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)

The human malaria parasite Plasmodium falciparum synthesizes fatty acids using a type II pathway that is absent in humans. The final step in fatty acid elongation is catalyzed by enoyl acyl carrier protein reductase, a validated antimicrobial drug target. Here, we report the cloning and expression of the P. falciparum enoyl acyl carrier protein reductase gene, which encodes a 50-kDa protein (PfENR) predicted to target to the unique parasite apicoplast. Purified PfENR was crystallized, and its structure resolved as a binary complex with NADH, a ternary complex with triclosan and NAD(+), and as ternary complexes bound to the triclosan analogs 1 and 2 with NADH. Novel structural features were identified in the PfENR binding loop region that most closely resembled bacterial homologs; elsewhere the protein was similar to ENR from the plant Brassica napus (root mean square for Calphas, 0.30 A). Triclosan and its analogs 1 and 2 killed multidrug-resistant strains of intra-erythrocytic P. falciparum parasites at sub to low micromolar concentrations in vitro. These data define the structural basis of triclosan binding to PfENR and will facilitate structure-based optimization of PfENR inhibitors.
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PMID:Structural elucidation of the specificity of the antibacterial agent triclosan for malarial enoyl acyl carrier protein reductase. 1179 10

Malarial resistance is an escalating global problem and consequently new and more efficacious treatments to combat malaria are urgently needed. The transdermal delivery of anti-malarials may provide an effective alternative or adjunct to conventional regimens. Triclosan is widely used as an anti-bacterial agent and it has recently been demonstrated that this compound has anti-malarial properties. Its high lipophilicity makes it a potential candidate for delivery across the skin and this paper examines in vitro the potential for the transdermal delivery of triclosan from 'drug-in-glue' formulations. Model patches were prepared using DuroTak 2287, 2516 and 2051 acrylic polymer adhesives loaded with 0, 30 and 50 mg per 0.785 cm(-2) triclosan and dissolution was measured over a 12-h period. There was no apparent difference between the adhesives at the 30 mg patch loading, but at 50 mg, the trend for increased release was 2051>2516>2287. No significant burst effect was apparent. Patches of 50 mg per 0.785 cm2 were then used to determine the permeation of triclosan across heat-separated human epidermal membranes in Franz diffusion cells, over a period of 48 h. The above general trend was reflected in the steady state flux values obtained: 2051:16.91 microg x cm(-2) x h(-1) (S.E.M. 1.29), 2516:15.05 microg x cm(-2) x h(-1) (S.E.M. 1.00), 2287 12.83 microg x cm(-2) x h(-1) (S.E.M. 2.81). Although pharmacokinetic data are not currently available to permit calculation of an efficacious patch size, the transdermal delivery of triclosan is feasible.
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PMID:Triclosan: release from transdermal adhesive formulations and in vitro permeation across human epidermal membranes. 1187 57

Triclosan, a known antibacterial, acts by inhibiting enoyl-ACP (acyl-carrier protein) reductase (ENR), a key enzyme of the type II fatty acid synthesis (FAS) system. Plasmodium falciparum, the human malaria-causing parasite, harbours the type II FAS; in contrast, its human host utilizes type I FAS. Due to this striking difference, ENR has emerged as an important target for the development of new antimalarials. Modelling studies, and the crystal structure of P. falciparum ENR, have highlighted the features of ternary complex formation between the enzyme, triclosan and NAD+ [Suguna, A. Surolia and N. Surolia (2001) Biochem. Biophys. Res. Commun. 283, 224-228; Perozzo, Kuo, Sidhu, Valiyaveettil, Bittman, Jacobs, Fidock, and Sacchettini (2002) J. Biol. Chem. 277, 13106-13114; and Swarnamukhi, Kapoor, N. Surolia, A. Surolia and Suguna (2003) PDB1UH5]. To address the issue of the importance of the residues involved in strong specific and stoichiometric binding of triclosan to P. falciparum ENR, we mutated the following residues: Ala-217, Asn-218, Met-281, and Phe-368. The affinity of all the mutants was reduced for triclosan as compared with the wild-type enzyme to different extents. The most significant mutation was A217V, which led to a greater than 7000-fold decrease in the binding affinity for triclosan as compared with wild-type PfENR. A217G showed only 10-fold reduction in the binding affinity. Thus, these studies point out significant differences in the triclosan-binding region of the P. falciparum enzyme from those of its bacterial counterparts.
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PMID:Mutational analysis of the triclosan-binding region of enoyl-ACP (acyl-carrier protein) reductase from Plasmodium falciparum. 1513 52

Apicomplexan parasites infectious to humans include Plasmodium spp., Babesia spp., Toxoplasma gondii, Cryptosporidium spp., Isospora belli and Cyclospora cayetanensis. With exception of Cryptosporidium spp., these parasites possess a non-photosynthetic plastid-like organelle called apicoplast. The apicoplast possesses a small circular genome and harbours prokaryotic-type biochemical pathways. As the most important metabolic functions, the mevalonate independent 1-deoxy-D-xylulose 5-phosphate pathway of isoprenoid synthesis and the type II fatty acid synthesis system are operative inside the apicoplast. Classical antibacterial drugs such as ciprofloxacin, tetracycline, doxycycline, clindamycin and spiramycin inhibit the apicoplast-located gyrase and translation machinery, respectively, and are currently used in the clinic for the treatment of infections with apicomplexan parasites. As an inhibitor of isoprenoid synthesis, fosmidomycin was proven to be effective against acute P. falciparum malaria in clinical phase II studies. Triclosan, an inhibitor of fatty acid synthesis, was active in a malaria mouse model. In vitro antimalarial activity was shown for inhibitors of peptide deformylase and the import of apicoplast-targeted proteins. Work on various other inhibitors of apicoplast-located biochemical processes is ongoing.
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PMID:The plastid-like organelle of apicomplexan parasites as drug target. 1847 35