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)

A variety of tubular marker proteins, as compared to healthy controls, are excreted at an increased rate in the urine of patients with renal damage. Beside cytoplasmic glutathione-S-transferase and lysosomal beta-N-acetyl-glucosaminidase (beta-NAG) the majority of kidney-related urine proteins derives from membrane surface components of the most vulnerable proximal tubule epithelia, among them ala-(leu-gly)-aminopeptidase, gamma-glutamyl transpeptidase (GGT), the tubular portion of angiotensinase A, the major brush border glycoprotein 'SGP-240' and adenosine-deaminase-binding protein. Urinary tissue proteins, e.g. brush border (BB) microvilli, are immunologically identical with those antigens prepared from cell membranes of the human kidney itself. BB antigens are shed into the urine of patients with glomerulonephritis, interstitial nephritis, systemic diseases, e.g. systemic lupus erythematosus (SLE), diabetes mellitus and multiple myeloma, arterial hypertension, infectious diseases (malaria, AIDS) and after operations, renal grafting and administration of X-ray contrast media, aminoglycosides or certain cytostatics (cis-platinum). Tissue proteinuria of tubular proteins is determined by enzyme-kinetic or quantitative immunological assays applying either poly- or monoclonal antikidney antibodies. Clinical, ultrastructural and histochemical studies support the idea that both 'soluble' and high-molecular-weight membrane particles (vacuolar blebs, greater than 10(6) dalton) as well as microfilamental components of the epithelial cytoskeleton contribute to tubular 'histuria' which appears as a sensitive parameter in monitoring tubular damage under clinical conditions at a very early phase.
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PMID:Urinary proteins of tubular origin: basic immunochemical and clinical aspects. 225 76

In the course of an investigation of hexosamine catabolism in the human malaria parasite, Plasmodium falciparum, it became apparent that a basic understanding of the relevant enzymatic reactions in the host erythrocyte is lacking. To acquire the necessary basic knowledge, we have determined the activities of several enzymes involved in hexosamine metabolism in normal human red blood cells. In the present communication we report the results of studies of glucosamine 6-phosphate deaminase (GlcN6-P) using a newly developed sensitive radiometric assay. The mean specific activity in extracts of fresh erythrocytes assayed within 4h of collection was 14.7 nmol/h/mg protein, whereas preparations from older erythrocytes that had been stored at 4 degrees C for up to 4 weeks had a mean specific activity of 6.2 nmol/h/mg. Characterization of the deaminase by chromatofocusing gave a pI of 8.55. The enzyme was optimally active at pH 9.0 and had a Km of 41 microM. The metal chelators EDTA and EGTA were non-inhibitory; however, inhibition was observed in the presence of metal ions, especially Cu2+, Ni2+ and Zn2+. In addition, the deaminase was also inhibited by several sugar phosphates including the reaction product, fructose 6-phosphate.
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PMID:Glucosamine 6-phosphate deaminase in normal human erythrocytes. 757 55

A male patient presented with malaria tertiana due to Plasmodium vivax. He developed a severe attack of rhabdomyolysis with acute renal failure. The patient was treated successfully with chloroquine medication. After complete recovery further muscle study revealed a deficiency of myoadenyl deaminase (MAD). The infection with P. vivax probably has been the triggering factor in the process of muscle necrosis, because the patient also had MAD deficiency.
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PMID:Rhabdomyolysis associated with malaria tertiana in a patient with myoadenylate deaminase deficiency. 851 18

The pathways of glucose utilization for energy production in the malaria parasite, Plasmodium falciparum, have been studied extensively. Little is known, however, about the reactions by which glucose is converted into complex carbohydrates in the parasite, and knowledge of the catabolism of these substances is likewise scanty. The present investigation was undertaken to determine whether the parasites possess a key enzyme of glucosamine catabolism, i.e. glucosamine 6-phosphate deaminase (EC 5.3.1.40), which catalyses the conversion of the sugar phosphate to fructose 6-phosphate and ammonia. Lysates of Plasmodium-infected erythrocytes had substantially higher deaminase activity than control samples from normal erythrocytes, and an even higher specific activity was observed in extracts of isolated parasites, amounting to 20-40 times that of uninfected cells. Anion exchange chromatography indicated that the parasite deaminase eluted in a retarded position when compared to the elution profile of the erythrocyte enzyme. The charge difference suggested by these findings was established more directly by chromatofocusing, which indicated pI values of 6.85 and 8.55 for the parasite and erythrocyte deaminases, respectively. Other differences were also observed, notably a greater thermolability on the part of the parasite enzyme. These results indicated that the parasites synthesize a specific deaminase that is distinct from the normal erythrocyte enzyme. Studies on synchronized parasite cultures further indicated that the parasite deaminase is developmentally regulated, because a dramatic increase in activity levels occurred during the later stages of parasite development.
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PMID:Glucosamine 6-phosphate deaminase in Plasmodium falciparum. 855 58

Genomic information is rapidly accumulating for the human malaria pathogen, Plasmodium falciparum. Our ability to perform genetic manipulations to understand Plasmodium gene function is limited. Dihydrofolate reductase is the only selectable marker presently available for transfection of P. falciparum. Additional markers are needed for complementation and for expression of mutated forms of essential genes. We tested parasite sensitivity to different drugs for which selectable markers are available. Two of these drugs that were very effective as antiplasmodial inhibitors in culture, blasticidin and geneticin (G418), were selected for further study. The genes BSD, encoding blasticidin S deaminase of Aspergillus terreus, and NEO, encoding neomycin phosphotransferase II from transposon Tn 5, were expressed under the histidine-rich protein III (HRPIII) gene promoter and tested for their ability to confer resistance to blasticidin or G418, respectively. After transfection, blasticidin and G418-resistant parasites tested positive for plasmid replication and BSD or NEO expression. Cross-resistance assays indicate that these markers are independent. The plasmid copy number and the enzymatic activity depended directly on the concentration of the drug used for selection. These markers set the stage for new methods of functional analysis of the P. falciparum genome.
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PMID:A set of independent selectable markers for transfection of the human malaria parasite Plasmodium falciparum. 1041 41

With the near-completion of the genome sequence of Plasmodium falciparum, further understanding of this major human pathogen urgently requires more effective genetic tools. These must include faster and more reliable gene replacement or gene knockout techniques, essential for the analysis of gene function. We describe a serial system which uses the blasticidin S deaminase (bsd) gene of Aspergillus and the neomycin phosphotransferase II (neo) gene from transposon Tn5 as selectable markers for, respectively, transient transfection of malaria parasites and the selection of stable integrants. Challenge with blasticidin S (BS) enriches the parasite population transiently expressing the bsd gene, laying the foundation for the subsequent, much less frequent, integration event. Positive selection for this rare event is enormously facilitated by fusing the neo gene in frame to the replacement or knockout targeting gene. The sequence employed for the targeting (the polymorphic pppk-dhps gene of P. falciparum, as a model system) is truncated at the 5' end with no promoter located upstream, therefore neo cannot be expressed without specifically integrating within the genomic copy of the target gene. After BS selection, the culture is immediately exposed to geneticin (G418), leading to an apparently homogenous population of mutant parasites. As well as excluding spurious integrants at non-targeted sequences, this system greatly reduces the lengthy selection period for obtaining the desired mutants by eliminating the drug-on and drug-off cycles for the production of stable integrants, which are normally required by the single marker systems currently in use for transfection of malaria parasites.
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PMID:Rapid positive selection of stable integrants following transfection of Plasmodium falciparum. 1216 84

Plasmodium knowlesi provides a highly versatile transfection system for malaria, since it enables rapid genetic modification of the parasite both in vivo as well as in vitro. However, it is not possible to perform multiple genetic manipulations within one parasite line because of a lack of selectable markers. In an effort to develop additional selectable markers for this parasite, positive and negative selectable markers that have recently been successfully used in Plasmodium falciparum were tested. It was shown that the positive selectable markers human dihydrofolate reductase (hdhfr), blasticidin S deaminase (bsd) and neomycin phosphotransferase II (neo) all conferred drug resistance to P. knowlesi when introduced as episomes. The plasmid containing the hdhfr selectable marker was not only successfully introduced as circular form, but also as linear fragment, demonstrating for the first time single crossover integration in P. knowlesi. Thymidine kinase was tested for its potential as negative selectable marker and it was shown that recombinant P. knowlesi parasites expressing thymidine kinase from episomes were highly sensitive to ganciclovir compared to wild-type P. knowlesi. The availability of new positive selectable markers and a strong candidate for a negative selectable marker for P. knowlesi, in combination with the opportunity to perform targeted single crossover integration in P. knowlesi, significantly increases the flexibility of this transfection system, making it one of the most versatile systems available for Plasmodium.
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PMID:New selectable markers and single crossover integration for the highly versatile Plasmodium knowlesi transfection system. 1474 47

The enzyme alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD) is a zinc-dependent amidohydrolase that participates in picolinic acid (PA), quinolinic acid (QA) and NAD homeostasis. Indeed, the enzyme stands at a branch point of the tryptophan to NAD pathway, and determines the final fate of the amino acid, i.e. transformation into PA, complete oxidation through the citric acid cycle, or conversion into NAD through QA synthesis. Both PA and QA are key players in a number of physiological and pathological conditions, mainly affecting the central nervous system. As their relative concentrations must be tightly controlled, modulation of ACMSD activity appears to be a promising prospect for the treatment of neurological disorders, including cerebral malaria. Here we report the 2.0 A resolution crystal structure of human ACMSD in complex with the glycolytic intermediate 1,3-dihydroxyacetonephosphate (DHAP), refined to an R-factor of 0.19. DHAP, which we discovered to be a potent enzyme inhibitor, resides in the ligand binding pocket with its phosphate moiety contacting the catalytically essential zinc ion through mediation of a solvent molecule. Arg47, Asp291 and Trp191 appear to be the key residues for DHAP recognition in human ACMSD. Ligand binding induces a significant conformational change affecting a strictly conserved Trp-Met couple, and we propose that these residues are involved in controlling ligand admission into ACMSD. Our data may be used for the design of inhibitors with potential medical interest, and suggest a regulatory link between de novo NAD biosynthesis and glycolysis.
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PMID:The crystal structure of human alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase in complex with 1,3-dihydroxyacetonephosphate suggests a regulatory link between NAD synthesis and glycolysis. 1984 66

The factors that determine red blood cell (RBC) lifespan and the rate of RBC aging have not been fully elucidated. In several genetic conditions, including sickle cell disease, thalassemia, and G6PD deficiency, erythrocyte lifespan is significantly shortened. Many of these diseases are also associated with protection from severe malaria, suggesting a role for accelerated RBC senescence and clearance in malaria resistance. Here, we report a novel, N-ethyl-N-nitrosourea-induced mutation that causes a gain of function in adenosine 5'-monophosphate deaminase (AMPD3). Mice carrying the mutation exhibit rapid RBC turnover, with increased erythropoiesis, dramatically shortened RBC lifespan, and signs of increased RBC senescence/eryptosis, suggesting a key role for AMPD3 in determining RBC half-life. Mice were also found to be resistant to infection with the rodent malaria Plasmodium chabaudi. We propose that resistance to P. chabaudi is mediated by increased RBC turnover and higher rates of erythropoiesis during infection.
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PMID:Adenosine monophosphate deaminase 3 activation shortens erythrocyte half-life and provides malaria resistance in mice. 2746 15

To capture the transcriptional dynamics within proliferating cells, methods to differentiate nascent transcription from preexisting mRNAs are desired. One approach is to label newly synthesized mRNA transcripts in vivo through the incorporation of modified pyrimidines. However, the human malaria parasite, Plasmodium falciparum, is incapable of pyrimidine salvage for mRNA biogenesis. To capture cellular mRNA dynamics during Plasmodium development, we engineered parasites that can salvage pyrimidines through the expression of a single bifunctional yeast fusion gene, cytosine deaminase/uracil phosphoribosyltransferase (FCU). We show that expression of FCU allows for the direct incorporation of thiol-modified pyrimidines into nascent mRNAs. Using developmental stage-specific promoters to express FCU-GFP enables the biosynthetic capture and in-depth analysis of mRNA dynamics from subpopulations of cells undergoing differentiation. We demonstrate the utility of this method by examining the transcriptional dynamics of the sexual gametocyte stage transition, a process that is essential to malaria transmission between hosts. Using the pfs16 gametocyte-specific promoter to express FCU-GFP in 3D7 parasites, we found that sexual stage commitment is governed by transcriptional reprogramming and stabilization of a subset of essential gametocyte transcripts. We also measured mRNA dynamics in F12 gametocyte-deficient parasites and demonstrate that the transcriptional program required for sexual commitment and maturation is initiated but likely aborted due to the absence of the PfAP2-G transcriptional regulator and a lack of gametocyte-specific mRNA stabilization. Biosynthetic labeling of Plasmodium mRNAs is incredibly versatile, can be used to measure transcriptional dynamics at any stage of parasite development, and will allow for future applications to comprehensively measure RNA-protein interactions in the malaria parasite.
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PMID:Capturing in vivo RNA transcriptional dynamics from the malaria parasite Plasmodium falciparum. 2841 33


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