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)

Plasmodium falciparum growth is impaired in glucose-6-phosphate dehydrogenase (G6PD)-deficient red blood cells (RBCs), and malaria has been implicated in the spreading of deficient variants in malaria-endemic areas. Recent reports suggest that the malaria parasite can adapt itself to grow in these variant RBCs by producing its own G6PD, but studies on parasite G6PD are very limited. In this report, we define the properties of the parasite G6PD. G6PD was partially purified from infected and uninfected variant RBCs associated with severe G6PD deficiency. G6PD from infected RBCs contained two components separable by starch gel electrophoresis: a major component (approximately 90% activity) with a very slow anodal electrophoretic mobility and a minor component (approximately 10% activity) with the same mobility as the host G6PD. Parasite G6PD exhibited much higher affinity (low Km) to G6P and nicotinamide-adenine dinucleotide phosphate (NADP) than did human G6PD. Southern blot hybridization indicated that the parasite genome contained nucleotide sequences that were hybridizable with the human G6PD cDNA. These data indicate that the parasite is capable of adapting to G6PD-deficient RBCs by producing its own G6PD.
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PMID:Glucose-6-phosphate dehydrogenase of malaria parasite Plasmodium falciparum. 355 78

A simple, efficient, sensitive, reproducible and high throughput assay for measuring the cytoadhesion of Plasmodium falciparum-infected red blood cells (human malaria) is described. The assay format uses 96-well microplates, with the number of P. falciparum parasitized erythrocytes bound determined by measuring Plasmodium specific lactic dehydrogenase activity colorimetrically (absorbance at 655 nm) using the 3-acetylpyridine analog of nicotinamide adenine dinucleotide, nitro blue tetrazolium and diaphorase. The results of the described microplate assay were found to be comparable to those using microscopic analysis but much less time consuming.
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PMID:A high capacity in vitro assay for measuring the cytoadherence of Plasmodium falciparum-infected erythrocytes. 1055 1

Many malaria control programmes are based on insecticide application as adulticides, often in the form of pyrethroid-impregnated bed nets. However, the efficacy of this control measure can be reduced by genetic changes in vector insecticide susceptibility. Pyrethroid resistance has been detected in the major African malaria vector, Anopheles gambiae, and has been attributed to a combination of target site insensitivity and increased oxidative metabolism of the insecticide, catalysed by cytochrome P450s. An adult-specific cytochrome P450 monooxygenase 6 (CYP6) P450 gene, CYP6Z1, located within a large cluster of cytochrome P450 genes in chromosome arm 3R of An. gambiae, is expressed approximately 11-fold higher in males and 4.5-fold in females from a pyrethroid-resistant strain than in a susceptible strain from the same geographical area. In both strains, CYP6Z1 expression is higher in males than females. Southern blot analysis discounted gene amplification as a cause of this overexpression. The isolation of An. gambiae cDNAs encoding cytochrome b(5) and nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH)-cytochrome P450 reductase cDNAs is also reported.
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PMID:An adult-specific CYP6 P450 gene is overexpressed in a pyrethroid-resistant strain of the malaria vector, Anopheles gambiae. 1458 2

The crystal structure of the tetrameric form of D-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) isolated from rabbit muscle was solved at 2.4 A resolution after careful dynamic light-scattering experiments to find a suitable buffer for crystallization trials. The refined model has a crystallographic R factor of 20.3%. Here, the first detailed model of a mammalian GAPDH is presented. The cofactor NAD(+) (nicotinamide adenine dinucleotide) is bound to two subunits of the tetrameric enzyme, which is consistent with the negative cooperativity of NAD(+) binding to this enzyme. The structure of rabbit-muscle GAPDH is of interest because it shares 91% sequence identity with the human enzyme; human GAPDH is a potential target for the development of anti-apoptotic drugs. In addition, differences in the cofactor-binding pocket compared with the homology-model structure of GAPDH from the malaria parasite Plasmodium falciparum could be exploited in order to develop novel selective and potential antimalaria drugs.
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PMID:Structure of rabbit-muscle glyceraldehyde-3-phosphate dehydrogenase. 1464 80

Plasmodium falciparum, the causative agent of malaria, relies extensively on glycolysis coupled with homolactic fermentation during its blood-borne stages for energy production. Selective inhibitors of the parasite lactate dehydrogenase (LDH), central to NAD(+) regeneration, therefore potentially provide a route to new antimalarial drugs directed against a novel molecular target. A series of heterocyclic, azole-based compounds are described that preferentially inhibit P. falciparum LDH at sub-micromolar concentrations, typically at concentrations about 100-fold lower than required for human lactate dehydrogenase inhibition. Crystal structures show these competitive inhibitors form a network of interactions with amino acids within the active site of the enzyme, stacking alongside the nicotinamide ring of the NAD(+) cofactor. These compounds display modest activity against parasitized erythrocytes, including parasite strains with known resistance to existing anti-malarials and against Plasmodium berghei in BALB/c mice. Initial toxicity data suggest the azole derivatives have generally low cytotoxicity, and preliminary pharmoco-kinetic data show favorable bioavailability and circulation times. These encouraging results suggest that further enhancement of these structures may yield candidates suitable for consideration as new therapeutics for the treatment of malaria. In combination these studies also provide strong support for the validity of targeting the Plasmodium glycolytic pathway and, in particular, LDH in the search for novel anti-malarials.
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PMID:Identification and activity of a series of azole-based compounds with lactate dehydrogenase-directed anti-malarial activity. 1511 37

A major manifestation of complicated malaria especially among children is severe anaemia, the pathogenesis of which is not well understood. Among other factors, suppression of the bone marrow's response to erythropoietin, which is rapidly reversed after successful treatment of the malaria, has been implicated in its pathogenesis. Since resolution of malaria restores erythropoiesis, we hypothesized that drug-resistant strains of Plasmodium falciparum would increase the risk of severe anaemia developing from initially uncomplicated malaria. Using both in vivo and in vitro drug-sensitivity tests we compared the prevalence of drug-resistant malaria between severe malarial anaemia SA and non-anaemic malaria NAM patients. Assessment of treatment outcome using the WHO in vivo criteria showed no significant difference in parasite resistance between the two groups. The mean parasite clearance time was also comparable. Treatment failures of about 14 per cent and 12 per cent were observed between SA and NAM patients respectively. The in vitro drug susceptibility test showed overall mean IC50 values of 0.41x10(-6) mol/l and 0.32x10(-6) mol/l blood for SA and NAM groups respectively. Geometric mean pre-treatment blood levels of chloroquine did not differ much between the two groups. Findings from this study could not therefore implicate drug-resistant parasites in the pathogenesis of severe malarial anaemia.
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PMID:Factors contributing to the development of anaemia in Plasmodium falciparum malaria: what about drug-resistant parasites? 1632 51

The crystal structure of D-glyceraldehyde-3-phosphate dehydrogenase (PfGAPDH) from the major malaria parasite Plasmodium falciparum is solved at 2.25 A resolution. The structure of PfGAPDH is of interest due to the dependence of the malaria parasite in infected human erythrocytes on the glycolytic pathway for its energy generation. Recent evidence suggests that PfGAPDH may also be required for other critical activities such as apical complex formation. The cofactor NAD(+) is bound to all four subunits of the tetrameric enzyme displaying excellent electron densities. In addition, in all four subunits a completely unexpected large island of extra electron density in the active site is observed, approaching closely the nicotinamide ribose of the NAD(+). This density is most likely the protease inhibitor AEBSF, found in maps from two different crystals. This putative AEBSF molecule is positioned in a crucial location and hence our structure, with expected and unexpected ligands bound, can be of assistance in lead development and design of novel antimalarials.
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PMID:Crystal structure of glyceraldehyde-3-phosphate dehydrogenase from Plasmodium falciparum at 2.25 A resolution reveals intriguing extra electron density in the active site. 1634 73

Anaemia in pregnancy has serious consequences including maternal morbidity and impairment of infant cognitive development. Several authors have however reported inconsistent findings on risk factors for anaemia in pregnancy. This study was carried out to determine risk factors for anaemia in pregnancy among women at primary care level and document the contribution of HIV/AIDS to anaemia in pregnancy in low risk pregnant women at primary care level. A prospective study carried out among pregnant women attending the booking clinics of primary health care centres in Ibadan, Nigeria. HIV positive and HIV negative mothers were followed throughout pregnancy till delivery of their babies. History of use of iron, folate, Vitamin B complex and daraprim were obtained. Haemoglobin, malaria parasitaemia, and HIV serostatus were determined. Use of iron (P < 0.006), folate (P = 0.032), vitamin B complex (P = 0.001) and treatment for malaria (P = 0.05) significantly reduced the risk for anaemia in pregnancy. Malaria parasitaemia (P = 0.0001) significantly increased the risk of anaemia. However, use of daraprim and HIV seropositivity increased the risk of anaemia in pregnancy but not significantly. In a logistic regression analysis, iron (P = 0.001) and folate supplementation (P = 0.015) significantly protected against anaemia in pregnancy while malaria parasitaemia (P = 0.006) and HIV seropositivity (P = 0.015) were significant adverse risk factors. HIV is an additional risk factor for anaemia in pregnancy. Voluntary counseling and testing of pregnant women for HIV is therefore also indicated at primary care level to detect asymptomatic anaemia in pregnancy that may be due to HIV.
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PMID:HIV as an additional risk factors for anaemia in pregnancy: evidence from primary care level in Ibadan, Southwestern Nigeria. 1674 61

Vitamin B(1) is an essential cofactor for key enzymes such as 2-oxoglutarate dehydrogenase and pyruvate dehydrogenase. Plants, bacteria and fungi, as well as Plasmodium falciparum, are capable of synthesising vitamin B(1)de novo, whereas mammals have to take up this cofactor from their diet. Thiamine, a B(1) vitamer, has to be pyrophosphorylated by thiamine pyrophosphokinase (TPK) to the active form. The human malaria parasite P. falciparum expresses an N-terminally extended pyrophosphokinase throughout the entire erythrocytic life cycle, which was analysed by Northern and Western blotting. The recombinant enzyme shows a specific activity of 27 nmol min(-1) mg(-1) protein and specificity for thiamine with a K(m) value of 73 microM, while thiamine monophosphate is not accepted. Mutational analysis of the N-terminal extension of the plasmodial TPK showed that it influences thiamine binding as well as metal dependence, which suggests N-terminal participation in the conformation of the active site. Protein sequences of various plasmodial TPKs were analysed for their phylogeny, which classified the Plasmodium TPKs to a group distinct from the mammalian TPKs. To verify the location of the parasite TPK within the cell, immunofluorescence analyses were performed. Co-staining of PfTPK with a GFP marker visualised its cytosolic localisation.
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PMID:The human malaria parasite Plasmodium falciparum expresses an atypical N-terminally extended pyrophosphokinase with specificity for thiamine. 1713 4

Pellagra is a curable dietary illness that unchecked leads to dementia, diarrhoea, dermatitis and death due to lack of the precursors for NAD(H). In addition it caused a wide range of monosyndromic degenerative and functional neurological disorders as well as profound developmental, premature aging and metabolic syndromes. Pellagrins harbour many chronic infections including tuberculosis, yeasts and malaria, that may be symbionts supplying nicotinamide adenine dinucleotide {NAD(H)} when the diet is poor. Many common diseases and aging may be caused by electrogenic energy mismatches from lack of a timely supply of NAD(H) creating disturbed metabolic fields and "protonopathies". Initially these may present in compartments fronted by homeostatic corrections from chronic symbiotic infections to inflammatory disease, cancer and degenerative/autophagic diseases that can all release NAD(H).
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PMID:Pellagra: A clue as to why energy failure causes diseases? 1734 50


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