Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The malaria parasite Plasmodium falciparum faces drastic osmotic changes during kidney passages and is engaged in the massive biosynthesis of glycerolipids during its development in the blood-stage. We identified a single aquaglyceroporin (PfAQP) in the nearly finished genome of P. falciparum with highest similarity to the Escherichia coli glycerol facilitator (50.4%), but both canonical Asn-Pro-Ala (NPA) motifs in the pore region are changed to Asn-Leu-Ala (NLA) and Asn-Pro-Ser (NPS), respectively. Expression in Xenopus oocytes renders them highly permeable for both water and glycerol. Sugar alcohols up to five carbons and urea pass the pore. Mutation analyses of the NLA/NPS motifs showed their structural importance, but the symmetrical pore properties were maintained. PfAQP is expressed in blood-stage parasites throughout the development from rings via trophozoites to schizonts and is localized to the parasite but not to the erythrocyte cytoplasm or membrane. Its unique bi-functionality indicates functions in the protection from osmotic stress and efficiently provides access to the serum glycerol pool for the use in ATP generation and primarily in the phospholipid synthesis.
 ...
PMID:A single, bi-functional aquaglyceroporin in blood-stage Plasmodium falciparum malaria parasites. 1172 4

The malaria parasite can use host plasma glycerol for lipid biosynthesis and membrane biogenesis during the asexual intraerythrocytic development. The molecular basis for glycerol uptake into the parasite is undefined. We hypothesize that the Plasmodium aquaglyceroporin provides the pathway for glycerol uptake into the malaria parasite. To test this hypothesis, we identified the orthologue of Plasmodium falciparum aquaglyceroporin (PfAQP) in the rodent malaria parasite, Plasmodium berghei (PbAQP), and examined the biological role of PbAQP by performing a targeted deletion of the PbAQP gene. PbAQP and PfAQP are 62% identical in sequence. In contrast to the canonical NPA (Asn-Pro-Ala) motifs in most aquaporins, the PbAQP has NLA (Asn-Leu-Ala) and NPS (Asn-Leu-Ser) in those positions. PbAQP expressed in Xenopus oocytes was permeable to water and glycerol, suggesting that PbAQP is an aquaglyceroporin. In P. berghei, PbAQP was localized to the parasite plasma membrane. The PbAQP-null parasites were viable; however, they were highly deficient in glycerol transport. In addition, they proliferated more slowly compared with the WT parasites, and mice infected with PbAQP-null parasites survived longer. Taken together, these findings suggest that PbAQP provides the pathway for the entry of glycerol into P. berghei and contributes to the growth of the parasite during the asexual intraerythrocytic stages of infection. In conclusion, we demonstrate here that PbAQP plays an important role in the blood-stage development of the rodent malaria parasite during infection in mice and could be added to the list of targets for the design of antimalarial drugs.
 ...
PMID:Aquaglyceroporin PbAQP during intraerythrocytic development of the malaria parasite Plasmodium berghei. 1728 93

Aquaporins (AQPs) are widely distributed in all kingdoms of life and act as facilitators in the transport of water and other small solutes through cell membranes. Since the plasmodial and human AQPs are different in their primary and secondary structure, an intervention targeting plasmodial AQP without affecting human AQPs is discussed to identify an attractive novel target against malaria. Therefore, it is crucial to understand the action mechanisms of these plasmodial AQPs. To explore the progression of the plasmodial real AQPs in vivo at work, a molecular dynamic simulation system was successfully developed for a PfAQP tetramer in silico. The results showed that the transporting work was not synchronous in the four channels at the same time, and that it was different at different times in the same channel. The hole sizes varied in different channels with time. The structure analysis showed that both hydrophobic and hydrophilic residues composed the inner surface of the channels, and the asparagines Asn-193 and Asn-70 assembled into two motifs of NLA and NPS in the center of the channel in place of the signature motifs of NPA in other AQPs. In brief, we successfully developed an equilibrated PfAQP-lipid system by molecular dynamics simulations, and investigated the structure of the PfAQP channel, which should aid our understanding of the AQP structure and its functional implications.
 ...
PMID:Molecular dynamics simulations of PfAQP from the malarial parasite Plasmodium falciparum. 2239 37