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)

Triclosan, a known antibacterial, acts by inhibiting enoyl-ACP (acyl-carrier protein) reductase (ENR), a key enzyme of the type II fatty acid synthesis (FAS) system. Plasmodium falciparum, the human malaria-causing parasite, harbours the type II FAS; in contrast, its human host utilizes type I FAS. Due to this striking difference, ENR has emerged as an important target for the development of new antimalarials. Modelling studies, and the crystal structure of P. falciparum ENR, have highlighted the features of ternary complex formation between the enzyme, triclosan and NAD+ [Suguna, A. Surolia and N. Surolia (2001) Biochem. Biophys. Res. Commun. 283, 224-228; Perozzo, Kuo, Sidhu, Valiyaveettil, Bittman, Jacobs, Fidock, and Sacchettini (2002) J. Biol. Chem. 277, 13106-13114; and Swarnamukhi, Kapoor, N. Surolia, A. Surolia and Suguna (2003) PDB1UH5]. To address the issue of the importance of the residues involved in strong specific and stoichiometric binding of triclosan to P. falciparum ENR, we mutated the following residues: Ala-217, Asn-218, Met-281, and Phe-368. The affinity of all the mutants was reduced for triclosan as compared with the wild-type enzyme to different extents. The most significant mutation was A217V, which led to a greater than 7000-fold decrease in the binding affinity for triclosan as compared with wild-type PfENR. A217G showed only 10-fold reduction in the binding affinity. Thus, these studies point out significant differences in the triclosan-binding region of the P. falciparum enzyme from those of its bacterial counterparts.
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PMID:Mutational analysis of the triclosan-binding region of enoyl-ACP (acyl-carrier protein) reductase from Plasmodium falciparum. 1513 52

Plasmodium vivax is one of four Plasmodium species that cause human malaria. P. vivax and a related simian malaria parasite, Plasmodium knowlesi, invade erythrocytes by binding the Duffy antigen/receptor for chemokines (DARC) through their respective Duffy binding proteins. Here we show that tyrosines 30 and 41 of DARC are modified by addition of sulphate groups, and that the sulphated tyrosine 41 is essential for association of the Duffy binding proteins of P. vivax (PvDBP) and P. knowlesi (PkDaBP) with DARC-expressing cells. These sulphated tyrosines also participate in the association of DARC with each of its four known chemokine ligands. Alteration of tyrosine 41 to phenylalanine interferes with MCP-1, RANTES and MGSA association with DARC, but not with that of IL8. In contrast, alteration of tyrosine 30 to phenylalanine interferes with the association of IL8 with DARC. A soluble sulphated amino-terminal domain of DARC, but not one modified to phenylalanine at residue 41, can be used to block the association of PvDBP and PkDaBP with red blood cells, with an IC50 of approximately 5 nM. These data are consistent with a role for tyrosine sulphation in the association of many or most chemokines with their receptors, and identify a key molecular determinant of erythrocyte invasion by P. vivax.
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PMID:Sulphated tyrosines mediate association of chemokines and Plasmodium vivax Duffy binding protein with the Duffy antigen/receptor for chemokines (DARC). 1572 May 50

Point mutations in the voltage-gated sodium channel gene involved in knockdown resistance to DDT and pyrethroid insecticides have been described in several insect species. In the malaria vector Anopheles gambiae Giles sensu stricto (Diptera: Culicidae) two mutations have been identified. The first, consisting of a leucine-phenylalanine substitution at amino acid position 1014, is widespread in West Africa. The second, a leucine-serine substitution at the same position, has to date only been detected in western Kenya. Analysis of the kdr polymorphism in a sample of 106 An. gambiae s.s. of the rDNA S-form/Type I collected in Libreville (Gabon) surprisingly revealed the presence of both East and West African kdr mutations with frequencies of 63% and 37%, respectively. No wild-type alleles were detected and there was an excess of heterozygous genotypes (P = 0.04). In addition, an inconsistency was found during the kdr genotyping procedures by polymerase chain reaction, which could have lead to an underestimation of resistance alleles. The implications of these findings are discussed.
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PMID:Co-occurrence of East and West African kdr mutations suggests high levels of resistance to pyrethroid insecticides in Anopheles gambiae from Libreville, Gabon. 1660 87

We report the first finding of the knockdown Leu-Phe and Leu-Ser mutations associated with resistance to pyrethroids and DDT insecticides in the malaria mosquito Anopheles gambiae from Cameroon. The Leu-Phe mutation was found in both the M and S molecular forms of An. gambiae. Importantly, two specimens of the S molecular form were found to carry both mutations in a heterozygous state.
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PMID:First report of knockdown mutations in the malaria vector Anopheles gambiae from Cameroon. 1668 82

Cerebral malaria is associated with decreased production of nitric oxide and decreased levels of its precursor, l-arginine. Abnormal amino acid metabolism may thus be an important factor in malaria pathogenesis. We sought to determine if other amino acid abnormalities are associated with disease severity in falciparum malaria. Subjects were enrolled in Dar es Salaam, Tanzania (children) (n = 126), and Papua, Indonesia (adults) (n = 156), in two separate studies. Plasma samples were collected from subjects with WHO-defined cerebral malaria (children), all forms of severe malaria (adults), and uncomplicated malaria (children and adults). Healthy children and adults without fever or illness served as controls. Plasma amino acids were measured using reverse-phase high-performance liquid chromatography with fluorescence detection. Several plasma amino acids were significantly lower in the clinical malaria groups than in healthy controls. Despite the differences, phenylalanine was the only amino acid with mean levels outside the normal range (40 to 84 microM) and was markedly elevated in children with cerebral malaria (median [95% confidence interval], 163 [134 to 193] microM; P < 0.0001) and adults with all forms of severe malaria (median [95% confidence interval], 129 [111 to 155] microM; P < 0.0001). In adults who survived severe malaria, phenylalanine levels returned to normal, with clinical improvement (P = 0.0002). Maintenance of plasma phenylalanine homeostasis is disrupted in severe malaria, leading to significant hyperphenylalaninemia. This is likely a result of an acquired abnormality in the function of the liver enzyme phenylalanine hydroxylase. Determination of the mechanism of this abnormality may contribute to the understanding of neurological complications in malaria.
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PMID:Elevated plasma phenylalanine in severe malaria and implications for pathophysiology of neurological complications. 1671 64

Nutrient amino acid transporters (NATs, subfamily of sodium neurotransmitter symporter family SNF, a.k.a. SLC6) represent a set of phylogenetically and functionally related transport proteins, which perform intracellular absorption of neutral, predominantly essential amino acids. Functions of NATs appear to be critical for the development and survival in organisms. However, mechanisms of specific and synergetic action of various NAT members in the amino acid transport network are virtually unexplored. A new transporter, agNAT8, was cloned from the malaria vector mosquito Anopheles gambiae (SS). Upon heterologous expression in Xenopus oocytes it performs high-capacity, sodium-coupled (2:1) uptake of nutrients with a strong preference for aromatic catechol-branched substrates, especially phenylalanine and its derivatives tyrosine and L-DOPA, but not catecholamines. It represents a previously unknown SNF phenotype, and also appears to be the first sodium-dependent B(0) type transporter with a narrow selectivity for essential precursors of catecholamine synthesis pathways. It is strongly and specifically transcribed in absorptive and secretory parts of the larval alimentary canal and specific populations of central and peripheral neurons of visual-, chemo- and mechano-sensory afferents. We have identified a new SNF transporter with previously unknown phenotype and showed its important role in the accumulation and redistribution of aromatic substrates. Our results strongly suggest that agNAT8 is an important, if not the major, provider of an essential catechol group in the synthesis of catecholamines for neurochemical signaling as well as ecdysozoan melanization and sclerotization pathways, which may include cuticle hardening/coloring, wound curing, oogenesis, immune responses and melanization of pathogens.
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PMID:Molecular characterization of the first aromatic nutrient transporter from the sodium neurotransmitter symporter family. 1688 66

Mosquitoes are unique in having evolved two alanine glyoxylate aminotransferases (AGTs). One is 3-hydroxykynurenine transaminase (HKT), which is primarily responsible for catalyzing the transamination of 3-hydroxykynurenine (3-HK) to xanthurenic acid (XA). Interestingly, XA is used by malaria parasites as a chemical trigger for their development within the mosquito. This 3-HK to XA conversion is considered the major mechanism mosquitoes use to detoxify the chemically reactive and potentially toxic 3-HK. The other AGT is a typical dipteran insect AGT and is specific for converting glyoxylic acid to glycine. Here we report the 1.75A high-resolution three-dimensional crystal structure of AGT from the mosquito Aedes aegypti (AeAGT) and structures of its complexes with reactants glyoxylic acid and alanine at 1.75 and 2.1A resolution, respectively. This is the first time that the three-dimensional crystal structures of an AGT with its amino acceptor, glyoxylic acid, and amino donor, alanine, have been determined. The protein is dimeric and adopts the type I-fold of pyridoxal 5-phosphate (PLP)-dependent aminotransferases. The PLP co-factor is covalently bound to the active site in the crystal structure, and its binding site is similar to those of other AGTs. The comparison of the AeAGT-glyoxylic acid structure with other AGT structures revealed that these glyoxylic acid binding residues are conserved in most AGTs. Comparison of the AeAGT-alanine structure with that of the Anopheles HKT-inhibitor complex suggests that a Ser-Asn-Phe motif in the latter may be responsible for the substrate specificity of HKT enzymes for 3-HK.
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PMID:Crystal structures of Aedes aegypti alanine glyoxylate aminotransferase. 1699 Feb 63

Mutations in the dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genes of Plasmodium falciparum have been correlated with and used to detect antifolate treatment failure, such as sulfadoxine-pyrimethamine (SP), in regions endemic for malaria. To determine the association between molecular markers of SP resistance and in vivo drug resistance, a quick and simple technique that detects single nucleotide polymorphisms in the DHFR and DHPS genes, using PCR-ELISA and sequence-specific oligonucleotide probes, was applied to 53 isolates obtained from an in vivo study in Sistan and Baluchistan Province, in southeastern Iran. Overall, 11.3% of these isolates were obtained from patients with SP treatment failure. Four DHFR polymorphisms (codons 51, 59, 108, and 164) and five DHPS polymorphisms (codons 436, 437, 540, 581, and 613) were investigated. Mutations DHFR Asn-108, DHFR Arg-59, and DHPS 436-Ala/Phe were very common (100, 81.1, and 85%, respectively). Plasmodium falciparum was isolated from 96% of patients with at least two DHFR/DHPS mutations. All resistant isolates had at least three mutations. The high prevalence of mutation associated with antifolate resistance may point toward low drug efficacy in the future.
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PMID:Genotypes and in vivo resistance of Plasmodium falciparum isolates in an endemic region of Iran. 1702 59

The Indian urban malaria vector Anopheles stephensi Liston was selected for deltamethrin resistance for 25 generations (F25) at larval and adult stages separately in the laboratory. There was roughly a 151-fold increase in the lethal concentration (LC)50 and a 99-fold increase in the LC90 in larval selection, when the F25 was compared with the parent colony. Similarly, adult selection resulted in a 39-fold increase in the LC50 and a 31-fold increase in the LC90 in the adults. Knockdown bioassays conducted on adults (selected at the larval and adult stages) against the diagnostic concentration of insecticide-impregnated papers, namely, deltamethrin (0.05%), permethrin (0.75%), lambda-cyhalothrin (0.05%), and cyfluthrin (0.15%), revealed that the adults selected at the adult stage were more resistant to deltamethrin and the other pyrethroids than those selected at the larval stage. A significant cross-resistance to DDT was noticed only in the adults selected at the adult stage, and no cross-resistance to malathion and propoxur was observed in the adults of both resistant colonies. Polymerase chain reaction studies revealed an occurrence of heterozygote level of kdr mutation (leucine to phenylalanine) in the adults selected at the adult stage. This event was not observed in the adults selected at the larval stage. Moreover, this is the first report on the occurrence of kdr mutation in Indian An. stephensi resistant to deltamethrin.
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PMID:Reduced susceptibility to deltamethrin and kdr mutation in Anopheles stephensi Liston, a malaria vector in India. 1730 37

A colony of Anopheles arabiensis Patton (Diptera: Culicidae) from the Sennar region of Sudan was selected for resistance to dichlorodiphenyltrichloroethane (DDT). Adults from the F-16 generation of the resistant strain were exposed to all four classes of insecticides approved for use in malaria vector control and showed high levels of resistance to them all (24-h mortalities: malathion, 16.7%; bendiocarb, 33.3%; DDT, 12.1%; dieldrin, 0%; deltamethrin, 24.0%; permethrin, 0%). Comparisons between the unselected base colony and the DDT-resistant strain showed elevated glutathione-S-transferase (P<0.05) in both sexes and elevated esterases (P<0.05) in males only. The Leu-Phe mutation in the sodium channel gene was detected by polymerase chain reaction and sequencing, but showed no correlation with the resistant phenotype. These results do not provide any explanation as to why this colony exhibits such widespread resistance and further studies are needed to determine the precise mechanisms involved. The implications for malaria vector control in central Sudan are serious and resistance management (e.g. through the rotational use of different classes of insecticides) is recommended.
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PMID:Insecticide resistance in the malarial mosquito Anopheles arabiensis and association with the kdr mutation. 1737 52


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