Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.1.2.13 (aldolase)
3,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apicomplexan parasites constitute one of the most significant groups of pathogens infecting humans and animals. The liver stage sporozoites of Plasmodium spp. and tachyzoites of Toxoplasma gondii, the causative agents of malaria and toxoplasmosis, respectively, use a unique mode of locomotion termed gliding motility to invade host cells and cross cell substrates. This amoeboid-like movement uses a parasite adhesin from the thrombospondin-related anonymous protein (TRAP) family and a set of proteins linking the extracellular adhesin, via an actin-myosin motor, to the inner membrane complex. The Plasmodium blood stage merozoite, however, does not exhibit gliding motility. Here we show that homologues of the key proteins that make up the motor complex, including the recently identified glideosome-associated proteins 45 and 50 (GAP40 and GAP50), are present in P. falciparum merozoites and appear to function in erythrocyte invasion. Furthermore, we identify a merozoite TRAP homologue, termed MTRAP, a micronemal protein that shares key features with TRAP, including a thrombospondin repeat domain, a putative rhomboid-protease cleavage site, and a cytoplasmic tail that, in vitro, binds the actin-binding protein aldolase. Analysis of other parasite genomes shows that the components of this motor complex are conserved across diverse Apicomplexan genera. Conservation of the motor complex suggests that a common molecular mechanism underlies all Apicomplexan motility, which, given its unique properties, highlights a number of novel targets for drug intervention to treat major diseases of humans and livestock.
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PMID:A conserved molecular motor drives cell invasion and gliding motility across malaria life cycle stages and other apicomplexan parasites. 1632 76

Malaria is a parasitological emergency requiring safe quick accurate diagnosis so that appropriate therapy can be implemented. A number of rapid diagnostic tests based on detection of HRP2 Ag, enzymes, LDH or aldolase are now available. However the use of these tests is restricted to trained, experienced staff in special situations. The purpose of this report is to describe the different tests on the market and clarify the limitations for their use.
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PMID:[Rapid immunochromatographic tests for detection of malaria: principles and strategies for use]. 1654 97

Malaria-specific rapid diagnostic tests (RDTs) targeting aldolase show highly variable sensitivities. We assessed diversity in Plasmodium falciparum and P. vivax aldolases by sequencing the coding genes from parasites of various origins. The results show that aldolases are highly conserved, indicating that antigenic diversity is not a cause of variable RDT sensitivity.
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PMID:Assessing the genetic diversity of the aldolase genes of Plasmodium falciparum and Plasmodium vivax and its potential effect on performance of aldolase-detecting rapid diagnostic tests. 1702 Oct 60

A complex molecular motor empowers substrate-dependent motility and host cell invasion in malaria parasites. The interaction between aldolase and the transmembrane adhesin thrombospondin-related anonymous protein (TRAP) transduces the motor force across the parasite surface. Here, we analyzed this interaction by using state-of-the-art flexible docking. Besides algorithms to account for induced fit in the side-chains of the Plasmodium falciparum aldolase (PfAldo) structure, we used additional in silico receptors modeled upon crystallographic structures of evolutionarily related aldolases to incorporate enzyme backbone flexibility, and to overcome structure inaccuracies due to the relatively low resolution (3.0 A) of the genuine PfAldo structure. Our results indicate that, in spite of multiple intermolecular contacts, only the six C-terminal residues of the TRAP cytoplasmic tail bind in an ordered manner to PfAldo. This portion of TRAP targets the PfAldo active site, with its n-1 Trp residue, which is essential for this interaction, buried within the PfAldo catalytic pocket. Docking of a TRAP peptide bearing a Trp to Ala mutation rendered the lower energy configurations either bound weakly outside the active site or not bound to PfAldo at all. The position of the bound TRAP peptide, and particularly the close proximity between the carbonyl of its n-2 Asp residue and the experimentally determined position of the phosphate-6 group of fructose 1,6-phosphate bound to mammalian aldolases, predicts an inhibitory effect of TRAP on catalysis. Enzymatic and TRAP-binding assays using mutant PfAldo molecules strongly support the overall structural model. These results might provide the initial framework for the identification of novel antiparasitic compounds.
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PMID:Modeling the interaction between aldolase and the thrombospondin-related anonymous protein, a key connection of the malaria parasite invasion machinery. 1715 57

Plasmodium falciparum is a significant cause of morbidity and mortality in travelers to areas where the parasite is endemic. Non-specific clinical manifestations may result in failure to recognize malaria until autopsy, when it is often too late to obtain whole blood for microscopic evaluation. The use of immunohistochemical (IHC) assays in the detection of three P. falciparum antigens, histidine rich protein-2 (HRP-2), aldolase, and Plasmodium lactate dehydrogenase (pLDH), was evaluated in formalin-fixed paraffin-embedded autopsy tissues from five travelers to malaria-endemic areas, whose deaths were initially suspected to have been caused by other bacterial or viral hemorrhagic fevers. The HRP-2 assay was specific for P. falciparum, whereas the aldolase and pLDH assays also reacted with P. vivax. Immunostaining patterns were predominately cytoplasmic and membranous. P. falciparum antigens were detected in a variety of organs but were most abundant in the blood vessels of brain, heart, and lung tissues.
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PMID:Fatal malaria infection in travelers: novel immunohistochemical assays for the detection of Plasmodium falciparum in tissues and implications for pathogenesis. 1729 32

An actomyosin motor located underneath the plasma membrane drives motility and host-cell invasion of apicomplexan parasites such as Plasmodium falciparum and Plasmodium vivax, the causative agents of malaria. Aldolase connects the motor actin filaments to transmembrane adhesive proteins of the thrombospondin-related anonymous protein (TRAP) family and transduces the motor force across the parasite surface. The TRAP-aldolase interaction is a distinctive and critical trait of host hepatocyte invasion by Plasmodium sporozoites, with a likely similar interaction crucial for erythrocyte invasion by merozoites. Here, we describe 2.4-A and 2.7-A structures of P. falciparum aldolase (PfAldo) obtained from crystals grown in the presence of the C-terminal hexapeptide of TRAP from Plasmodium berghei. The indole ring of the critical penultimate Trp-residue of TRAP fits snugly into a newly formed hydrophobic pocket, which is exclusively delimited by hydrophilic residues: two arginines, one glutamate, and one glutamine. Comparison with the unliganded PfAldo structure shows that the two arginines adopt new side-chain rotamers, whereas a 25-residue subdomain, forming a helix-loop-helix unit, shifts upon binding the TRAP-tail. The structural data are in agreement with decreased TRAP binding after mutagenesis of PfAldo residues in and near the induced TRAP-binding pocket. Remarkably, the TRAP- and actin-binding sites of PfAldo seem to overlap, suggesting that both the plasticity of the aldolase active-site region and the multimeric nature of the enzyme are crucial for its intriguing nonenzymatic function in the invasion machinery of the malaria parasite.
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PMID:Aldolase provides an unusual binding site for thrombospondin-related anonymous protein in the invasion machinery of the malaria parasite. 1742 53

Fructose-1,6-bisphosphate aldolase (FBPA) is an ubiquitous enzyme essential for glycolysis, gluconeogenesis and the Calvin cycle. It has been demonstrated to induce immune responses and to be useful in the immunodiagnosis of malaria. In this study, FBPA was cloned from the adult worms of Schistosoma japonicum and tested as an antigen for the diagnosis of S. japonicum infection in water buffaloes. Enzyme-linked immunosorbent assay (ELISA) was performed on the sera from 32 infected water buffaloes and 20 negative controls using the recombinant FBPA protein or soluble worm antigen preparation (SWAP) as an antigen. The OD cut-off values were determined to be 0.57 with 100% specificity and 100% sensitivity for the FBPA ELISA and 1.13 with 93.8% specificity and 95.0% sensitivity for the SWAP ELISA. These findings indicate that the recombinant FBPA of S. japonicum should be an useful diagnostic tool for the detection of antibodies against S. japonicum.
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PMID:Evaluation of recombinant fructose-1,6-bisphosphate aldolase ELISA test for the diagnosis of Schistosoma japonicum in water buffaloes. 1837 96

Efficient and specific host cell entry is of exquisite importance for intracellular pathogens. Parasites of the phylum Apicomplexa are highly motile and actively enter host cells. These functions are mediated by type I transmembrane invasins of the TRAP family that link an extracellular recognition event to the parasite actin-myosin motor machinery. We systematically tested potential parasite invasins for binding to the actin bridging molecule aldolase and complementation of the vital cytoplasmic domain of the sporozoite invasin TRAP. We show that the ookinete invasin CTRP and a novel, structurally related protein, termed TRAP-like protein (TLP), are functional members of the TRAP family. Although TLP is expressed in invasive stages, targeted gene disruption revealed a nonvital role during life cycle progression. This is the first genetic analysis of TLP, encoding a redundant TRAP family invasin, in the malaria parasite.
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PMID:Functional characterization of a redundant Plasmodium TRAP family invasin, TRAP-like protein, by aldolase binding and a genetic complementation test. 1844 Nov 24

The invasive stages of parasites of the protozoan phylum Apicomplexa have the capacity to traverse host tissues and invade host cells using a unique type of locomotion called gliding motility. Gliding motility is powered by a sub-membranous actin-myosin motor, and the force generated by the motor is transduced to the parasite surface by transmembrane proteins of the apicomplexan-specific thrombospondin-related anonymous protein (TRAP) family. These proteins possess short cytoplasmic tails that interact with the actin-myosin motor via the glycolytic enzyme aldolase. Gliding motility of the Plasmodium sporozoite, the stage of the malaria parasite that is transmitted by the mosquito to the mammalian host, depends on the TRAP protein. We describe a second protein, herein termed TREP, which also plays a role in the gliding motility of the Plasmodium sporozoite. TREP is a transmembrane protein that possesses a short cytoplasmic tail typical of members of the TRAP family of proteins, as well as a large extracellular region that contains a single thrombospondin type 1 repeat domain. TREP transcripts are expressed predominantly in oocyst stage sporozoites. Plasmodium berghei sporozoites harbouring a disrupted TREP gene have a highly diminished capacity to invade mosquito salivary glands and display a severe defect in gliding motility. We conclude that the gliding motility of the Plasmodium sporozoite in the mosquito depends on at least two proteins, TRAP and TREP.
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PMID:TREP, a novel protein necessary for gliding motility of the malaria sporozoite. 1900 Sep 11

Phage-displayed chicken single-chain antibody fragment libraries can provide useful diagnostic and research reagents. Using avian immunoglobulin genes simplifies the construction of such repertoires since far fewer primer sets are required to access the avian antibody repertoire than is the case with mice or humans. Libraries constructed using mRNA from an immune source are enriched in affinity-matured sequences and consequently need not be as large as "universal" non-immune repertoires to have a reasonable probability of yielding high-affinity binders. Repertoires focused on a number of defined targets can be constructed using lymphocyte mRNA from chickens immunized with a mixture of several different antigens. This approach was evaluated with the aim of economically and rapidly deriving immunodiagnostic reagents for malaria, trypanosomiasis, and malignant catarrhal fever, all of which are important to health or food security in Africa. Two chickens were each immunized with a mixture comprised of recombinantly expressed histidine-rich protein, the aldolase and the lactate dehydrogenase of Plasmodium falciparum, the variant surface glycoprotein of Trypanosoma sp., and purified malignant catarrhal fever virus, a herpesvirus that causes an economically important disease of cattle and other ruminants. Immune responses to each of the individual antigens were determined by extracting egg-yolk IgY and testing for antigen-specific antibodies in ELISA. The chicken splenocytes were then recovered, RNA was extracted, and after reverse transcription, the immunoglobulin VH and VL regions were amplified by PCR and joined via a single glycyl residue for surface expression on a collection of filamentous bacteriophages. The resulting display library was then screened by panning to isolate binders. The immunized chickens did not, however, respond equally well to all the different antigens, nor was it possible to derive antibody fragments against all the targets. These limitations notwithstanding, several useful binders with the potential to be used in malaria diagnosis were obtained.
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PMID:Single-chain antibody fragments from a display library derived from chickens immunized with a mixture of parasite and viral antigens. 1910 14


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