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)

Polyamine biosynthesis of the malaria parasite, Plasmodium falciparum, is regulated by a single, hinge-linked bifunctional PfAdoMetDC/ODC [ P. falciparum AdoMetDC (S-adenosylmethionine decarboxylase)/ODC (ornithine decarboxylase)] with a molecular mass of 330 kDa. The bifunctional nature of AdoMetDC/ODC is unique to Plasmodia and is shared by at least three species. The PfAdoMetDC/ODC contains four parasite-specific regions ranging in size from 39 to 274 residues. The significance of the parasite-specific inserts for activity and protein-protein interactions of the bifunctional protein was investigated by a single- and multiple-deletion strategy. Deletion of these inserts in the bifunctional protein diminished the corresponding enzyme activity and in some instances also decreased the activity of the neighbouring, non-mutated domain. Intermolecular interactions between AdoMetDC and ODC appear to be vital for optimal ODC activity. Similar results have been reported for the bifunctional P. falciparum dihydrofolate reductase-thymidylate synthase [Yuvaniyama, Chitnumsub, Kamchonwongpaisan, Vanichtanankul, Sirawaraporn, Taylor, Walkinshaw and Yuthavong (2003) Nat. Struct. Biol. 10, 357-365]. Co-incubation of the monofunctional, heterotetrameric approximately 150 kDa AdoMetDC domain with the monofunctional, homodimeric ODC domain (approximately 180 kDa) produced an active hybrid complex of 330 kDa. The hinge region is required for bifunctional complex formation and only indirectly for enzyme activities. Deletion of the smallest, most structured and conserved insert in the ODC domain had the biggest impact on the activities of both decarboxylases, homodimeric ODC arrangement and hybrid complex formation. The remaining large inserts are predicted to be non-globular regions located on the surface of these proteins. The large insert in AdoMetDC in contrast is not implicated in hybrid complex formation even though distinct interactions between this insert and the two domains are inferred from the effect of its removal on both catalytic activities. Interference with essential protein-protein interactions mediated by parasite-specific regions therefore appears to be a viable strategy to aid the design of selective inhibitors of polyamine metabolism of P. falciparum.
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PMID:Parasite-specific inserts in the bifunctional S-adenosylmethionine decarboxylase/ornithine decarboxylase of Plasmodium falciparum modulate catalytic activities and domain interactions. 1297 75

In the malaria parasite, the two main regulatory activities of polyamine biosynthesis, ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC) occur in a single bifunctional protein. The AdoMetDC domain was modeled using the human and potato X-ray crystal structures as templates. Three parasite-specific inserts and the core active site region was identified using a structure-based alignment approach. The domain was modeled without the two largest inserts, to give a root mean square deviation of 1.85 angstroms from the human template. Contact with the rest of the bifunctional complex is predicted to occur on one face of the Plasmodium falciparum AdoMetDC (PfAdoMetDC) domain. In the active site there are four substitutions compared to the human template. One of these substitutions may be responsible for the lack of inhibition by Tris, compared to mammalian AdoMetDC. The model also provides an explanation for the lack of putrescine stimulation in PfAdoMetDC compared to mammalian AdoMetDC. A network of residues that connects the putrescine-binding site with the active site in human AdoMetDC is conserved in the malarial and plant cognates. Internal basic residues are found to assume the role of putrescine, based on the model and site-directed mutagenesis: Arg11 is absolutely required for normal activity, while disrupting Lys15 and Lys215 each cause 50% inhibition of AdoMetDC activity. These novel features of malarial AdoMetDC suggest possibilities for the discovery of parasite-specific inhibitors.
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PMID:Novel properties of malarial S-adenosylmethionine decarboxylase as revealed by structural modelling. 1625 47

The vitamin B(6)-derived pyridoxal 5'-phosphate (PLP) is the cofactor of enzymes catalyzing a large variety of chemical reactions mainly involved in amino acid metabolism. These enzymes have been divided in five families and fold types on the basis of evolutionary relationships and protein structural organization. Almost 1.5% of all genes in prokaryotes code for PLP-dependent enzymes, whereas the percentage is substantially lower in eukaryotes. Although about 4% of enzyme-catalyzed reactions catalogued by the Enzyme Commission are PLP-dependent, only a few enzymes are targets of approved drugs and about twenty are recognised as potential targets for drugs or herbicides. PLP-dependent enzymes for which there are already commercially available drugs are DOPA decarboxylase (involved in the Parkinson disease), GABA aminotransferase (epilepsy), serine hydroxymethyltransferase (tumors and malaria), ornithine decarboxylase (African sleeping sickness and, potentially, tumors), alanine racemase (antibacterial agents), and human cytosolic branched-chain aminotransferase (pathological states associated to the GABA/glutamate equilibrium concentrations). Within each family or metabolic pathway, the enzymes for which drugs have been already approved for clinical use are discussed first, reporting the enzyme structure, the catalytic mechanism, the mechanism of enzyme inactivation or modulation by substrate-like or transition state-like drugs, and on-going research for increasing specificity and decreasing side-effects. Then, PLP-dependent enzymes that have been recently characterized and proposed as drug targets are reported. Finally, the relevance of recent genomic analysis of PLP-dependent enzymes for the selection of drug targets is discussed.
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PMID:Pyridoxal 5'-phosphate enzymes as targets for therapeutic agents. 1750 14

Abstract Polyamines are essential polycationic molecules involved in multiple cellular events, including cell differentiation, division and death. Inhibition of polyamine biosynthesis has been considered in diverse therapeutic strategies ranging from tumour suppressors to anti-parasitic agents. In the human malaria parasite, Plasmodium falciparum, inhibition of ornithine decarboxylase (ODC) results in the arrest of schizogony due to polyamine depletion. However, the exact physiological role of the polyamines in the parasite is unknown. Here, we present results of the depletion of polyamines in the malaria parasite by alpha-difluoromethylornithine inhibition of ODC, as observed with differential transcriptome profiling. Upon depletion of their endogenous polyamines, the up- and downregulated parasite transcripts were selected with suppression subtractive hybridisation and differences were detected using blots or DNA microarrays. A direct linkage between polyamine depletion and the differential expression of two distinct transcripts was observed, indicating the existence of a transcriptional feedback response in the P. falciparum transcriptome upon drug challenge. The data presented provide input into the role of the polyamines in the cellular biology of P. falciparum and contribute towards the validation of polyamine biosynthesis as an antimalarial target.
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PMID:Transcriptional responses of Plasmodium falciparum to alpha-difluoromethylornithine-induced polyamine depletion. 1816 86

More than 30 years ago the potent ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) was designed as new anticancer drug. Its efficacy was not as expected since the polyamine metabolism in mammalian cells seemed to be far more complex. However when DFMO was applied to African trypanosomes its effect on this protozoan parasite was highly convincing. Thenceforward many researchers tested DFMO and also other polyamine synthesis inhibitors against different parasites among them the causative agent of malaria Plasmodium. This review recapitulates the different attempts to interfere chemically with the plasmodial polyamine metabolism, the impact on the disease as well as its biochemical and molecular background. It will show that this fast proliferating organism depends for growth on high amounts of polyamines and that Plasmodium has its own and unique polyamine synthesis, differing highly from the mammalian one mainly in the arrangement of the key enzymes, S-adenosylmethionine decarboxylase and ornithine decarboxylase (AdoMetDC/ODC), on a bifunctional protein.
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PMID:Assessing the polyamine metabolism of Plasmodium falciparum as chemotherapeutic target. 1845 48

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

New drugs are urgently needed for the treatment of tropical and subtropical parasitic diseases, such as African sleeping sickness, Chagas' disease, leishmaniasis and malaria. Enzymes in polyamine biosynthesis and thiol metabolism, as well as polyamine transporters, are potential drug targets within these organisms. In the present review, the current knowledge of unique properties of polyamine metabolism in these parasites is outlined. These properties include prozyme regulation of AdoMetDC (S-adenosylmethionine decarboxylase) activity in trypanosomatids, co-expression of ODC (ornithine decarboxylase) and AdoMetDC activities in a single protein in plasmodia, and formation of trypanothione, a unique compound linking polyamine and thiol metabolism in trypanosomatids. Particularly interesting features within polyamine metabolism in these parasites are highlighted for their potential in selective therapeutic strategies.
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PMID:Polyamine homoeostasis as a drug target in pathogenic protozoa: peculiarities and possibilities. 2183 94

Malaria is a deadly infectious disease which affects millions of people each year in tropical regions. There is no effective vaccine available and the treatment is based on drugs which are currently facing an emergence of drug resistance and in this sense the search for new drug targets is indispensable. It is well established that vitamin biosynthetic pathways, such as the vitamin B6 de novo synthesis present in Plasmodium, are excellent drug targets. The active form of vitamin B6, pyridoxal 5-phosphate, is, besides its antioxidative properties, a cofactor for a variety of essential enzymes present in the malaria parasite which includes the ornithine decarboxylase (ODC, synthesis of polyamines), the aspartate aminotransferase (AspAT, involved in the protein biosynthesis), and the serine hydroxymethyltransferase (SHMT, a key enzyme within the folate metabolism).
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PMID:Vitamin B6-dependent enzymes in the human malaria parasite Plasmodium falciparum: a druggable target? 2452 72

The Apicomplexa parasite Plasmodium is a major cause of death in developing countries which are less equipped to bring new medicines to the market. Currently available drugs used for treatment of malaria are limited either by inadequate efficacy, toxicity and/or increased resistance. Availability of the genome sequence, microarray data and metabolic profile of Plasmodium parasite offers an opportunity for the identification of stage-specific genes important to the organism's lifecycle. In this study, microarray data were analysed for differential expression and overlapped onto metabolic pathways to identify differentially regulated pathways essential for transition to successive erythrocytic stages. The results obtained indicate that S-adenosylmethionine decarboxylase/ornithine decarboxylase, a bifunctional enzyme required for polyamine synthesis, is important for the Plasmodium cell growth in the absence of exogenous polyamines. S-adenosylmethionine decarboxylase/ornithine decarboxylase is a valuable target for designing therapeutically useful inhibitors. One such inhibitor, [Formula: see text]-difluoromethyl ornithine, is currently in use for the treatment of African sleeping sickness caused by Trypanosoma brucei. Structural studies of ornithine decarboxylase along with known inhibitors and their analogues were carried out to screen drug databases for more effective and less toxic compounds.
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PMID:Screening of potential targets in Plasmodium falciparum using stage-specific metabolic network analysis. 2630 82

Polyamines are positively-charged organic molecules that are important for cellular growth and division. Polyamines and their synthesizing enzymes are particularly abundant in rapidly proliferating eukaryotic cells such as parasitic protozoa and cancer cells. Polyamine biosynthesis inhibitors, such as Elfornithine, are now being considered for cancer prevention and have been used effectively against Trypanosoma brucei Inhibitors of polyamine biosynthesis have caused growth arrest of Plasmodium falciparum blood stages in vitro, but in P. berghei only partial inhibition has been observed. While polyamine biosynthesis enzymes are characterized and conserved in Plasmodium spp., little is known on the biological roles of these enzymes inside malaria parasite hosts. The bifunctional polyamine biosynthesis enzyme S-adenosyl methionine decarboxylase/ornithine decarboxylase (AdoMetDC/ODC) was targeted for deletion in P. yoelii Deletion of AdoMetDC/ODC significantly reduced blood stage parasitemia but Anopheles transmission was completely blocked. We showed that male gametocytogenesis and male gamete exflagellation were abolished and consequently no ookinetes or oocyst sporozoites could be generated from adometdc/odc(-) parasites. Supplementation of putrescine and spermidine did not rescue the defective phenotypes of male gametocytes and gametes of the knockout parasites. These results highlight the crucial role of polyamine homeostasis in the development and functions of Plasmodium erythrocytic stages in the blood and in the mosquito vector and validate polyamine biosynthesis pathway enzymes as drug targeting candidates for malaria parasite transmission blocking.
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PMID:Plasmodium AdoMetDC/ODC bifunctional enzyme is essential for male sexual stage development and mosquito transmission. 2738 33


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