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)

In vitro, neopterin, a pyrazino-[2, 3-d]-pyrimidine compound, is produced by human monocytes-macrophages following induction by either supernatants from activated T lymphocytes or by recombinant gamma interferon. In vivo, its determination in urine or serum provides a sensitive and specific test for the activation grade of cell-mediated immune reactions. Urinary neopterin levels were measured in 128 Tanzanian individuals (age 6 months to 54 years) with parasitologically proven malaria. Levels in a subgroup of 117 previously untreated patients were compared with those previously reported from 19 untreated malarial patients from Bangkok, Thailand (age 7 to 62 years). The influence of concomitant variables such as age, fever, parasitaemia, duration of symptoms and local endemicity of malaria upon neopterin excretion levels was analysed. In the Thai patients, levels were considerably higher than in Tanzanian subjects of similar age. Among the Tanzanian patients, an overwhelming influence of age was detected, children showing extremely high neopterin excretion levels. The other variables did not influence neopterin levels significantly. Our findings are in accord with recent data on the prevalence and mean titres of antibodies to the circumsporozoite protein of Plasmodium falciparum, which indicate that in endemic areas acquired humoral immunity develops slowly with increasing age, while prevalence and severity of disease decline.
 ...
PMID:The dependence of cell-mediated immune activation in malaria on age and endemicity. 332 84

Following invasion of the human erythrocyte by the malaria parasite, Plasmodium falciparum, there appear in the parasitized cell new, high-capacity permeation pathways that transport a diverse range of low-molecular-mass solutes. In this study a series of 16 arylaminobenzoates, analogues of the Cl- channel blocker 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), were tested for their effects on the transport of choline, a univalent cation, into malaria-infected cells. A number of the arylaminobenzoates were found to be potent inhibitors of malaria-induced choline transport and to be similarly effective at blocking the induced transport of the uncharged pyrimidine nucleoside thymidine and the univalent anion lactate. The data are consistent with the hypothesis that much of the induced transport of cations, anions and non-electrolytes into parasitized cells is via broad-specificity, anion-selective pathways of a single type. A comparison of the effects of the arylaminobenzoates on malaria-induced transport with their effects on a number of representative anion transport systems in normal mammalian cells suggests that it is possible to identify pharmacological agents that block the malaria-induced pathway while not significantly affecting important transport mechanisms in host tissues. The most potent of the induced-transport inhibitors identified were shown to inhibit [3H]hypoxanthine incorporation in in vitro parasite growth assays. These data support the view that the induced-transport pathway may be a viable pharmacological target.
 ...
PMID:In search of a selective inhibitor of the induced transport of small solutes in Plasmodium falciparum-infected erythrocytes: effects of arylaminobenzoates. 748 30

Following the demonstration of the antimalarial effect of the long chain saturated alcohol n-hentriacontanol ((CH2)29CH2OH), isolated from the Bolivian endemic solanaceous plant Cuatresia sp., we have tested the effect of the C18 fatty acids oleic, elaidic, linoleic, and linoleic on malaria parasites. These fatty acids inhibited the parasitemic development in mice infected with Plasmodium vinckei petteri or with Plasmodium yoelii nigeriensis in a 4-day suppressive test. To gain a deeper discernment of the antimalarial mode of action, the effects of these compounds were evaluated on Plasmodium falciparum growth in culture. Whereas n-hentriacontanol did not show any inhibition of this parasite, on the contrary, the C18 acids displayed a considerably inhibitory activity at < or = 200 micrograms/ml both in intact infected cells and in free parasites. In order to understand the mechanism of their antimalarial action, several tests were performed. No hemolysis of infected cells could be observed up to 500 microgram/ml. No effect on the lipid peroxidation, ATP levels, transport through the parasite-induced permeability pathways, or on the phagocytosis of the infected cells could be observed. The cytotoxic effect of the fatty acids was very rapid: full inhibition of nucleic acids and protein syntheses was observed in less than 30 min. This inhibition was not relieved by the addition of deferrioxamine or FeCl3, indicating that fatty acids (FA) do not act by facilitating the transport of iron. Inhibition was relieved in neither the presence of orotic acid or its methyl ester, indicating that FA do not act at the mitochondrial level of pyrimidine synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Antimalarial effects of C18 fatty acids on Plasmodium falciparum in culture and on Plasmodium vinckei petteri and Plasmodium yoelii nigeriensis in vivo. 762 73

Previous studies have shown that 100 nM 5-fluoroorotate (5-FO) is sufficient to block the in vitro proliferation of Plasmodium falciparum without causing toxicity to mammalian cells. In anticipation of potential drug resistance, a study was undertaken to identify P. falciparum cells that would proliferate in the presence of 5-FO. About 3 x 10(6) UV-irradiated as well as nonirradiated parasites were subjected to a one-step selection with 100 nM 5-FO both in the absence and in the presence of preformed pyrimidines (uracil, uridine, thymine, and thymidine). The P. falciparum cells that emerged after 3 weeks were cloned, and the 90% inhibitory concentration of 5-FO for the cloned cells was found to be 100- to 400-fold greater than that for the parent cell line. Two clones that were further characterized retained resistance to 5-FO even after prolonged propagation in culture without drug pressure. Since the mutants were not cross-resistant to 5-fluorouracil or to dihydrofolate reductase inhibitors, it was unlikely that alteration of thymidylate synthase or overproduction of the bifunctional dihydrofolate reductase-thymidylate synthase was responsible for 5-FO resistance. Similarly, resistance was not due to the expression of a pyrimidine salvage pathway since the cells were not pyrimidine auxotrophs, they did not show increased utilization of pyrimidine nucleosides, and they did not show increased susceptibility to 5-fluoropyrimidine nucleosides. When the selection experiments were repeated, without mutagenesis, in the presence of 10(-7) M 5-FO with fewer than 10(6) parasites or in the presence of more than 10(-7) M 5-FO with more than 10(8) parasites, viable mutants could not be recovered from the cultures. The implications of these findings for the in vivo use of 5-FO for malaria chemotherapy are discussed.
 ...
PMID:Selection and characterization of 5-fluoroorotate-resistant Plasmodium falciparum. 769 75

The mitochondrial dihydroorotate dehydrogenase (DHODase), the single redox reaction in the pyrimidine de novo synthetic pathway, was purified to near homogeneity by detergent solubilization and fast protein liquid chromatography (FPLC) techniques from the mature trophozoites and schizonts of Plasmodium falciparum, human malaria parasite. The purified DHODase was monofunctional protein with a M(r) of 56,000 +/- 4000, based on Superose 12 gel filtration FPLC and SDS-PAGE analyses. Polyclonal antibodies raised against the purified P. falciparum protein was cross-reacted with P. berghei, rodent malaria parasite. The optimal activity of DHODase required long chain of coenzyme Q (CoQ6-10) which were essential for electron transfer. The Km and kcat values for L-dihydroorotate were 14.4 +/- 5.9 microM and 15.0 +/- 1.4 min-1, respectively; for CoQ6, they were 22.5 +/- 6.4 microM and 21.6 +/- 3.4 min-1. L-Orotate, an enzymatic product, was a strong competitive inhibitor with Ki of 18.2 +/- 3.6 microM. The 5-substituted L-orotates having antimalarial activities against P. falciparum in vitro were found to be competitive inhibitors. The inhibitory effect by these 5-substituted L-orotates on the malarial DHODase was different from the mammalian enzyme. Various benzoquinones and naphthoquinones were found to inhibit the purified DHODase activity at a different degree. Mitochondria from erythrocytic cycle of P. falciparum were purified, using differential centrifugation and followed by Percoll density gradient separation, with purifications of 13-fold and overall yields of 33%. The double-membraned mitochondria had a few tubular-like cristae structure as what found in many protozoan parasites. DHODase was localized inside the mitochondria as probed by immunogold labeling with the polyclonal antibodies and selective solubilization by digitonin.
 ...
PMID:Purification, characterization and localization of mitochondrial dihydroorotate dehydrogenase in Plasmodium falciparum, human malaria parasite. 772 9

The malarial parasite Plasmodium falciparum can only synthesize pyrimidine nucleotides via the de novo pathway which is therefore a suitable target for development of antimalarial drugs. New assay procedures have been developed using high-pressure liquid chromatography (HPLC) which enable concurrent measurement of pyrimidine intermediates in malaria. Synchronized parasites growing in erythrocytes were pulse-labeled with [14C]bicarbonate at 6-h intervals around the 48-h asexual life cycle. Analysis of malarial extracts by HPLC showed tht incorporation of [14C]bicarbonate into pyrimidine nucleotides was maximal during the transition from trophozoites to schizonts. The reaction, N-carbamyl-L-aspartate-->L-dihydroorotate (CA-asp-->DHO) catalyzed by malarial dihydroorotase is inhibited by L-6-thiodihydroorotate (TDHO) in vitro (Ki = 6.5 microM), and TDHO, as the free acid or methyl ester, induces a major accumulation of CA-asp in malaria. Atovaquone, a naphthoquinone, is a moderate inhibitor of dihydroorotate dehydrogenase in vitro (Ki = 27 microM) but induces major accumulations of CA-asp and DHO. Pyrazofurin induces accumulation of orotate and orotidine in malaria, consistent with inhibition of orotidine 5'-monophosphate (OMP) decarboxylase with subsequent dephosphorylation of the OMP accumulated. Although TDHO, atovaquone, and pyrazofurin arrest the growth of P. falciparum, only moderate decreases in UTP, CTP, and dTTP were observed. 5-Fluoroorotate also arrests the growth of P. falciparum with major accumulations of 5-fluorouridine mono-, di-, and triphosphates and the most significant inhibition of de novo biosynthesis of pyrimidine nucleotides.
 ...
PMID:Cytotoxic effects of inhibitors of de novo pyrimidine biosynthesis upon Plasmodium falciparum. 790 90

Dihydroorotate dehydrogenase (DHOD) is a key enzyme in de novo pyrimidine biosynthesis and the major source of electrons for the mitochondrial electron transport chain of intraerythrocytic malaria parasites. DHOD and the electron transport chain may also be the site of inhibition by certain antimalarial drugs. In order to test this, Plasmodium falciparum-infected erythrocytes were exposed in vitro to artemisinin or various 8-aminoquinolines, such as primaquine, WR 238605, WR 225448, and WR 255956, and then assayed for both enzyme activity and [3H]hypoxanthine incorporation, which is an indicator of viability. Atovaquone inhibits DHOD activity to a much greater extent than hypoxanthine incorporation, which is consistent with previous reports that it targets the parasite respiratory chain. However, artemisinin and the 8-aminoquinolines inhibit DHOD to the same or lesser extent than hypoxanthine incorporation, suggesting that these compounds have different modes of action.
 ...
PMID:The effects of antimalarials on the Plasmodium falciparum dihydroorotate dehydrogenase. 805 May 25

Plasmodium falciparum causes the most severe form of malaria that is fatal in many cases. Emergence of drug resistant strains of P. falciparum requires that new drug targets be identified. This review considers in detail enzymes of the glycolytic pathway, purine salvage pathway, pyrimidine biosynthesis and proteases involved in catabolism of haemoglobin. Structural features of P. falciparum triosephosphate isomerase which could be exploited for parasite specific drug development have been highlighted. Utility of P. falciparum hypoxanthine-guanine-phosphoribosyltransferase, adenylosuccinate synthase, dihydroorotate dehydrogenase, thymidylate synthase-dihydrofolate reductase, cysteine and aspartic proteases have been elaborated in detail. The review also briefly touches upon other potential targets in P. falciparum.
 ...
PMID:Metabolic enzymes as potential drug targets in Plasmodium falciparum. 929 79

Carbon dioxide (CO2) is essential for the growth of intraerythrocytic malaria parasites to synthesize pyrimidine through CO2 fixation and to regulate intracellular pH. CO2 transport across the plasma membrane of erythrocytes is facilitated by carbonic anhydrase (CA). With the use of electron microscopy and CA-specific Hansson's stain, CA is found also in all the intraerythrocytic stages of Plasmodium falciparum. When CA inhibitors, including acetazolamide, potassium iodide, and sodium deoxycholate, were added to continuous culture of P. falciparum, they, particularly sodium deoxycholate, produced a marked reduction in parasitemia. These results explain the biochemical basis of some of the clinical conditions associated with malaria and strongly suggest that CA inhibitors have potential as a new class of antimalarials.
 ...
PMID:The pivotal role of carbonic anhydrase in malaria infection. 948 77

A basis for the intrinsic resistance of some Plasmodium vivax isolates to pyrimethamine is suggested following the isolation of the bifunctional gene encoding dihydrofolate reductase-thymidylate synthase (DHFR-TS) of this human malaria parasite. Malaria parasites are dependent on this enzyme for folate biosynthesis. Specific inhibition of the DHFR domain of the enzyme by pyrimethamine blocks pyrimidine biosynthesis, leading to an inhibition of DNA replication. The gene was isolated by the polymerase chain reaction (PCR) from genomic DNA using degenerate oligonucleotides designed to hybridize on the highly conserved regions of the sequence. The nucleotide sequence was completed by screening P. vivax genomic bank. Sequence analysis revealed an open reading frame (ORF) of 1872 nucleotides encoding a deduced protein of 623 amino acids (aa). Alignment with other malarial DHFR-TS genes showed that a 237-residue DHFR domain and a 286-residue TS domain were separated by a 100-aa linker region. Comparison with other malarial species showed low and essentially no isology in the DHFR and junctional domains, respectively, whereas an extensive isology was observed in the TS domain. The characteristic features of the P. vivax DHFR-TS gene sequence include an insertion of a short repetitive tandem array within the DHFR domain that is absent in another human malaria parasite, P. falciparum, and a GC-biased aa composition, giving rise to highly GC-rich DHFR (50.8%), junctional (58.7%), and TS (40.5%) domains, as compared with other malaria parasites. Analysis of the 5' noncoding region revealed the presence of a putative TATA box at 116 nucleotides upstream of the ATG start codon as well as a putative GC box at -636. Comparison of the DHFR sequences from pyrimethamine-sensitive and pyrimethamine-resistant P. vivax isolates revealed two residue changes: Ser Arg-58 and Ser Asn-117. These aa residues correspond to codons 59 and 108 in the P. falciparum DHFR active site in which similar aa substitutions (Cys Arg-59 and Ser Asn-108) are associated with pyrimethamine resistance. These findings may explain the intrinsic resistance of some P. vivax isolates to pyrimethamine.
 ...
PMID:Analysis of the Plasmodium vivax dihydrofolate reductase-thymidylate synthase gene sequence. 957 57


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>