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VOL. 72 (4), 629-642, 2006 PROTEIN PROCESSING IN PLASMODIUM FALCIPARUM?

genome sequences (2-4) has provided a vast amount of molecular
information. This, together with the transcriptome (5, 6) and
proteomic analysis along the parasitic developmental stages (7)
pursue a deep understanding of the peculiar parasite biology in the
context of exploring new therapeutic and immunization strategies.
Since 1993, different technologies of P. falciparum genetic
manipulation have been developed as gene disruption by homologous
recombination (8-13), antisense RNA (14, 15) and more recently,
RNA interference that has been successfully applied to understand
the in vivo functions of P. falciparum genes (16-18).

Genome comparison from lower eukaryotes have shown that
Plasmodium proteins are notably longer in size than their respective
orthologous genes. This is due to the extraordinary attribute of
Plasmodium proteins that are hugely enriched in stretches biased
toward 1-3 residues (mainly Asn, Lys, and Ile) due to the high A+T
content (about 80% average). Due to this particular composition
these stretches acquire low entropy or complexity (19). These regions
are embedded into highly conserved domains that form globular
structures with larger variety of residue composition with high
entropy and complexity (19). Although many eukaryotes have also
low complexity areas in nuclear proteins, transcription factors,
and some cytoskeletal proteins, Plasmodium species display low
complexity stretches in unique genes, not observed before in genomes
from other organisms. In addition, these unusual regions even
penetrate in independent functional domains with unpredictably
length between 10 and 100 residues (20).

P. falciparum G6PD-6PGL is a bifunctional enzyme exclusive
to Plasmodium species (21) that probably arose from the fusion
of two genes in a common ancestor (22). The deduced protein
has a subunit molecular mass of 107 kDa, in agreement with
the tetramer molecular weight calculated by size exclusion
chromatography (23). Its C-terminal half (residues 311-911) is clearly
homologous to other described G6PDs (with glucose 6-phosphate
dehydrogenase activity) though sequence similarity is interrupted
by a 62 amino-acid stretch with no similarity found to date. It has
been nevertheless experimentally shown that this 62 amino acid
insertion is essential for the activity of the bifunctional enzyme (24).
In contrast, the 310 amino-acid protein sequence of the amino

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