct interaction
with the catalytic domains.
REVERSIBLE PROTEIN
PHOSPHORYLATION
Reversible protein phosphorylation is widely
used by eukaryotic cells to transmit signals.
Phosphorylation–dephosphorylation of serine,
threonine and tyrosine residues can trigger
remarkable changes in protein conformation.
The conformational changes, in turn, alter a
variety of properties such as catalytic activity,
intracellular localization, interaction with other
proteins, and degradation. It is reasonable to
predict that a wide range of protein kinases
and phosphatases will function as molecular
switches regulating various cellular activities.
Recently, the complete sequencing of various
genomes has shown the veracity of this prediction
(Table 11.1). The yeast genome can be
used as a gauge to roughly estimate the number
of protein kinases and phosphatases that
parasites might employ to regulate intracellular
signaling.
TABLE 11.1
Number of protein kinases and phosphatases from different species
Type Yeast Fly Worm Human
(S. cerevisiae) (Drosophila) (C. elegans)
Serine/threonine or 114 198 315 395
dual-specificity kinase
Tyrosine kinase 5 47 100 106
Serine/threonine 13 19 51 15
protein phosphatase
Tyrosine phosphatase 5 22 95 56
Dual-specificity protein 4 8 10 29
phosphatase
Number of genes 6000 13 000 19 000 30 000
BIOCHEMISTRY AND CELL BIOLOGY: PROTOZOA