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)

Many parasitic Apicomplexa, such as Plasmodium falciparum, contain an unpigmented chloroplast remnant termed the apicoplast, which is a target for malaria treatment. However, no close relative of apicomplexans with a functional photosynthetic plastid has yet been described. Here we describe a newly cultured organism that has ultrastructural features typical for alveolates, is phylogenetically related to apicomplexans, and contains a photosynthetic plastid. The plastid is surrounded by four membranes, is pigmented by chlorophyll a, and uses the codon UGA to encode tryptophan in the psbA gene. This genetic feature has been found only in coccidian apicoplasts and various mitochondria. The UGA-Trp codon and phylogenies of plastid and nuclear ribosomal RNA genes indicate that the organism is the closest known photosynthetic relative to apicomplexan parasites and that its plastid shares an origin with the apicoplasts. The discovery of this organism provides a powerful model with which to study the evolution of parasitism in Apicomplexa.
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PMID:A photosynthetic alveolate closely related to apicomplexan parasites. 1828 73

Plasmodium vivax is the most widespread species of human malaria parasite affecting 70-80 million people worldwide each year. In recent years, some potential vaccine candidate antigens from P. vivax have been identified including tryptophan-rich antigens PvTRAg and PvTARAg55. We report here the identification and partial characterization of a 74 kDa P. vivax alanine-tryptophan-rich antigen (PvATRAg74) which is expressed by all asexual blood stages of the parasite. This protein contains two major domains, i.e. alanine-rich domain (ARD) in N-terminal region and the tryptophan-rich domain (TRD) at C-terminus. PvATRAg74 also contains variable numbers of octa-peptide repeats in the ARD region. The C-terminal PvATRAg74 containing TRD was highly conserved among 32 P. vivax isolates while N-terminal ARD showed genetic polymorphisms. The 36 kDa TRD was expressed in E. coli and named here as His6-TRD. The purified recombinant His6-TRD showed binding with uninfected human erythrocytes. This antigen was also recognized by all 38 P. vivax patients' sera on ELISA thus showing a very high seropositivity rates. In vitro stimulation of lymphocytes with purified His6-TRD indicated that it induced T cell immune response in majority (94%, n=16) of P. vivax exposed individuals. The stimulated T cells produced higher amount of IL-4 and IL-10 than IFN-gamma, TNF-alpha, and IL-12 indicating a Th2 type of response bias. Unlike PvTARAg55, this antigen is more immunogenic in humans and possesses the erythrocyte-binding activity. Immunogenecity of PvATRAg74 is similar to PvTRAg whose erythrocyte-binding activity still remains unknown.
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PMID:High immunogenecity and erythrocyte-binding activity in the tryptophan-rich domain (TRD) of the 74-kDa Plasmodium vivax alanine-tryptophan-rich antigen (PvATRAg74). 1857 64

In the malaria vector Anopheles gambiae, tryptophan 2,3-dioxygenase (TDO) is the only enzyme able to initiate l-tryptophan degradation through the kynurenine pathway. TDO converts l-tryptophan to N-formylkynurenine by catalyzing the heme-dependent oxidative opening of the substrate indole ring. Despite the central role exerted by kynurenines in the physiology of living organisms, only a few insect TDOs have been subjected to biochemical characterization in vitro. We performed a RT-PCR-based analysis of the tissue distribution of TDO mRNA in A. gambiae that revealed a ubiquitous expression of the gene, thus further underlining the importance of the enzyme in the mosquito biology. We developed an expression/purification procedure yielding pure and active recombinant A. gambiae TDO. Spectral analyses showed that the enzyme was purified in its heme-ferric form that was subsequently used to determining the Michaelis-Menten constants of the TDO catalyzed reaction in the presence of reducing agents. The screening of a number of compounds as potential TDO modulators showed that several kynurenines and other Tryptophan-derived molecules interfere with the enzyme activity in vitro. Our study could contribute to understanding TDO regulation in vivo and to the identification of inhibitors to be used to alter Tryptophan homeostasis in the malaria vector.
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PMID:Purification and biochemical characterization of a recombinant Anopheles gambiae tryptophan 2,3-dioxygenase expressed in Escherichia coli. 1868 1

A new tryptophan-polyketide hybrid, codinaeopsin, was isolated from an endophytic fungus collected in Costa Rica. The structure of codinaeopsin, which was deduced from NMR and mass spectral data, contains an unusual heterocyclic unit linking indole and decalin fragments. Codinaeopsin is active against Plasmodium falciparum, the causative agent of the most lethal form of malaria (IC50 = 2.3 microg/mL or 4.7 microM).
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PMID:Codinaeopsin, an antimalarial fungal polyketide. 1869 86

The 3-hydroxykynurenine transaminase (3-HKT) gene plays a vital role in the development of malaria parasites by participating in the synthesis of xanthurenic acid, which is involved in the exflagellation of microgametocytes in the midgut of malaria vector species. The 3-HKT enzyme is involved in the tryptophan metabolism of Anophelines. The gene had been studied in the important global malaria vector, Anopheles gambiae. In this report, we have conducted a preliminary investigation to characterize this gene in the two important vector species of malaria in India, Anopheles culicifacies and Anopheles stephensi. The analysis of the genetic structure of this gene in these species revealed high homology with the An. gambiae gene. However, four non-synonymous mutations in An. stephensi and seven in An. culicifacies sequences were noted in the exons 1 and 2 of the gene; the implication of these mutations on enzyme structure remains to be explored.
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PMID:Characterization of the 3-HKT gene in important malaria vectors in India, viz: Anopheles culicifacies and Anopheles stephensi (Diptera: Culicidae). 1894 31

The formation and reactivity of excited states and free radicals from primaquine, a drug used in the treatment of malaria, was studied in order to evaluate the primary photochemical reaction mechanisms. The excited primaquine triplet was not detected, but is likely to be formed with a short lifetime (<50 ns) and with a triplet energy <250 kJ/mol as the drug is an efficient quencher of the fenbufen triplet and the biphenyl triplet, and forms (1)O(2) by laser flash photolysis ((PQ)Phi(Delta)=0.025). Primaquine (PQ) exists as the monocation (PQH(+)) in aqueous solution at physiological pH. PQH(+) photoionises by a biphotonic process and also forms the monoprotonated cation radical (PQH(2+)*) by one electron oxidation by HO* (k(q)=6.6 x 10(9) M(-1) s(-1)) and Br*(2)(-) (k(q)=4.7 x 10(9) M(-1) s(-1)) at physiological pH, detected as a long-lived transient decaying essentially by a second order process (k(2)=7.4 x 10(8) M(-1) s(-1)). PQH(2+)* is scavenged by O(2), although at a limited rate (k(q)=1.0 x 10(6) M(-1) s(-1)). The reduction potential (E degrees) of PQH(2+)*/PQH(+) is < +1015 mV, as measured versus tryptophan (TRP*/TRPH). Primaquine also forms PQH(2+)* at pH 2.4, by one electron oxidation by Br*(2)(-) and proton loss (k(q)=2.7 x 10(9) M(-1) s(-1)). The non-protonated cation radical (PQ(+)*) is formed during one electron oxidation with Br*(2)(-) at alkaline conditions (k(q)=4.2 x 10(9) M(-1) s(-1) at pH 10.8). The estimated pK(a)-value of PQH(2+)*/PQ(+)* is pK(a) approximately 7-8. Primaquine is not a scavenger of O*(2)(-) at physiological pH. Thus self-sensitization by O*(2)(-) is eliminated as a degradation pathway in the photochemical reactions. Impurities in the raw material and photochemical degradation products initiate photosensitized degradation of primaquine in deuterium oxide, prevented by addition of the (1)O(2) quencher sodium azide. Photosensitized degradation by formation of (1)O(2) is thus important for the initial photochemical decomposition of primaquine, which also proceeds by free radical reactions. Formation of PQH(2+)* is expected to play an essential part in the photochemical degradation process in a neutral, aqueous medium.
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PMID:Photoreactivity of biologically active compounds. XIX: excited states and free radicals from the antimalarial drug primaquine. 1911 11

The human malaria parasite Plasmodium falciparum is able to synthesize de novo pyridoxal 5-phosphate (PLP), a crucial cofactor, during erythrocytic schizogony. However, the parasite possesses additionally a pyridoxine/pyridoxal kinase (PdxK) to activate B6 vitamers salvaged from the host. We describe a strategy whereby synthetic pyridoxyl-amino acid adducts are channelled into the parasite. Trapped upon phosphorylation by the plasmodial PdxK, these compounds block PLP-dependent enzymes and thus impair the growth of P. falciparum. The novel compound PT3, a cyclic pyridoxyl-tryptophan methyl ester, inhibited the proliferation of Plasmodium very efficiently (IC(50)-value of 14 microM) without harming human cells. The non-cyclic pyridoxyl-tryptophan methyl ester PT5 and the pyridoxyl-histidine methyl ester PHME were at least one order of magnitude less effective or completely ineffective in the case of the latter. Modeling in silico indicates that the phosphorylated forms of PT3 and PT5 fit well into the PLP-binding site of plasmodial ornithine decarboxylase (PfODC), the key enzyme of polyamine synthesis, consistent with the ability to abolish ODC activity in vitro. Furthermore, the antiplasmodial effect of PT3 is directly linked to the capability of Plasmodium to trap this pyridoxyl analog, as shown by an increased sensitivity of parasites overexpressing PfPdxK in their cytosol, as visualized by GFP fluorescence.
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PMID:Poisoning pyridoxal 5-phosphate-dependent enzymes: a new strategy to target the malaria parasite Plasmodium falciparum. 1919 87

Nostocarboline, a chlorinated and N-methylated carbolinium alkaloid, displays potent and selective inhibition of photoautotrophic organisms as well as the malaria parasite Plasmodium falciparum, while showing very low toxicity to bacterial and fungal pathogens, rat myoblasts and crustaceans. New derivatives of nostocarboline incorporating Br, F or methyl substituents have been obtained through precursor-directed biosynthesis in Nostoc 78-12A (identical to Nostoc sp. ATCC 43238) by feeding this cyanobacterium with differently substituted tryptophan derivatives or 6-Br-norharmane (eudistomin N). These experiments substantiate the biosynthetic hypothesis and validate the inherent flexibility of the corresponding enzymes for metabolic engineering. The new derivatives inhibit the growth of the toxic-bloom-forming cyanobacterium Microcystis aeruginosa PCC 7806 above 1 microM. The mode of action of nostocarboline was investigated by using chlorophyll-a fluorescence imaging, and it was demonstrated that a decrease in photosynthesis precedes cell death, thus establishing the phytotoxic properties of this alkaloid.
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PMID:Directed biosynthesis of phytotoxic alkaloids in the cyanobacterium Nostoc 78-12A. 1926 50

The nutrient amino acid transporter (NAT) subfamily of the neurotransmitter sodium symporter family (NSS, also known as the solute carrier family 6, SLC6) represents transport mechanisms with putative synergistic roles in the absorption of essential and conditionally essential neutral amino acids. It includes a large paralogous expansion of insect-specific genes, with seven genes from the genome of the malaria mosquito, Anopheles gambiae. One of the An. gambiae NATs, AgNAT8, was cloned, functionally expressed and characterized in X. laevis oocytes as a cation-coupled symporter of aromatic amino acids, preferably l-phenylalanine, l-tyrosine and l-DOPA. To explore an evolutionary trend of NAT-SLC6 phenotypes, we have cloned and characterized AgNAT6, which represents a counterpart of AgNAT8 descending from a recent gene duplication (53.1% pairwise sequence identity). In contrast to AgNAT8, which preferably mediates the absorption of phenol-branched substrates, AgNAT6 mediates the absorption of indole-branched substrates with highest apparent affinity to tryptophan (K(0.5)(Trp)=1.3 micromol l(-1) vs K(0.5)(Phe)=430 micromol l(-1)) and [2 or 1 Na(+) or K(+)]:[aromatic substrate] stoichiometry. AgNAT6 is highly transcribed in absorptive and secretory regions of the alimentary canal and specific neuronal structures, including the neuropile of ventral ganglia and sensory afferents. The alignment of AgNATs and LeuT(Aa), a bacterial NAT with a resolved 3D structure, reveals three amino acid differences in the substrate-binding pocket that may be responsible for the indole- vs phenol-branch selectivity of AgNAT6 vs AgNAT8. The identification of transporters with a narrow selectivity for essential amino acids suggests that basal expansions in the SLC6 family involved duplication and retention of NATs, improving the absorption and distribution of under-represented essential amino acids and related metabolites. The identified physiological and expression profiles suggest unique roles of AgNAT6 in the active absorption of indole-branched substrates that are used in the synthesis of the neurotransmitter serotonin as well as the key circadian hormone and potent free-radical scavenger melatonin.
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PMID:Cloning and functional expression of the first eukaryotic Na+-tryptophan symporter, AgNAT6. 1941 50

Quinine is a major drug of choice for the treatment of malaria. However, the primary mode of quinine action is unclear, and its efficacy is marred by adverse reactions among patients. To help address these issues, a genome-wide screen for quinine sensitivity was carried out using the yeast deletion strain collection. Quinine-sensitive mutants identified in the screen included several that were defective for tryptophan biosynthesis (trp strains). This sensitivity was confirmed in independent assays and was suppressible with exogenous Trp, suggesting that quinine caused Trp starvation. Accordingly, quinine was found to inhibit [(3)H]Trp uptake by cells, and the quinine sensitivity of a trp1Delta mutant could be rescued by overexpression of Trp permeases, encoded by TAT1 and TAT2. The site of quinine action was identified specifically as the high affinity Trp/Tyr permease, Tat2p, with which quinine associated in a Trp-suppressible manner. A resultant action also on Tyr levels was reflected by the Tyr-suppressible quinine hypersensitivity of an aro7Delta deletion strain, which is auxotrophic for Tyr (and Phe). The present genome-wide dataset provides an important resource for discovering modes of quinine toxicity. That potential was validated with our demonstration that Trp and Tyr uptake via Tat2p is a major target of cellular quinine toxicity. The results also suggest that dietary tryptophan supplements could help to avert the toxic effects of quinine.
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PMID:The antimalarial drug quinine disrupts Tat2p-mediated tryptophan transport and causes tryptophan starvation. 1941 71


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