Sandbox Reserved 702: Difference between revisions

*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>

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>

<scene name='Sandbox_Reserved_702/Histidine_351/1'>Histidine 351</scene> also plays a key role in the [[adenylyl cyclase]] reaction. Histidine is a crucial amino acid because its pKa (6.8) is close to pH of cytoplasm.  

It may intervene in proton-transfer reactions. Histidine 351 has a critical role in the catalytic activity of edema factor but is not a catalytic base. Since it is about 6.0 Å away from the 3'O of cAMP, its role is to allow a water molecule to enter between them. Histidine does not act as a general base (acceptor of 3'OH proton), but is facilitates an increase in the concentration of HO- ions in the proximity of the 3'OH group. <ref> PMID: 15719022</ref>

==Mechanism of adenylyl cyclase of edema factor==

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==

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''' both in the test tube and in cultured cells 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>

==About this Structure==