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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The essential steps of the novel non-mevalonate pathway of isopentenyl diphosphate and isoprenoid biosynthesis in plants are described. The first five enzymes and genes of this 1-deoxy-D-xylulose 5-phosphate/2-C-methyl-D-erythritol 4-phosphate (DOXP/MEP) pathway are known. The herbicide fosmidomycin specifically blocks the second enzyme, the DOXP reductoisomerase. The DOXP/MEP pathway is also present in several pathogenic bacteria and the malaria parasite. Hence, all herbicides and inhibitors blocking this novel isoprenoid pathway in plants are also potential drugs against malaria and diseases caused by pathogenic bacteria.
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PMID:Non-mevalonate isoprenoid biosynthesis: enzymes, genes and inhibitors. 1117 Dec 8

Isoprenoids are biosynthesized from isopentenyl diphosphate and the isomeric dimethylallyl diphosphate via the mevalonate pathway or a mevalonate-independent pathway that was identified during the last decade. The non-mevalonate pathway is present in many bacteria, some algae and in certain protozoa such as the malaria parasite Plasmodium falciparum and in the plastids of higher plants, but not in mammals and archaea. Therefore, these enzymes have been recognised as promising drug targets. We report the crystal structure of Escherichia coli 2C- methyl-d-erythritol-2,4-cyclodiphosphate synthase (IspF), which converts 4-diphosphocytidyl-2C-methyl-d-erythritol 2-phosphate into 2C-methyl-d-erythritol 2,4-cyclodiphosphate and CMP in a Mg-dependent reaction. The protein forms homotrimers that tightly bind one zinc ion per subunit at the active site, which helps to position the substrate for direct attack of the 2-phosphate group on the beta-phosphate.
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PMID:Structure of 2C-methyl-d-erythritol-2,4-cyclodiphosphate synthase involved in mevalonate-independent biosynthesis of isoprenoids. 1182 4

Higher plants, several algae, bacteria, some strains of Streptomyces and possibly malaria parasite Plasmodium falciparum contain the novel, plastidic DOXP/MEP pathway for isoprenoid biosynthesis. This pathway, alternative with respect to the classical mevalonate pathway, starts with condensation of pyruvate and glyceraldehyde-3-phosphate which yields 1-deoxy-D-xylulose 5-phosphate (DOXP); the latter product can be converted to isopentenyl diphosphate (IPP) and eventually to isoprenoids or thiamine and pyridoxal. Subsequent reactions of this pathway involve transformation of DOXP to 2-C-methyl-D-erythritol 4-phosphate (MEP) which after condensation with CTP forms 4-diphosphocytidyl-2-amethyl-D-erythritol (CDP-ME). Then CDP-ME is phosphorylated to 4-diphosphocytidyl-2-amethyl-D-erythritol 2-phosphate (CDP-ME2P) and to 2-C-methyl-D-erythritol-2,4-cyclodiphosphate (ME-2,4cPP) which is the last known intermediate of the DOXP/MEP pathway. For- mation of IPP and dimethylallyl diphosphate (DMAPP) from ME-2,4cPP still requires clarification. This novel pathway appears to be involved in biosynthesis of carotenoids, phytol (side chain of chlorophylls), isoprene, mono-, di-, tetraterpenes and plastoquinone whereas the mevalonate pathway is responsible for formation of sterols, sesquiterpenes and triterpenes. Several isoprenoids were found to be of mixed origin suggesting that some exchange and/or cooperation exists between these two pathways of different biosynthetic origin. Contradictory results described below could indicate that these two pathways are operating under different physiological conditions of the cell and are dependent on the developmental state of plastids.
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PMID:Isoprenoid biosynthesis via 1-deoxy-D-xylulose 5-phosphate/2-C-methyl-D-erythritol 4-phosphate (DOXP/MEP) pathway. 1183 75

Isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) are the precursors for all isoprenoid compounds. Two pathways are found in Nature for their biosynthesis. The mevalonate (MVA) pathway is found in eukaryotes, algae, archae and some gram-positive bacteria. Gram-negative bacteria, plants and some gram-positive bacteria utilize the methyl erythritol phosphate (MEP) pathway. The distribution and the orthogonal nature of the pathways make the MEP pathway an attractive new target for antibiotics and herbicides. The MEP pathway is essential for bacterial viability. Inhibitors to the MEP pathway represent a "dual-use technology" because potential targets include potential biological warfare agents in addition to common human pathogens. The CDC has three categories designated for Biological Diseases/Agents. Three of the six entities designated as the highest priority (Category A) are organisms that utilize, or appear to utilize, the MEP pathway. Among the 12 second highest priority agents (Category B) listed, 8 are organisms that appear to utilize the MEP pathway. Common human pathogens that can be targeted include the organisms responsible for peptic ulcers, tuberculosis, malaria, food safety threats, and sexually transmitted diseases. There is so far only one inhibitor reported that specifically blocks the MEP pathway and is being investigated clinically. This compound, fosmidomycin, has been shown to be somewhat effective in treating Plasmodium falciparum, the parasite responsible for malaria. We foresee that new MEP pathway inhibitors will open up an entirely new class of antibiotics. An MEP pathway intermediate has also been shown to be the most potent gammadelta T cell activator.
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PMID:The methylerythritol phosphate pathway and its significance as a novel drug target. 1452 27

A number of parasitic protists and fungi have adopted extremely specialised characteristics of morphology, biochemistry, and molecular biology, sometimes making it difficult to discern their evolutionary origins. One aspect of several parasitic groups that reflects this is their metabolic organelles, mitochondria and plastids. These organelles are derived from endosymbiosis with an alpha-proteobacterium and a cyanobacterium respectively, and are home to a variety of core metabolic processes. As parasites adapted, new demands, or perhaps a relaxation of demands, frequently led to significant changes in these organelles. At the extreme, the organelles are degenerated and transformed beyond recognition, and are referred to as "cryptic". Generally, there is no prior cytological evidence for a cryptic organelle, and its presence is only discovered through phylogenetic analysis of molecular relicts followed by their localisation to organelle-like structures. Since the organelles are derived from eubacteria, the genes for proteins and RNAs associated with them are generally easily recognisable, and since the metabolic activities retained in these organelles are prokaryotic, or at least very unusual, they often serve as an important target for therapeutics. Cryptic mitochondria are now known in several protist and fungal parasites. In some cases (e.g., Trichomonas), well characterised but evolutionarily enigmatic organelles called hydrogenosomes were shown to be derived from mitochondria. In other cases (e.g., Entamoeba and microsporidia), "amitochondriate" parasites have been shown to harbour a previously undetected mitochondrial organelle. Typically, little is known about the functions of these newly discovered organelles, but recent progress in several groups has revealed a number of potential functions. Cryptic plastids have now been found in a small number of parasites that were not previously suspected to have algal ancestors. One recent case is the discovery that helicosporidian parasites are really highly adapted green alga, but the most spectacular case is the discovery of a plastid in the Apicomplexa. Apicomplexa are very well-studied parasites that include the malaria parasite, Plasmodium, so the discovery of a cryptic plastid in Apicomplexa came as quite a surprise. The apicomplexan plastid is now very well characterised and has been shown to function in the biosynthesis of fatty acids, isopentenyl diphosphate and heme, activities also found in photosynthetic plastids.
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PMID:Cryptic organelles in parasitic protists and fungi. 1471 Oct 83

The mevalonate-independent methylerythritol phosphate pathway is a long overlooked metabolic pathway for isoprenoid biosynthesis. It is present in most bacteria, including pathogens and opportunistic pathogens, in some unicellular eukaryotes, including the parasite responsible for malaria, and in the chloroplasts of all phototrophic organisms. It represents an alternative to the mevalonate pathway, which is only present in animals, fungi, the plant cytoplasm, archaebacteria and some eubacteria. This biosynthetic pathway is thus a potential target for antibacterial and antiparasitic drugs. An isopentenyl diphosphate isomerase that differs from the previously known isopentenyl diphosphate isomerase found in all other organisms, including animals, was discovered in several Gram-positive bacteria possessing the mevalonate pathway, adding another target related to isoprenoid biosynthesis.
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PMID:Isoprenoid biosynthesis as a novel target for antibacterial and antiparasitic drugs. 1504 89

Isoprenoids, a diverse group of compounds derived from the five-carbon building units isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP), are essential for survival in all organisms. Animals synthesize their isoprenoids from mevalonic acid (MVA), whereas most pathogenic bacteria and the malaria parasites utilize a completely different pathway for IPP and DMAPP synthesis, the methylerythritol phosphate (MEP) pathway. Plants use both pathways for the synthesis of isoprenoid precursors. The recent elucidation of the MEP pathway has opened the possibility to develop new strategies against microbial pathogens. Novel immunotherapeutic agents can be developed based on the MEP pathway intermediates known to activate the proliferation of human V-delta-9 V-gamma-2 T-cells after infection by many pathogenic bacteria and protozoa. Moreover, the design of specific inhibitors of MEP pathway enzymes (which are highly conserved but show no homology to mammalian proteins) should result in herbicides and drugs with broad-spectrum antimicrobial activity without mechanism-based toxicity to humans. A good example is the cure of bacterial infections and malaria with fosmidomycin, a highly stable inhibitor of the MEP pathway. The use of plants as test systems has led to the identification of additional inhibitors such as ketoclomazone. Biochemical, genetic and crystallographic approaches with the MEP pathway enzymes are now starting to characterize the inhibition kinetics and identify which residues play a structural or catalytic role. Current efforts should eventually contribute to an effective drug designed to fight against microbial pathogens that show resistance to currently available agents.
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PMID:The MEP pathway: a new target for the development of herbicides, antibiotics and antimalarial drugs. 1527 16

IPP (isopentenyl diphosphate) and DMAPP (dimethylallyl diphosphate) serve as the universal precursors for the biosynthesis of isoprenoids. Besides the well-known mevalonate pathway, the existence of a second biosynthetic pathway conducive to IPP and DMAPP formation through 1-deoxy-D-xylulose 5-phosphate and 2C-methyl-D-erythritol 4-phosphate was discovered approx. 10 years ago in plants and certain eubacteria. It is now known that this pathway is widely distributed in the bacterial kingdom including major human pathogens, such as Mycobacterium tuberculosis and Helicobacter pylori. The pathway is also essential in the malaria vector Plasmodium falciparum. During the last few years, the genes, enzymes, intermediates and mechanisms of the biosynthetic route have been elucidated by a combination of comparative genomics, enzymology, advanced NMR technology and crystallography. The results provide the basis for the development of novel anti-infective drugs.
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PMID:Isoprenoid biosynthetic pathways as anti-infective drug targets. 1604 99

Biosynthesis of the universal terpenoid precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), from three acetyl CoA moieties through mevalonate was studied extensively in the 1950s. For several decades, the mevalonate paradigm reigned supreme and a mevalonate origin was attributed to a growing number of natural products, in many cases erroneously. Besides this biosynthetic pathway, the existence of a second one leading to IPP and DMAPP through 1-deoxy-D-xylulose 5-phosphate and 2C-methyl-D-erythritol 4-phosphate was discovered more recently in plants and some eubacteria. This pathway is widely distributed in the bacterial kingdom including major human pathogens, such as Mycobacterium tuberculosis or Helicobacter pylori and is also essential in the malaria vector Plasmodium falciparum. During the last few years, the genes, enzymes, intermediates and mechanisms of the biosynthetic route have been elucidated by a combination of methods including comparative genomics, enzymology, advanced NMR technology and crystallography. The present crystallographic review of enzymes involved in isoprenoid biosynthesis will be useful for understanding the various catalytic mechanisms and could potentially help for structure-based drug design.
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PMID:Structure-based drug design targeting biosynthesis of isoprenoids: a crystallographic state of the art of the involved enzymes. 1839 84

Molecular evolution has evolved two metabolic routes for isoprenoid biosynthesis: the mevalonate and the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway. The MEP pathway is used by most pathogenic bacteria and some parasitic protozoa (including the malaria parasite, Plasmodium falciparum) as well as by plants, but is not present in animals. The terminal reaction of the MEP pathway is catalyzed by (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) reductase (LytB), an enzyme that converts HMBPP into isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Here, we present the structure of Aquifex aeolicus LytB, at 1.65 A resolution. The protein adopts a cloverleaf or trefoil-like structure with each monomer in the dimer containing three alpha/beta domains surrounding a central [Fe3S4] cluster ligated to Cys13, Cys96, and Cys193. Two highly conserved His (His 42 and His 124) and a totally conserved Glu (Glu126) are located in the same central site and are proposed to be involved in ligand binding and catalysis. Substrate access is proposed to occur from the front-side face of the protein, with the HMBPP diphosphate binding to the two His and the 4OH of HMBPP binding to the fourth iron thought to be present in activated clusters, while Glu126 provides the protons required for IPP/DMAPP formation.
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PMID:Structure of (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate reductase, the terminal enzyme of the non-mevalonate pathway. 1903 30


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