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)

To receive actual information about the clinical course of falciparum malaria case history of 373 patients hospitalized in Chemin de Fer Hospital in Phnom Penh from May 1 till October 1, 1985 were evaluated. No patients were infected in Phnom Penh. We estimated that only 8.3% of patients had higher parasitaemia than 100,000 or more asexual parasites in microliter of peripheral blood which is considered as a heavy infection. Complicated malaria was found in 39 patients (10.4%). The most frequent complications were cerebral complications (80.0%), renal failure (23.3%), and liver failure (16.6%). Ten patients had multiple organ complications and they represented 25.6% of patients with complications. The 100% mortality was observed in those in coma stage III; with haemoglobinuria, epistaxis and melena. Only coma stage III as a single symptom caused the death. In other cases death resulted from multiple organ complications.
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PMID:Malaria in Kampuchea: clinical course of falciparum malaria in Chemin de Fer Hospital, Phnom Penh. 355 50

Apicomplexan parasites are a large phylum of unicellular and obligate intracellular organisms of great medical importance. They include the human pathogens Plasmodium spp., the causative agent of malaria, and Toxoplasma gondii, an opportunistic parasite of immunosuppressed individuals and a common cause of congenital disease, together affecting several hundred million people worldwide. The search for new and effective drugs against these pathogens has been boosted during the last years by an unexpected finding. Through molecular and cell biological analysis it was realized that probably most members of this phylum harbor a plastid-like organelle, called the apicoplast, which probably is derived from the engulfment of a red alga in ancient times. Although the apicoplast itself contains a small circular genome, most of the proteome of this organelle is encoded in the nuclear genome, and the proteins are subsequently transported to the apicoplast. It is assumed to contain a number of unique metabolic pathways not found in the vertebrate host, making it an ideal "playground" for those interested in drug targets. Recent reports have shown that the rationale of this approach is valid and that new drugs which are urgently needed especially for plasmodial infections, might be developed in the near future based on these targets. Amongst them are three enzymes of the plant-like fatty acid synthesis machinery and enzymes of the non-mevalonat isoprenoid biosynthesis pathway. From their presence in the apicoplast it can be concluded that fatty acid and lipid biosynthesis seems to be a major function of the apicoplast. Another recently described apicoplast enzyme, ferredoxin-NADP(+)-reductase and its redox partner, ferredoxin, points to another interesting organelle-specific biosynthetic pathway, namely [Fe-S] cluster biosynthesis. In the present review, the fundamental aspects of the apicoplast as drug target will be described, together with the specific pathways and their currently known inhibitors. Furthermore, based on the recent findings potentially new targets will be discussed. A short overview of the presently available high-throughput methods for Apicomplexa to evaluate the potency of new inhibitory substances will also be given.
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PMID:Biosynthetic pathways of plastid-derived organelles as potential drug targets against parasitic apicomplexa. 1276 82

Heme-degrading enzymes are involved in human diseases ranging from stroke, cancer, and multiple sclerosis to infectious diseases such as malaria, diphtheria, and meningitis. All mammalian and microbial enzymes identified to date are members of the heme oxygenase superfamily and assume similar monomeric structures with an all alpha-helical fold. Here we describe the crystal structures of IsdG and IsdI, two heme-degrading enzymes from Staphylococcus aureus. The structures of both enzymes resemble the ferredoxin-like fold and form a beta-barrel at the dimer interface. Two large pockets found on the outside of the barrel contain the putative active sites. Sequence homologs of IsdG and IsdI were identified in multiple Gram-positive pathogens. Substitution of conserved IsdG amino acid residues either reduced or abolished heme degradation, suggesting a common catalytic mechanism. This mechanism of IsdG-mediated heme degradation may be similar to that of the structurally related monooxygenases, enzymes involved in the synthesis of antibiotics in Streptomyces. Our results imply the evolutionary adaptation of microbial enzymes to unique environments.
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PMID:Staphylococcus aureus IsdG and IsdI, heme-degrading enzymes with structural similarity to monooxygenases. 1552 15

(E)-4-Hydroxy-3-methylbut-2-enyl diphosphate synthase (GcpE), which catalyzes the conversion of 2-C-methyl-D-erythritol cyclodiphosphate (MEcPP) into (E)-4-hydroxy-3-methylbut-2-enyl diphosphate (HMBPP), is an essential enzyme of the non-mevalonate (2-C-methyl-D-erythritol-4-phosphate (MEP)) pathway for isoprenoid biosynthesis. The terminal steps of the MEP pathway are still not fully understood, although this pathway is necessary for survival in various organisms such as cyanobacteria, plastids of algae and higher plants, and the apicoplast of human malaria parasites. To determine the efficient redox partner for thermophilic cyanobacterial GcpE, We have expressed the gcpE and petF genes in Escherichia coli and studied the protein-protein interaction of GcpE protein with ferredoxin I (PetF) from the thermophilic cyanobacterium Thermosynechococcus elongatus BP-1. Recombinant GcpE protein was purified by an N-terminal His(6) tag and reconstituted as a [4Fe-4S](2+) metalloprotein. GcpE was shown to interact strongly with PetF via the bacterial two-hybrid system designed to detect protein-protein interactions. Moreover, a direct protein-protein interaction between PetF and GcpE was confirmed in an in vitro glutathione S-transferase (GST) pull-down assay. To investigate electron transfer activity from PetF to GcpE, we also constructed a NADPH-dependent reducing shuttle system with purified recombinant ferredoxin-NADP(+) oxidoreductase (PetH) and PetF. The result demonstrated that PetF has the ability to transfer electrons to GcpE. Thus, the combined data provide the first evidence that GcpE is a ferredoxin-dependent enzyme in T. elongatus BP-1.
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PMID:Cyanobacterial non-mevalonate pathway: (E)-4-hydroxy-3-methylbut-2-enyl diphosphate synthase interacts with ferredoxin in Thermosynechococcus elongatus BP-1. 1579 53

Apicomplexa are unicellular, obligate intracellular parasites of great medical importance. They include human pathogens like Plasmodium spp., the causative agent of malaria, and Toxoplasma gondii, an opportunistic parasite of immunosuppressed individuals and a common cause of congenital disease (toxoplasmosis). They alone affect several hundred million people worldwide so that new drugs, especially for plasmodial infections, are urgently needed. This review will focus on a recently emerged, potential drug target, a plant-type redox system consisting of ferredoxin-NADP(+) reductase (FNR) and its redox partner, ferredoxin (Fd). Both reside in an unique organelle of these parasites, named apicoplast, which is of algal origin. The apicoplast has been shown to be required for pathogen survival. In addition to other pathways already identified in this compartment, the FNR/Fd redox system represents a promising drug target because homologous proteins are not present in host organisms. Furthermore, a wealth of structural information exists on the closely related plant proteins, which can be exploited for structure-function studies of the apicomplexan protein pair. T. gondii and P. falciparum FNRs have been cloned, and the T. gondii enzyme was shown to be a flavoprotein active as a NADPH-dependent oxidoreductase. Both phylogenetic and biochemical analyses indicate that T. gondii FNR is similar in function to the isoform present in non-photosynthetic plastids whereby electron flow is from NADPH to oxidized Fd. The resulting reduced Fd is then presumably used as a reductant for various target enzymes whose nature is just starting to emerge. Among the likely candidates is the iron-sulfur cluster biosynthesis pathway, which is also located in the apicoplast and dependent on reducing power. Furthermore, lipoic acid synthase and enzymes of the isoprenoid biosynthetic pathway may be other conceivable targets. Since all these metabolic steps are vital for the parasite, blocking electron flow from FNR to Fd by inhibition of either FNR activity or its molecular interaction with Fd should also interfere with these pathways, ultimately killing the parasite. Although the three-dimensional structure of FNR from T. gondii is not yet known, experimental and computational evidence shows that apicomplexan and plant enzymes are very similar in structure. Furthermore, single amino acid changes can have profound effects on the enzyme activity and affinity for Fd. This knowledge may be exploited for the design of inhibitors of protein-protein interaction. On the other hand, specifically tailored NAD(P) analogues or mimetics based on previously described substances might be useful lead compounds for apicomplexan FNR inhibitors.
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PMID:The plant-type ferredoxin-NADP+ reductase/ferredoxin redox system as a possible drug target against apicomplexan human parasites. 1617 51

In the malaria parasite Plasmodium falciparum isoprenoid precursors are synthesised inside a plastid-like organelle (apicoplast) by the mevalonate independent 1-deoxy-d-xylulose-5-phosphate (DOXP) pathway. The last reaction step of the DOXP pathway is catalysed by the LytB enzyme which contains a [4Fe-4S] cluster. In this study, LytB of P. falciparum was shown to be catalytically active in the presence of an NADPH dependent electron transfer system comprising ferredoxin and ferredoxin-NADP(+) reductase. LytB and ferredoxin were found to form a stable protein complex. These data suggest that the ferredoxin/ferredoxin-NADP(+) reductase redox system serves as the physiological electron donor for LytB in the apicoplast of P. falciparum.
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PMID:Reconstitution of an apicoplast-localised electron transfer pathway involved in the isoprenoid biosynthesis of Plasmodium falciparum. 1628 98

The plant-type ferredoxin/ferredoxin-NADP(+) reductase (Fd/FNR) redox system found in parasites of the phylum Apicomplexa has been proposed as a target for novel drugs used against life-threatening diseases such as malaria and toxoplasmosis. Like many proteins from these protists, apicomplexan FNRs are characterized by the presence of unique peptide insertions of variable length and yet unknown function. Since three-dimensional data are not available for any of the parasite FNRs, we used limited proteolysis to carry out an extensive study of the conformation of Toxoplasma gondii FNR. This led to identification of 11 peptide bonds susceptible to the action of four different proteases. Cleavage sites are clustered in four regions of the enzyme, which include two of its three species-specific insertions. Such regions are thus predicted to form flexible surface loops. The protein substrate Fd protected FNR against cleavage both at its N-terminal peptide and at its largest sequence insertion (28 residues). Deletion by protein engineering of the species-specific subdomain containing the latter insertion resulted in an enzyme form that, although catalytically active, displayed a 10-fold decreased affinity for Fd. In contrast, removal of the first 15 residues of the enzyme unexpectedly enhanced its interaction with Fd. Thus, two flexible polypeptide regions of T. gondii FNR are involved in Fd interaction but have opposite roles in modulating the binding affinity for the protein ligand. In this respect, T. gondii FNR differs from plant FNRs, where the N-terminal peptide contributes to the stabilization of their complex with Fd.
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PMID:Roles of the species-specific subdomain and the N-terminal peptide of Toxoplasma gondii ferredoxin-NADP+ reductase in ferredoxin binding. 1653 38

The human malaria parasite (Plasmodium falciparum) possesses a plastid-derived organelle called the apicoplast, which is believed to employ metabolisms crucial for the parasite's survival. We cloned and studied the biochemical properties of plant-type ferredoxin (Fd) and Fd-NADP+ reductase (FNR), a redox system that potentially supplies reducing power to Fd-dependent metabolic pathways in malaria parasite apicoplasts. The recombinant P. falciparum Fd and FNR proteins were produced by synthetic genes with altered codon usages preferred in Escherichia coli. The redox potential of the Fd was shown to be considerably more positive than those of leaf-type and root-type Fds from plants, which is favourable for a presumed direction of electron flow from catabolically generated NADPH to Fd in the apicoplast. The backbone structure of P. falciparum Fd, as solved by X-ray crystallography, closely resembles those of Fds from plants, and the surface-charge distribution shows several acidic regions in common with plant Fds and some basic regions unique to this Fd. P. falciparum FNR was able to transfer electrons selectively to P. falciparum Fd in a reconstituted system of NADPH-dependent cytochrome c reduction. These results indicate that an NADPH-FNR-Fd cascade is operative in the apicoplast of human malaria parasites.
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PMID:Cloning and characterization of ferredoxin and ferredoxin-NADP+ reductase from human malaria parasite. 1725 Dec

The malaria parasite possesses plant-type ferredoxin (Fd) and ferredoxin-NADP(+) reductase (FNR) in a plastid-derived organelle called the apicoplast. This Fd/FNR redox system, which potentially provides reducing power for essential biosynthetic pathways in the apicoplast, has been proposed as a target for the development of specific new anti-malarial agents. We studied the molecular interaction of Fd and FNR of human malaria parasite (Plasmodium falciparum), which were produced as recombinant proteins in Escherichia coli. NMR chemical shift perturbation analysis mapped the location of the possible FNR interaction sites on the surface of P. falciparum Fd. Site-specific mutation of acidic Fd residues in these regions and the resulting analyses of electron transfer activity and affinity chromatography of those mutants revealed that two acidic regions (a region including Asp26, Glu29 and Glu34, and the other including Asp65 and Glu66) dominantly contribute to the electrostatic interaction with P. falciparum FNR. The combination of Asp26/Glu29/Glu34 conferred a larger contribution than that of Asp65/Glu66, and among Asp26, Glu29 and Glu34, Glu29 was shown to be the most important residue for the interaction with P. falciparum FNR. These findings provide the basis for understanding molecular recognition between Fd and FNR of the malaria parasite.
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PMID:Molecular interaction of ferredoxin and ferredoxin-NADP+ reductase from human malaria parasite. 1793 42

In the apicoplast of apicomplexan parasites, plastidic-type ferredoxin and ferredoxin-NADP(+) reductase (FNR) form a short electron transport chain that provides reducing power for the synthesis of isoprenoid precursors. These proteins are attractive targets for the development of novel drugs against diseases such as malaria, toxoplasmosis, and coccidiosis. We have obtained ferredoxin and FNR of both Toxoplasma gondii and Plasmodium falciparum in recombinant form, and recently we solved the crystal structure of the P. falciparum reductase. Here we report on the functional properties of the latter enzyme, which differ markedly from those of homologous FNRs. In the physiological reaction, P. falciparum FNR displays a k(cat) five-fold lower than those usually determined for plastidic-type FNRs. By rapid kinetics, we found that hydride transfer between NADPH and protein-bound FAD is slower in the P. falciparum enzyme. The redox properties of the enzyme were determined, and showed that the FAD semiquinone species is highly destabilized. We propose that these two features, i.e. slow hydride transfer and unstable FAD semiquinone, are responsible for the poor catalytic efficiency of the P. falciparum enzyme. Another unprecedented feature of the malarial parasite FNR is its ability to yield, under oxidizing conditions, an inactive dimeric form stabilized by an intermolecular disulfide bond. Here we show that the monomerdimer interconversion can be controlled by oxidizing and reducing agents that are possibly present within the apicoplast, such as H(2)O(2), glutathione, and lipoate. This finding suggests that modulation of the quaternary structure of P. falciparum FNR might represent a regulatory mechanism, although this needs to be verified in vivo.
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PMID:The ferredoxin-NADP+ reductase/ferredoxin electron transfer system of Plasmodium falciparum. 1952 13


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