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TRENDS in Parasitology Vol.18 No.4 April 2002
http://parasites.trends.com 1471-4922/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
150 News&Comment
Ovalocytosis, the occurrence of red bloodcells with an oval biconcave shape andvarying degrees of elliptical aberration, isassociated with protection against malaria.It was often said that once a genotypicmarker for the occurrence of ovalocytosis in Papua New Guinea (PNG) was found, the whole story of protection providedagainst falciparum malaria would beunravelled. That seemed to be the casewhen a 27-bp deletion in Band 3 (the major red blood cell transmembrane anion transporter) was associated withovalocytosis in many coastal, malaria-endemic areas of PNG. However, in another area of PNG, the Wosera, whereovalocytosis is also common, Patel et al.,have found that only one out of 1019individuals had this 27-bp deletion [1].Instead, another deletion in exon 3 of the
glycophorin C gene, which is homologousto glycophorin A (a major receptor forPlasmodium falciparum) and encodes asialoglycoprotein found on the surface ofred blood cells, achieved a gene frequencyof 0.465. This deletion also leads to theovalocytosis phenotype.
The genotype frequencies of the normalglycophorin C heterozygote and homozygotewere in Hardy–Weinberg equilibrium, which argues against the selective advantageof this genotype in malaria. However, evenmore striking, was the identification ofindividuals who possessed ovalocytic redblood cells but did not have a mutation inBand 3 or the glycophorin C gene. This wouldindicate that there could be other geneticcauses for ovalocytic cells. Over a seven-month period, Patel et al., examined theblood films of between 325 and 696
individuals monthly, but were unable to show any difference in the prevalence ordensity of P. falciparum and Plasmodiumvivax infections in the different glycophorin Cgenotypes. However, examining individuals who either develop severedisease or die would reveal moreinformation. This fascinating story ofovalocytosis in PNG continues to unraveland, in doing so, has exposed more thanexpected. The story is far from complete – sowatch this space!
1 Patel, S.S. et al. (2001) The association of the glycophorin C exon 3 deletion withovalocytosis in malaria susceptibility in theWosera, Papua New Guinea. Blood 98,3489–3491
Geoffrey Pasvol
Ovalocytosis in Papua New Guinea
Four aspartic proteases occur in the Plasmodium falciparum foodvacuoleHemoglobin (Hb) is a major food source for the malaria parasite during theintraerythrocytic blood stage. Hb is ingested into a specialized acidiccompartment, the food vacuole (FV), where it is broken down into short peptidesand the released haem is incorporated into hemozoin. Amino acids are thenliberated from these peptides outside the FV and used by the parasite. This Hbproteolysis process is catalyzed by a series of enzymes, including plasmepsins.Plasmepsins are aspartic protease enzymes, two of which, plasmepsin (PM) I and PM II, have been wellcharacterized. These enzymes are capable of cleaving native Hb. A cysteineprotease enzyme, falcipain, and ametalloprotease, falcilysin, are involved infurther degrading the protein to shortpeptides. Given the central role of theseprocesses in the blood stage, theseenzymes represent an important potentialdrug target for novel antimalarials. Indeed, several protease inhibitors exhibitactivity both in vitro and in vivo. In thecurrent climate of resurgent malaria andserious problems of drug resistance, adeeper understanding of these processes is vital.
The sequence of the Plasmodiumfalciparum genome has revealed tenaspartic protease genes, including nineplasmepsins (I, II, IV–X) and histo-asparticprotease (HAP). Two key questions thenarise. Which of these genes are expressed inthe blood stage? Which play a role in the FVand what is their enzymatic activity? Thesequestions have been addressed by Banerjeeet al. [1]. They have shown that seven ofthese genes are expressed during the bloodstage (PM I, II, IV, V, IX, X and HAP), but onlyfour of these proteins are localized in the FV(PM I, II, IV and HAP). Interestingly, theseenzymes are closely related. Their genesoccur as a cluster on chromosome 14,exhibit 50–70% amino acid sequencehomology and are initially expressed as51-kDa proenzymes and are cleaved into37-kDa active enzymes. Two active-sitemotifs are conserved in these plasmepsins,but HAP exhibits two conservative aminoacid substitutions and one aspartate isreplaced by histidine. PM IV and HAP areexpressed somewhat later in the life cyclethan PM I and II.
PM IV, although similar to PM I and II in many respects, exhibits significantlyreduced activity against native Hb, althoughit shows a marked synergistic effect with
PM II. The authors also addressed whetherHAP is an active enzyme given that itlacks one active-site aspartate moiety.Although recombinant HAP is inactive, thenative protein is shown to have strongproteolytic activity against globin (althoughnot against native Hb). Similar to PM IV, HAP also exhibits a synergistic effect withPM II against native Hb.
The study has thus shown that fouraspartic proteases probably act in concert in breaking down Hb in the FV. Theemerging picture suggests that PM I and II probably initiate hemoglobinproteolysis, releasing globin that is then proteolyzed further by PM IV and HAP, and subsequently by falcipain andfalcilysin. What is also significant is theunique active site and unusual inhibitorprofile of HAP, which marks this enzyme as aparticularly interesting candidate for novelantimalarial drugs.
1 Banerjee, R. et al. (2002) Four plasmepsins areactive in the Plasmodium falciparum foodvacuole, including a protease with an active-sitehistidine. Proc. Natl. Acad. Sci. U. S. A. 99,990–995
Timothy J. Egan
