Sandbox Reserved 702: Difference between revisions
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*cyclic nucleotide gated channels | *cyclic nucleotide gated channels | ||
*guanine nucleotide exchange factor for Ras GTPase homologs Rap1 and Rap2. <ref>Fouet, A. 2009. The surface of Bacillus anthracis. Mol. Aspects Med. 30:374–385</ref> <ref>Moayeri, M., and S. H. Leppla. 2009. Cellular and systemic effects of anthrax lethal toxin and edema toxin. Mol. Aspects Med. 30:439–455</ref> | *guanine nucleotide exchange factor for Ras GTPase homologs Rap1 and Rap2. <ref>Fouet, A. 2009. The surface of Bacillus anthracis. Mol. Aspects Med. 30:374–385</ref> <ref>Moayeri, M., and S. H. Leppla. 2009. Cellular and systemic effects of anthrax lethal toxin and edema toxin. Mol. Aspects Med. 30:439–455</ref> | ||
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The edema factor is delivered into host cells thanks to the protective antigen. Indeed, the protective antigen binds to cellular receptors (CMP2, capillary morphogenesis protein 2 or TEM8, tumor endothelial marker 8) and is cleaved at the sequence arginine-lysine-lysine-arginine by cell surface proteases. This '''proteolytic activation''' leads to the oligomerisation of a '''protective antigen heptamer'''. The heptamer is composed of the <scene name='Sandbox_Reserved_702/Coloration_from_n_to_c_term/1'>C-terminal</scene> 63 kDa fragment. One heptamer can bind three molecules of edema factor (or lethal factor). Such a complex gets into the cell by endocytosis and finally the protective antigen helps the translocation of the edema factor from late endosome into the cytoplasm. Once it is in the host cell, the '''edema factor becomes membrane-associated'''. ''It is not known whether it is due to its association with [[calmodulin]] or to its binding with other cellular elements''. <ref> PMID: 19560485</ref> | The edema factor is delivered into host cells thanks to the protective antigen. Indeed, the protective antigen binds to cellular receptors (CMP2, capillary morphogenesis protein 2 or TEM8, tumor endothelial marker 8) and is cleaved at the sequence arginine-lysine-lysine-arginine by cell surface proteases. This '''proteolytic activation''' leads to the oligomerisation of a '''protective antigen heptamer'''. The heptamer is composed of the <scene name='Sandbox_Reserved_702/Coloration_from_n_to_c_term/1'>C-terminal</scene> 63 kDa fragment. One heptamer can bind three molecules of edema factor (or lethal factor). Such a complex gets into the cell by endocytosis and finally the protective antigen helps the translocation of the edema factor from late endosome into the cytoplasm. Once it is in the host cell, the '''edema factor becomes membrane-associated'''. ''It is not known whether it is due to its association with [[calmodulin]] or to its binding with other cellular elements''. <ref> PMID: 19560485</ref> | ||
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==Two magnesium ions are coordinated by the catalytic site== | ==Two magnesium ions are coordinated by the catalytic site== | ||
<Structure load='1lvc' size=' | <Structure load='1lvc' size='400' frame='true' align='right' caption='Magnesium ions coordinated by D491, D498 and H577.' /> | ||
[[Adenylyl cyclase]] activity of the edema factor requires two magnesium ions. One of them is coordinated by <scene name='Sandbox_Reserved_702/Asp_and_his/2'>two aspartic residues (D491 and D493) and the histidine 577.</scene> | [[Adenylyl cyclase]] activity of the edema factor requires two magnesium ions. One of them is coordinated by <scene name='Sandbox_Reserved_702/Asp_and_his/2'>two aspartic residues (D491 and D493) and the histidine 577.</scene> | ||
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The products, pysophosphate and cyclic AMP dissociate through different solvent accessible channels in a two-step process facilitated by product protonation. They are linked to the enzyme by electrostatic interactions with the magnesium ions. The binding of a water molecule to the ions is competitive with thier binding to reaction products and breaks the electrostatic links. Ligands are progressively solvated. In a first time the most important electrostatic interactions are preserved. This depends on the flexibility of the active site. Then the electrostatic interactions are broken and the products can diffuse into solvent. <ref> PMID: 21425348</ref> | The products, pysophosphate and cyclic AMP dissociate through different solvent accessible channels in a two-step process facilitated by product protonation. They are linked to the enzyme by electrostatic interactions with the magnesium ions. The binding of a water molecule to the ions is competitive with thier binding to reaction products and breaks the electrostatic links. Ligands are progressively solvated. In a first time the most important electrostatic interactions are preserved. This depends on the flexibility of the active site. Then the electrostatic interactions are broken and the products can diffuse into solvent. <ref> PMID: 21425348</ref> | ||
==Prevention and treatment== | ==Prevention and treatment== | ||
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===Structural comparison of AC families and the development of selective EF inhibitor=== | ===Structural comparison of AC families and the development of selective EF inhibitor=== | ||
There are at least six classes of [[adenylyl cyclase]] (the classification is based on their primary sequence). Five classes are found only in bacteria and the last one, class III, exists as well in prokaryotes as in eukaryotes. Class II [[adenylyl cyclase]] are secreted by pathogenic bacteria and the edema factor belongs to this class. The catalytic site of these several classes are different. This enables the fact that some molecules could '''inhibit the adenylyl cyclase toxins without inhibiting those of the class III'''. Inhibitors can be designed to interfere either with the binding of [[calmodulin]] or with the binding of the substrate. | There are at least six classes of [[adenylyl cyclase]] (the classification is based on their primary sequence). Five classes are found only in bacteria and the last one, class III, exists as well in prokaryotes as in eukaryotes. Class II [[adenylyl cyclase]] are secreted by pathogenic bacteria and the edema factor belongs to this class. The catalytic site of these several classes are different. This enables the fact that some molecules could '''inhibit the adenylyl cyclase toxins without inhibiting those of the class III'''. Inhibitors can be designed to interfere either with the binding of [[calmodulin]] or with the binding of the substrate. <ref>Shen et al. 2004</ref> | ||
These inhibitors could be further developed as an anti-anthrax treatment, which will be administered with antibiotics. Among those, the most potent EF inhibitor is an approved drug, '''Adefovir'''. Adefovir can selectively '''inhibit the activity of EF''' | These inhibitors could be further developed as an anti-anthrax treatment, which will be administered with antibiotics. Among those, the most potent EF inhibitor is an approved drug, '''Adefovir'''. Adefovir can selectively '''inhibit the activity of EF''' with no inhibition of the activity of endogenous host AC. | ||
Adefovir is an acyclic nucleoside and it can treat chronic hepatitis B virus infection. '''Tenofovir''', another acyclic nucleoside which is a drug against '''human immunodeficiency virus''', also show high affinity to EF. <ref>Suryanarayana et al., Distinct Interactions of 2′- and 3′-O-(N-Methyl)anthraniloyl-Isomers of ATP and GTP with the Adenylyl Cyclase Toxin of Bacillus anthracis, Edema Factor, Biochem Pharmacol. 2009 August 1; 78(3): 224–230</ref> | Adefovir is an acyclic nucleoside and it can treat chronic hepatitis B virus infection. '''Tenofovir''', another acyclic nucleoside which is a drug against '''human immunodeficiency virus''', also show high affinity to EF. <ref>Suryanarayana et al., Distinct Interactions of 2′- and 3′-O-(N-Methyl)anthraniloyl-Isomers of ATP and GTP with the Adenylyl Cyclase Toxin of Bacillus anthracis, Edema Factor, Biochem Pharmacol. 2009 August 1; 78(3): 224–230</ref> | ||
