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

Chloroquine inhibits the growth of susceptible malaria parasites at low (nanomolar) concentrations because of an energy-requiring drug-concentrating mechanism in the parasite secondary lysosome (food vacuole) which is dependent on the acidification of that vesicle. Chloroquine resistance results from another energy-requiring process: efflux of chloroquine from the resistant parasite with a half-time of 2 min. Chloroquine efflux is inhibited reversibly by the removal of metabolizable substrate (glucose); it is also reduced by the ATPase inhibitor vanadate. These results suggest that chloroquine efflux is an energy-requiring process dependent on the generation and hydrolysis of ATP. Chloroquine efflux cannot be explained by differences in drug accumulation between chloroquine-susceptible and -resistant parasites because the 40-50-fold difference in initial efflux rates between -susceptible and -resistant parasites is unchanged when both parasites contain the same amount of chloroquine. Although chloroquine efflux is phenotypically similar to the efflux of anticancer drugs from multidrug-resistant (mdr) mammalian cells, it is not linked to either of the mdr-like genes of the parasite.
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PMID:Energy dependence of chloroquine accumulation and chloroquine efflux in Plasmodium falciparum. 153 Nov 76

Malaria parasites of the genus Plasmodium spend much of their asexual life cycle inside the erythrocytes of their vertebrate hosts. Parasites presumably have to exploit metabolic and transport mechanisms to adapt themselves to the host erythrocyte's physicochemical environment. This review surveys the metabolism and transport of Ca2+, alkali cations, and H+ in malaria-infected erythrocytes. The Ca2+ content of Plasmodium-infected erythrocytes increases as the parasite matures. An increase in the influx of extracellular Ca2+ into infected erythrocytes is evident at later stages of parasite development. In infected erythrocytes, Ca2+ is almost exclusively localized in the parasite compartment and changes but little in the cytosol of the host cell. The importance of Ca2+ in supporting the growth of intraerythrocytic parasites and the invasion of erythrocytes by the merozoite has been assessed by depletion of extracellular Ca2+ with chelators, or by disturbance of the metabolism and transport of Ca2+ with a variety of Ca2+ modulators. Membranes of malaria-infected erythrocytes change their permeability to alkali cations. Hence, levels of K+ decrease and levels of Na+ increase in the cytosol of infected erythrocytes. Intraerythrocytic parasites maintain a high K+, low Na+ state, suggesting a mechanism for transporting K+ inward and Na+ outward against concentration gradients of the alkali cations across the parasite plasma membrane and/or the parasitophorous vacuole membrane (PVM). Concomitantly, P. falciparum can grow in Na(+)-enriched human erythrocytes. Experimental evidence suggests that Plasmodium possesses in its plasma membrane a proton pump which is very sensitive to orthovanadate, carbonylcyanide m-chlorophenylhydrazone, a protonophore, and dicyclohexylcarbodiimide, an inhibitor of H(+)-ATPase, but is only slightly sensitive to inhibitors of bacterial and mitochondrial respiration, such as antimycin A, CN-, or N3-, and ouabain, a Na+, K(+)-ATPase inhibitor. By operating this proton pump, parasites extrude H+ and thus generate an electrochemical gradient of protons (an internal negative membrane potential and a concentration gradient of protons) across the parasite plasma membrane. The electrochemical gradient apparently drives inward movement of Ca2+ and, possibly, glucose from the cytosol of infected erythrocytes. Little is known about the transport properties of the PVM. Recent sequence studies suggest that Plasmodium contains a cation-transporting ATPase which exhibits a high homology to the Ca2(+)-ATPase of rabbit skeletal muscle sarcoplasmic reticulum.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ion metabolism in malaria-infected erythrocytes. 209 86

Progressively expanding area of multiresistant falciparum malaria and the profile of its resistance to drugs successively implemented into practice necessitate the elaboration of approaches to the "revival" of the drugs used. As with neoplastic cells, a correlation between plasmodium multiresistance with increased "outflow" of specific drugs from the cell is suggested, which is blocked by inhibition of Ca2+ transport. Reversion of resistance to chloroquine by a combination with Ca2+ channel blockers verapamil, tricyclic antidepressants (desipramine, protritreline, etc.), tricyclic antihistamine drugs (cyproheptadine), and reversion of resistance to sulfadoxine in combination with the antihistamine drug ketodiphene have been shown in vivo and in vitro. The function of Ca2+ channels is directly related to Ca2(+)-, Mg2(+)-dependent ATPase. Ph-metric techniques elaborated in the USSR make it possible to evaluate its activity, determine the inhibitors, differentiate them according to the effect. The authors have established reversion of P. berghei resistance to chloroquine, with the tricyclic antidepressants azaphen, aminazin, triftazin correlating with the degree of Ca2+, Mg2(+)-ATPase inhibition and to praziquantel, whose effect might be associated with the increased permeability of the cellular membrane to Ca2+. The inhibitors of Ca2+ transport have various parasitocidal activities which might be accounted for by the deficiency of this cation necessary for plasmodium development. The task is to elaborate safe optimum antimalarial drug/modulator of Ca2+ transport combinations. Multiresistance (genetically predetermined multifactorial cellular changes) may be associated with enhanced synthesis of transmembrane glycoprotein with varying molecular mass depending on the direction of resistance.
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PMID:[A new approach to overcoming the drug resistance of the causative agents of malaria]. 226 96

Transport of nutrients into animal cells is driven by transmembrane gradient of Na+ across the plasma membrane. The protozoan malaria parasite, Plasmodium falciparum, however, grows within the host human erythrocytes, in which the cytoplasmic concentration of Na+ is maintained low by the membrane Na+, K+-ATPase. Our experiments show that human erythrocytes enriched with Na+ by treatment with ouabain (an inhibitor of the ATPase) will support the growth of P. falciparum in culture.
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PMID:Growth of Plasmodium falciparum in sodium-enriched human erythrocytes. 351 4

Free parasites were isolated from Plasmodium chabaudi-infected rat erythrocytes by N2-cavitation and purified on Percoll gradients. The membrane potential of the free parasites determined from the transmembrane distribution of the lipophilic cation, tetraphenylphosphonium, was -93 +/- 10 mV for late stage parasites and -90 +/- 3 mV for ring forms. Studies with intact infected erythrocytes demonstrated that the membrane potential of ring forms was much smaller compared to late trophozoites and schizonts and thus the present findings with free parasites suggest that host cell cytoplasmic factors may determine the magnitude of the parasite membrane potential. Both extracellular pH and [Na+] were found to modify the membrane potential of free parasites. Electrogenic protonophores, the H+-ATPase inhibitor dicyclohexylcarbodiimide and orthovanadate collapsed the potential of free parasites. Ouabain (or its membrane permeant derivative, strophanthidin), and oligomycin were without effect. These inhibitor studies suggest that an electrogenic H+-ATPase similar to that found in yeast generates in part the membrane potential of malaria parasites. Using weak acid distribution or a pH sensitive fluorescent dye, it was demonstrated that free parasites maintain an alkaline intracellular pH at extracellular pH greater than 6.5. The pH gradient was partially collapsed by orthovanadate or dicyclohexylcarbodiimide and by substitution of Na+ for K+ in the suspending buffer. The H+-ATPase and K+:H+ exchange may therefore both contribute to regulation of intracellular pH in Plasmodium.
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PMID:Membrane potential of erythrocytic stages of Plasmodium chabaudi free of the host cell membrane. 377 36

A Ca(2+)-ATPase gene was cloned from the genomic libraries of Plasmodium falciparum. From the deduced amino acid sequence of the gene, a 139 kDa protein with a total of 1228 amino acids was predicted. Sequence of a partial cDNA clone of the gene identified two introns near the 3'-end at the regions identical to the regions assumed for the Ca(2+)-ATPase gene of P. yoelii, a rodent malaria species. As compared with a variety of Ca(2+)-ATPases, the P. falciparum Ca(2+)-ATPase had the highest amino acid sequence homology (78%) to the P. yoelii Ca(2+)-ATPase, moderate homology (45-50%) to vertebrate sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPases (SERCAs), and lowest homology (20%) to a plasma membrane Ca(2+)-ATPase. The P. falciparum protein conserved sequences and residues that are important for the function and/or structure of the organellar type Ca(2+)-ATPase, such as high affinity Ca(2+)-binding sites, fluorescein isothiocyanate (FITC)-binding regions, and the phosphorylation site, but the protein did not contain calmodulin-binding regions that occur in the plasma membrane type Ca(2+)-ATPase. Thus we concluded the cloned gene was the organellar type Ca(2+)-ATPase of P. falciparum. In a region between the phosphorylation site and FITC-binding region, the P. falciparum protein was about 200 residues longer than the rabbit SERCA and lacked a sequence that binds to phospholamban, a protein that regulates the activity of the rabbit SERCA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cloning of a Ca(2+)-ATPase gene of Plasmodium falciparum and comparison with vertebrate Ca(2+)-ATPases. 831 97

Growth of the human malaria parasite, Plasmodium falciparum, within the red blood cell (RBC) requires external Ca++ and is associated with a markedly elevated intracellular Ca++ concentration, [Ca++]i. We used 45Ca++ flux studies and patch clamp recordings to examine the mechanisms responsible for this increased [Ca++]i. The 45Ca++ flux studies indicated that net Ca++ entry into parasitized RBCs (PRBCs) is 18 times faster than into unparasitized ATPase that keeps the [Ca++]i of unparasitized RBCs exceedingly low. Acceleration of the preexisting Ca++ entry, ATPase that keeps the [Ca++] of unparasitized RBCs exceedingly low. Acceleration of the preexisting Ca++ entry, mediated by a divalent cation carrier, also cannot explain Ca++ accumulation in PRBCs: there are fundamental differences in substrate preference and in the effects of external Ca++ on 45Ca++ efflux between unparasitized RBCs and PRBCs. Patch clamp of intact PRBC surface membranes revealed rare unitary channel openings not observed on unparasitized RBCs. With 80 mM of CaCl2 in the patch pipette, this channel carried inward current, suggesting Ca++ entry at a rate comparable with the observed 45Ca++ flux. These data indicate that the malaria parasite induces a novel pathway in the host RBC membrane for Ca++ entry and suggest that this pathway is a Ca++-permeable channel.
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PMID:A novel pathway for Ca++ entry into Plasmodium falciparum-infected blood cells. 864 99

The isolation and study of Anopheles gambiae genes that are differentially expressed in development, notably in tissues associated with the maturation and transmission of the malaria parasite, is important for the elucidation of basic molecular mechanisms underlying vector-parasite interactions. We have used the differential display technique to screen for mRNAs specifically expressed in adult males, females, and midgut tissues of blood-fed and unfed females. We also screened for mRNAs specifically induced upon bacterial infection of larval stage mosquitoes. We have characterized 19 distinct cDNAs, most of which show developmentally regulated expression specificity during the mosquito life cycle. The most interesting are six new sequences that are midgut-specific in the adult, three of which are also modulated by blood-feeding. The gut-specific sequences encode a maltase, a V-ATPase subunit, a GTP binding protein, two different lectins, and a nontrypsin serine protease. The latter sequence is also induced in larvae subjected to bacterial challenge. With the exception of a mitochondrial DNA fragment, the other 18 sequences constitute expressed genomic sequence tags, 4 of which have been mapped cytogenetically.
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PMID:Identification and characterization of differentially expressed cDNAs of the vector mosquito, Anopheles gambiae. 891 45

Penetration of the mosquito midgut epithelium is obligatory for the further development of Plasmodium parasites. Therefore, blocking the parasite from invading the midgut wall disrupts the transmission of malaria. Despite such a pivotal role in malaria transmission, the cellular and molecular interactions that occur during the invasion are not understood. Here, we demonstrate that the ookinetes of Plasmodium gallinaceum, which is related closely to the human malaria parasite Plasmodium falciparum, selectively invade a cell type in the Aedes aegypti midgut. These cells, unlike the majority of the cells in the midgut, do not stain with a basophilic dye (toluidine blue) and are less osmiophilic. In addition, they contain minimal endoplasmic reticulum, lack secretory granules, and have few microvilli. Instead, these cells are highly vacuolated and express large amounts of vesicular ATPase. The enzyme is associated with the apical plasma membrane, cytoplasmic vesicles, and tubular extensions of the basal membrane of the invaded cells. The high cost of insecticide use in endemic areas and the emergence of drug resistant malaria parasites call for alternative approaches such as modifying the mosquito to block the transmission of malaria. One of the targets for such modification is the parasite receptor on midgut cells. A step toward the identification of this receptor is the realization that malaria parasites invade a special cell type in the mosquito midgut.
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PMID:Plasmodium gallinaceum preferentially invades vesicular ATPase-expressing cells in Aedes aegypti midgut. 952 Mar 75

We cloned a guanylyl cyclase of 280 kDa from the ciliate Paramecium which has an N-terminus similar to that of a P-type ATPase and a C-terminus with a topology identical to mammalian adenylyl cyclases. Respective signature sequence motifs are conserved in both domains. The cytosolic catalytic C1a and C2a segments of the cyclase are inverted. Genes coding for topologically identical proteins with substantial sequence similarities have been cloned from Tetrahymena and were detected in sequences from Plasmodium deposited by the Malaria Genome Project. After 99 point mutations to convert the Paramecium TAA/TAG-Gln triplets to CAA/CAG, together with partial gene synthesis, the gene from Paramecium was heterologously expressed. In Sf9 cells, the holoenzyme is proteolytically processed into the two domains. Immunocytochemistry demonstrates expression of the protein in Paramecium and localizes it to cell surface membranes. The data provide a novel structural link between class III adenylyl and guanylyl cyclases and imply that the protozoan guanylyl cyclases evolved from an ancestral adenylyl cyclase independently of the mammalian guanylyl cyclase isoforms. Further, signal transmission in Ciliophora (Paramecium, Tetrahymena) and in the most important endoparasitic phylum Apicomplexa (Plasmodium) is, quite unexpectedly, closely related.
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PMID:Guanylyl cyclases with the topology of mammalian adenylyl cyclases and an N-terminal P-type ATPase-like domain in Paramecium, Tetrahymena and Plasmodium. 1042 60


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