Sandbox Reserved 702: Difference between revisions
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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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<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. | <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> | 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== | ==Mechanism of adenylyl cyclase of edema factor== | ||
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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> | ||
==About this Structure== | ==About this Structure== | ||
