User:Charlotte Kern/Sandbox 702 - Revision history

Charlotte Kern at 10:58, 6 January 2013

Charlotte Kern — Sun, 06 Jan 2013 10:58:58 GMT

←Older revision		Revision as of 10:58, 6 January 2013
Line 11:		Line 11:
	In fact [[Adenylyl cyclase]] catalyze the conversion of adenosine triphosphate (ATP) into cAMP and pyrophosphate. The cellular level of cAMP increases, upsetting water homeostasis and causing disruption of signaling pathways.[[Image:CAMP synthesis.png\|300px\|thumb\|left]]		In fact [[Adenylyl cyclase]] catalyze the conversion of adenosine triphosphate (ATP) into cAMP and pyrophosphate. The cellular level of cAMP increases, upsetting water homeostasis and causing disruption of signaling pathways.[[Image:CAMP synthesis.png\|300px\|thumb\|left]]

-	EF is produced in an inactive form. When it is in the cell, EF [[Adenylyl cyclase]] activity is induced by complexation with [[calmodulin]], so it is allosterically activated. Its enzymatic activity leads to a dramatic elevation of the cAMP range.	+	EF is produced in an inactive form. When it is in the cell, EF [[Adenylyl cyclase]] activity is induced by complexation with [[calmodulin]], so it is allosterically activated.
		+	Its enzymatic activity leads to a dramatic elevation of the cAMP range.
	[[Calmodulin]] is ubiquitous eukaryotic cellular protein and a Ca2+ ion sensor present in host cells.		[[Calmodulin]] is ubiquitous eukaryotic cellular protein and a Ca2+ ion sensor present in host cells.

-	Cyclic AMP is a second messenger that plays key roles in the signal transduction pathways and thus regulates diverse cellular responses. It binds to three families of signal transducers: cAMP-dependent protein kinases, cyclic nucleotide gated channels~~, and the~~ guanine nucleotide exchange factor for Ras GTPase homologs Rap1 and Rap2 ~~(EPAC)~~. <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>	+	Cyclic AMP is a second messenger that plays key roles in the signal transduction pathways and thus regulates diverse cellular responses. It binds to three families of signal transducers:
		+	*cAMP-dependent protein kinases
		+	*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>

	==Anthrax toxin==		==Anthrax toxin==

Charlotte Kern at 10:49, 6 January 2013

Charlotte Kern — Sun, 06 Jan 2013 10:49:46 GMT

←Older revision		Revision as of 10:49, 6 January 2013
Line 77:		Line 77:


-	[[........ ~~j'ai pas continué à mettre ta partie, mais je me suis occupée de la mienne :)~~]]	+	[[........]]

	==Prevention and treatment==		==Prevention and treatment==

Charlotte Kern at 10:08, 6 January 2013

Charlotte Kern — Sun, 06 Jan 2013 10:08:53 GMT

←Older revision		Revision as of 10:08, 6 January 2013
Line 3:		Line 3:
	{{STRUCTURE_1lvc\| PDB=1lvc \| SCENE= }}		{{STRUCTURE_1lvc\| PDB=1lvc \| SCENE= }}

-	'''Anthrax edema factor (EF)''' is an enzyme which is part of the Bacillus anthracis anthrax toxin. Here we study 1lvc – EF [[adenylate cyclase]] domain + [[calmodulin]] + anthraniloyl-deoxy-ATP.	+	'''Anthrax edema factor (EF)''' is an enzyme which is part of the Bacillus anthracis anthrax toxin.
		+	Here we study 1lvc – EF [[adenylate cyclase]] domain + [[calmodulin]] + anthraniloyl-deoxy-ATP.

	==Introduction==		==Introduction==

-	The edema factor is a '''[[calmodulin]]-dependent [[adenylate cyclase]]'''. [[Adenylate cyclase]] [ATP pyrophosphate-lyase (cyclizing), (ADCY, EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.6.1.1 4.6.1.1])] increases intracellular cyclic AMP (cAMP) concentrations in eukaryotic cells. In fact [[Adenylyl cyclase]] catalyze the conversion of adenosine triphosphate (ATP) into cAMP and pyrophosphate. The cellular level of cAMP increases, upsetting water homeostasis and causing disruption of signaling pathways.[[Image:CAMP synthesis.png\|~~400px~~\|thumb\|left]]	+	The edema factor is a '''[[calmodulin]]-dependent [[adenylate cyclase]]'''. [[Adenylate cyclase]] [ATP pyrophosphate-lyase (cyclizing), (ADCY, EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.6.1.1 4.6.1.1])] increases intracellular cyclic AMP (cAMP) concentrations in eukaryotic cells.
		+	In fact [[Adenylyl cyclase]] catalyze the conversion of adenosine triphosphate (ATP) into cAMP and pyrophosphate. The cellular level of cAMP increases, upsetting water homeostasis and causing disruption of signaling pathways.[[Image:CAMP synthesis.png\|300px\|thumb\|left]]

	EF is produced in an inactive form. When it is in the cell, EF [[Adenylyl cyclase]] activity is induced by complexation with [[calmodulin]], so it is allosterically activated. Its enzymatic activity leads to a dramatic elevation of the cAMP range.		EF is produced in an inactive form. When it is in the cell, EF [[Adenylyl cyclase]] activity is induced by complexation with [[calmodulin]], so it is allosterically activated. Its enzymatic activity leads to a dramatic elevation of the cAMP range.
	[[Calmodulin]] is ubiquitous eukaryotic cellular protein and a Ca2+ ion sensor present in host cells.		[[Calmodulin]] is ubiquitous eukaryotic cellular protein and a Ca2+ ion sensor present in host cells.
		+
	Cyclic AMP is a second messenger that plays key roles in the signal transduction pathways and thus regulates diverse cellular responses. It binds to three families of signal transducers: cAMP-dependent protein kinases, cyclic nucleotide gated channels, and the guanine nucleotide exchange factor for Ras GTPase homologs Rap1 and Rap2 (EPAC). <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>		Cyclic AMP is a second messenger that plays key roles in the signal transduction pathways and thus regulates diverse cellular responses. It binds to three families of signal transducers: cAMP-dependent protein kinases, cyclic nucleotide gated channels, and the guanine nucleotide exchange factor for Ras GTPase homologs Rap1 and Rap2 (EPAC). <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>

Charlotte Kern at 10:07, 6 January 2013

Charlotte Kern — Sun, 06 Jan 2013 10:07:07 GMT

←Older revision		Revision as of 10:07, 6 January 2013
Line 4:		Line 4:

	'''Anthrax edema factor (EF)''' is an enzyme which is part of the Bacillus anthracis anthrax toxin. Here we study 1lvc – EF [[adenylate cyclase]] domain + [[calmodulin]] + anthraniloyl-deoxy-ATP.		'''Anthrax edema factor (EF)''' is an enzyme which is part of the Bacillus anthracis anthrax toxin. Here we study 1lvc – EF [[adenylate cyclase]] domain + [[calmodulin]] + anthraniloyl-deoxy-ATP.
		+
		+	==Introduction==

	The edema factor is a '''[[calmodulin]]-dependent [[adenylate cyclase]]'''. [[Adenylate cyclase]] [ATP pyrophosphate-lyase (cyclizing), (ADCY, EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.6.1.1 4.6.1.1])] increases intracellular cyclic AMP (cAMP) concentrations in eukaryotic cells. In fact [[Adenylyl cyclase]] catalyze the conversion of adenosine triphosphate (ATP) into cAMP and pyrophosphate. The cellular level of cAMP increases, upsetting water homeostasis and causing disruption of signaling pathways.[[Image:CAMP synthesis.png\|400px\|thumb\|left]]		The edema factor is a '''[[calmodulin]]-dependent [[adenylate cyclase]]'''. [[Adenylate cyclase]] [ATP pyrophosphate-lyase (cyclizing), (ADCY, EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.6.1.1 4.6.1.1])] increases intracellular cyclic AMP (cAMP) concentrations in eukaryotic cells. In fact [[Adenylyl cyclase]] catalyze the conversion of adenosine triphosphate (ATP) into cAMP and pyrophosphate. The cellular level of cAMP increases, upsetting water homeostasis and causing disruption of signaling pathways.[[Image:CAMP synthesis.png\|400px\|thumb\|left]]

Charlotte Kern at 09:53, 6 January 2013

Charlotte Kern — Sun, 06 Jan 2013 09:53:52 GMT

←Older revision		Revision as of 09:53, 6 January 2013
Line 5:		Line 5:
	'''Anthrax edema factor (EF)''' is an enzyme which is part of the Bacillus anthracis anthrax toxin. Here we study 1lvc – EF [[adenylate cyclase]] domain + [[calmodulin]] + anthraniloyl-deoxy-ATP.		'''Anthrax edema factor (EF)''' is an enzyme which is part of the Bacillus anthracis anthrax toxin. Here we study 1lvc – EF [[adenylate cyclase]] domain + [[calmodulin]] + anthraniloyl-deoxy-ATP.

-	The edema factor is a '''[[calmodulin]]-dependent [[adenylate cyclase]]'''. [[Adenylate cyclase]] [ATP pyrophosphate-lyase (cyclizing), (ADCY, EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.6.1.1 4.6.1.1])] increases intracellular cyclic AMP (cAMP) concentrations in eukaryotic cells. In fact [[Adenylyl cyclase]] catalyze the conversion of adenosine triphosphate (ATP) into cAMP and pyrophosphate. The cellular level of cAMP increases, upsetting water homeostasis and causing disruption of signaling pathways.[[Image:CAMP synthesis.png\|400px\|thumb\|left]]]	+	The edema factor is a '''[[calmodulin]]-dependent [[adenylate cyclase]]'''. [[Adenylate cyclase]] [ATP pyrophosphate-lyase (cyclizing), (ADCY, EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.6.1.1 4.6.1.1])] increases intracellular cyclic AMP (cAMP) concentrations in eukaryotic cells. In fact [[Adenylyl cyclase]] catalyze the conversion of adenosine triphosphate (ATP) into cAMP and pyrophosphate. The cellular level of cAMP increases, upsetting water homeostasis and causing disruption of signaling pathways.[[Image:CAMP synthesis.png\|400px\|thumb\|left]]

	EF is produced in an inactive form. When it is in the cell, EF [[Adenylyl cyclase]] activity is induced by complexation with [[calmodulin]], so it is allosterically activated. Its enzymatic activity leads to a dramatic elevation of the cAMP range.		EF is produced in an inactive form. When it is in the cell, EF [[Adenylyl cyclase]] activity is induced by complexation with [[calmodulin]], so it is allosterically activated. Its enzymatic activity leads to a dramatic elevation of the cAMP range.

Charlotte Kern at 09:52, 6 January 2013

Charlotte Kern — Sun, 06 Jan 2013 09:52:14 GMT

←Older revision		Revision as of 09:52, 6 January 2013
Line 3:		Line 3:
	{{STRUCTURE_1lvc\| PDB=1lvc \| SCENE= }}		{{STRUCTURE_1lvc\| PDB=1lvc \| SCENE= }}

-	'''Anthrax edema factor (EF)''' is an enzyme which is part of the Bacillus anthracis anthrax toxin. Here we study 1lvc – EF adenylate cyclase domain + [[calmodulin]] + anthraniloyl-deoxy-ATP.	+	'''Anthrax edema factor (EF)''' is an enzyme which is part of the Bacillus anthracis anthrax toxin. Here we study 1lvc – EF [[adenylate cyclase]] domain + [[calmodulin]] + anthraniloyl-deoxy-ATP.

-	The edema factor is a '''[[calmodulin]]-dependent adenylate cyclase'''. [[Adenylate cyclase]] [ATP pyrophosphate-lyase (cyclizing), (ADCY, EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.6.1.1 4.6.1.1])] increases intracellular cyclic AMP (cAMP) concentrations in eukaryotic cells. In fact [[Adenylyl cyclase]] catalyze the conversion of adenosine triphosphate (ATP) into cAMP and pyrophosphate. The cellular level of cAMP increases, upsetting water homeostasis and causing disruption of signaling pathways.[[Image:CAMP synthesis.png\|400px\|thumb\|left]]]	+	The edema factor is a '''[[calmodulin]]-dependent [[adenylate cyclase]]'''. [[Adenylate cyclase]] [ATP pyrophosphate-lyase (cyclizing), (ADCY, EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.6.1.1 4.6.1.1])] increases intracellular cyclic AMP (cAMP) concentrations in eukaryotic cells. In fact [[Adenylyl cyclase]] catalyze the conversion of adenosine triphosphate (ATP) into cAMP and pyrophosphate. The cellular level of cAMP increases, upsetting water homeostasis and causing disruption of signaling pathways.[[Image:CAMP synthesis.png\|400px\|thumb\|left]]]

	EF is produced in an inactive form. When it is in the cell, EF [[Adenylyl cyclase]] activity is induced by complexation with [[calmodulin]], so it is allosterically activated. Its enzymatic activity leads to a dramatic elevation of the cAMP range.		EF is produced in an inactive form. When it is in the cell, EF [[Adenylyl cyclase]] activity is induced by complexation with [[calmodulin]], so it is allosterically activated. Its enzymatic activity leads to a dramatic elevation of the cAMP range.
Line 24:		Line 24:

	====Edema factor (EF)====		====Edema factor (EF)====
-	EF is a [[calmodulin]]-dependent adenylyl cyclase that depletes cellular adenosine triphosphate (ATP) while creating 3',5'-cyclic adenosine monophosphate (cAMP), a cellular second messenger. <ref>Leppla, 1982, Anthrax toxin edema factor: a bacterial adenylate cyclase that increases cAMP concentration in eukaryotic cells. Proc. Natl. Acad. Sci. USA 79:3162-3163</ref>	+	EF is a [[calmodulin]]-dependent adenylyl cyclase that depletes cellular adenosine triphosphate (ATP) while creating 3',5'-cyclic adenosine monophosphate (cAMP), a cellular second messenger. <ref>Leppla, 1982, Anthrax toxin edema factor: a bacterial [[adenylate cyclase]] that increases cAMP concentration in eukaryotic cells. Proc. Natl. Acad. Sci. USA 79:3162-3163</ref>
	Both toxins can be reconstituted vitro, by combining PA with LF or EF, to form lethal toxin (LT) or edema toxin (ET).		Both toxins can be reconstituted vitro, by combining PA with LF or EF, to form lethal toxin (LT) or edema toxin (ET).

Charlotte Kern at 09:47, 6 January 2013

Charlotte Kern — Sun, 06 Jan 2013 09:47:15 GMT

Charlotte Kern at 09:40, 6 January 2013

Charlotte Kern — Sun, 06 Jan 2013 09:40:43 GMT

←Older revision		Revision as of 09:40, 6 January 2013
Line 5:		Line 5:
	'''Anthrax edema factor (EF)''' is an enzyme which is part of the Bacillus anthracis anthrax toxin. Here we study 1lvc – EF adenylate cyclase domain + calmodulin + anthraniloyl-deoxy-ATP.		'''Anthrax edema factor (EF)''' is an enzyme which is part of the Bacillus anthracis anthrax toxin. Here we study 1lvc – EF adenylate cyclase domain + calmodulin + anthraniloyl-deoxy-ATP.

-	The edema factor is a '''calmodulin-dependent adenylate cyclase'''. [[Adenylate cyclase]] [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] increases intracellular cyclic AMP (cAMP) concentrations in eukaryotic cells. In fact [[Adenylyl cyclase]] catalyze the conversion of adenosine triphosphate (ATP) into cAMP and pyrophosphate. The cellular level of cAMP increases, upsetting water homeostasis and causing disruption of signaling pathways.[[Image:CAMP synthesis.png\|400px\|thumb\|left]]]	+	The edema factor is a '''calmodulin-dependent adenylate cyclase'''. [[Adenylate cyclase]] [ATP pyrophosphate-lyase (cyclizing), (ADCY, EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.6.1.1 4.6.1.1])] increases intracellular cyclic AMP (cAMP) concentrations in eukaryotic cells. In fact [[Adenylyl cyclase]] catalyze the conversion of adenosine triphosphate (ATP) into cAMP and pyrophosphate. The cellular level of cAMP increases, upsetting water homeostasis and causing disruption of signaling pathways.[[Image:CAMP synthesis.png\|400px\|thumb\|left]]]

	EF is produced in an inactive form. When it is in the cell, EF [[Adenylyl cyclase]] activity is induced by complexation with calmodulin, so it is allosterically activated. Its enzymatic activity leads to a dramatic elevation of the cAMP range.		EF is produced in an inactive form. When it is in the cell, EF [[Adenylyl cyclase]] activity is induced by complexation with calmodulin, so it is allosterically activated. Its enzymatic activity leads to a dramatic elevation of the cAMP range.

Charlotte Kern at 09:39, 6 January 2013

Charlotte Kern — Sun, 06 Jan 2013 09:39:25 GMT

←Older revision		Revision as of 09:39, 6 January 2013
Line 5:		Line 5:
	'''Anthrax edema factor (EF)''' is an enzyme which is part of the Bacillus anthracis anthrax toxin. Here we study 1lvc – EF adenylate cyclase domain + calmodulin + anthraniloyl-deoxy-ATP.		'''Anthrax edema factor (EF)''' is an enzyme which is part of the Bacillus anthracis anthrax toxin. Here we study 1lvc – EF adenylate cyclase domain + calmodulin + anthraniloyl-deoxy-ATP.

-	The edema factor is a '''calmodulin-dependent adenylate cyclase'''. [[Adenylate cyclase]] [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] increases intracellular cyclic AMP (cAMP) concentrations in eukaryotic cells. In fact [[Adenylyl cyclase]] catalyze the conversion of adenosine triphosphate (ATP) into cAMP and pyrophosphate. The cellular level of cAMP increases, upsetting water homeostasis and causing disruption of signaling pathways.[[Image:CAMP synthesis.png]]	+	The edema factor is a '''calmodulin-dependent adenylate cyclase'''. [[Adenylate cyclase]] [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] increases intracellular cyclic AMP (cAMP) concentrations in eukaryotic cells. In fact [[Adenylyl cyclase]] catalyze the conversion of adenosine triphosphate (ATP) into cAMP and pyrophosphate. The cellular level of cAMP increases, upsetting water homeostasis and causing disruption of signaling pathways.[[Image:CAMP synthesis.png\|400px\|thumb\|left]]]

	EF is produced in an inactive form. When it is in the cell, EF [[Adenylyl cyclase]] activity is induced by complexation with calmodulin, so it is allosterically activated. Its enzymatic activity leads to a dramatic elevation of the cAMP range.		EF is produced in an inactive form. When it is in the cell, EF [[Adenylyl cyclase]] activity is induced by complexation with calmodulin, so it is allosterically activated. Its enzymatic activity leads to a dramatic elevation of the cAMP range.

Charlotte Kern at 09:38, 6 January 2013

Charlotte Kern — Sun, 06 Jan 2013 09:38:06 GMT

←Older revision		Revision as of 09:38, 6 January 2013
Line 5:		Line 5:
	'''Anthrax edema factor (EF)''' is an enzyme which is part of the Bacillus anthracis anthrax toxin. Here we study 1lvc – EF adenylate cyclase domain + calmodulin + anthraniloyl-deoxy-ATP.		'''Anthrax edema factor (EF)''' is an enzyme which is part of the Bacillus anthracis anthrax toxin. Here we study 1lvc – EF adenylate cyclase domain + calmodulin + anthraniloyl-deoxy-ATP.

-	The edema factor is a '''calmodulin-dependent adenylate cyclase'''. [[Adenylate cyclase]] [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] increases intracellular cyclic AMP (cAMP) concentrations in eukaryotic cells. In fact ~~adenylyl cyclases~~ catalyze the conversion of adenosine triphosphate (ATP) into cAMP and pyrophosphate. The cellular level of cAMP increases, upsetting water homeostasis and causing disruption of signaling pathways.[[Image:CAMP synthesis.png]]	+	The edema factor is a '''calmodulin-dependent adenylate cyclase'''. [[Adenylate cyclase]] [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] increases intracellular cyclic AMP (cAMP) concentrations in eukaryotic cells. In fact [[Adenylyl cyclase]] catalyze the conversion of adenosine triphosphate (ATP) into cAMP and pyrophosphate. The cellular level of cAMP increases, upsetting water homeostasis and causing disruption of signaling pathways.[[Image:CAMP synthesis.png]]

-	EF is produced in an inactive form. When it is in the cell, EF ~~adenylyl~~ cyclase activity is induced by complexation with calmodulin, so it is allosterically activated. Its enzymatic activity leads to a dramatic elevation of the cAMP range.	+	EF is produced in an inactive form. When it is in the cell, EF [[Adenylyl cyclase]] activity is induced by complexation with calmodulin, so it is allosterically activated. Its enzymatic activity leads to a dramatic elevation of the cAMP range.
	Calmodulin is ubiquitous eukaryotic cellular protein and a Ca2+ ion sensor present in host cells.		Calmodulin is ubiquitous eukaryotic cellular protein and a Ca2+ ion sensor present in host cells.
	Cyclic AMP is a second messenger that plays key roles in the signal transduction pathways and thus regulates diverse cellular responses. It binds to three families of signal transducers: cAMP-dependent protein kinases, cyclic nucleotide gated channels, and the guanine nucleotide exchange factor for Ras GTPase homologs Rap1 and Rap2 (EPAC). <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>		Cyclic AMP is a second messenger that plays key roles in the signal transduction pathways and thus regulates diverse cellular responses. It binds to three families of signal transducers: cAMP-dependent protein kinases, cyclic nucleotide gated channels, and the guanine nucleotide exchange factor for Ras GTPase homologs Rap1 and Rap2 (EPAC). <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>

←Older revision		Revision as of 09:47, 6 January 2013
Line 3:		Line 3:
	{{STRUCTURE_1lvc\| PDB=1lvc \| SCENE= }}		{{STRUCTURE_1lvc\| PDB=1lvc \| SCENE= }}

-	'''Anthrax edema factor (EF)''' is an enzyme which is part of the Bacillus anthracis anthrax toxin. Here we study 1lvc – EF adenylate cyclase domain + calmodulin + anthraniloyl-deoxy-ATP.	+	'''Anthrax edema factor (EF)''' is an enzyme which is part of the Bacillus anthracis anthrax toxin. Here we study 1lvc – EF adenylate cyclase domain + [[calmodulin]] + anthraniloyl-deoxy-ATP.

-	The edema factor is a '''calmodulin-dependent adenylate cyclase'''. [[Adenylate cyclase]] [ATP pyrophosphate-lyase (cyclizing), (ADCY, EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.6.1.1 4.6.1.1])] increases intracellular cyclic AMP (cAMP) concentrations in eukaryotic cells. In fact [[Adenylyl cyclase]] catalyze the conversion of adenosine triphosphate (ATP) into cAMP and pyrophosphate. The cellular level of cAMP increases, upsetting water homeostasis and causing disruption of signaling pathways.[[Image:CAMP synthesis.png\|400px\|thumb\|left]]]	+	The edema factor is a '''[[calmodulin]]-dependent adenylate cyclase'''. [[Adenylate cyclase]] [ATP pyrophosphate-lyase (cyclizing), (ADCY, EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.6.1.1 4.6.1.1])] increases intracellular cyclic AMP (cAMP) concentrations in eukaryotic cells. In fact [[Adenylyl cyclase]] catalyze the conversion of adenosine triphosphate (ATP) into cAMP and pyrophosphate. The cellular level of cAMP increases, upsetting water homeostasis and causing disruption of signaling pathways.[[Image:CAMP synthesis.png\|400px\|thumb\|left]]]

-	EF is produced in an inactive form. When it is in the cell, EF [[Adenylyl cyclase]] activity is induced by complexation with calmodulin, so it is allosterically activated. Its enzymatic activity leads to a dramatic elevation of the cAMP range.	+	EF is produced in an inactive form. When it is in the cell, EF [[Adenylyl cyclase]] activity is induced by complexation with [[calmodulin]], so it is allosterically activated. Its enzymatic activity leads to a dramatic elevation of the cAMP range.
-	Calmodulin is ubiquitous eukaryotic cellular protein and a Ca2+ ion sensor present in host cells.	+	[[Calmodulin]] is ubiquitous eukaryotic cellular protein and a Ca2+ ion sensor present in host cells.
	Cyclic AMP is a second messenger that plays key roles in the signal transduction pathways and thus regulates diverse cellular responses. It binds to three families of signal transducers: cAMP-dependent protein kinases, cyclic nucleotide gated channels, and the guanine nucleotide exchange factor for Ras GTPase homologs Rap1 and Rap2 (EPAC). <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>		Cyclic AMP is a second messenger that plays key roles in the signal transduction pathways and thus regulates diverse cellular responses. It binds to three families of signal transducers: cAMP-dependent protein kinases, cyclic nucleotide gated channels, and the guanine nucleotide exchange factor for Ras GTPase homologs Rap1 and Rap2 (EPAC). <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>

Line 24:		Line 24:

	====Edema factor (EF)====		====Edema factor (EF)====
-	EF is a calmodulin-dependent adenylyl cyclase that depletes cellular adenosine triphosphate (ATP) while creating 3',5'-cyclic adenosine monophosphate (cAMP), a cellular second messenger. <ref>Leppla, 1982, Anthrax toxin edema factor: a bacterial adenylate cyclase that increases cAMP concentration in eukaryotic cells. Proc. Natl. Acad. Sci. USA 79:3162-3163</ref>	+	EF is a [[calmodulin]]-dependent adenylyl cyclase that depletes cellular adenosine triphosphate (ATP) while creating 3',5'-cyclic adenosine monophosphate (cAMP), a cellular second messenger. <ref>Leppla, 1982, Anthrax toxin edema factor: a bacterial adenylate cyclase that increases cAMP concentration in eukaryotic cells. Proc. Natl. Acad. Sci. USA 79:3162-3163</ref>
	Both toxins can be reconstituted vitro, by combining PA with LF or EF, to form lethal toxin (LT) or edema toxin (ET).		Both toxins can be reconstituted vitro, by combining PA with LF or EF, to form lethal toxin (LT) or edema toxin (ET).

Line 53:		Line 53:
	The edema factor has a 30 kDa PA-binding domain at its N-terminus. EF PA binding domain can be divides into two subdomains. An N-terminal domain that is composed of three layers at the N-terminus, a/b sandwich domain (four b-sheets, b1–b4, sandwiched by four a-helices, a1–a4) and a domain of five helices at the C-terminus (Figure 1A and C). et le C-t ????? There are five joining loops, L1–L5, where L5 contributes the key residues to bind PA (Figure 1B) [[chez lf ou chez ef ? Lacy et al, 2002]]		The edema factor has a 30 kDa PA-binding domain at its N-terminus. EF PA binding domain can be divides into two subdomains. An N-terminal domain that is composed of three layers at the N-terminus, a/b sandwich domain (four b-sheets, b1–b4, sandwiched by four a-helices, a1–a4) and a domain of five helices at the C-terminus (Figure 1A and C). et le C-t ????? There are five joining loops, L1–L5, where L5 contributes the key residues to bind PA (Figure 1B) [[chez lf ou chez ef ? Lacy et al, 2002]]

-	The edema factor is delivered into host cells thanks to the protective antigen. Indeed the protective antigen binds to cellular receptors (TEM8 or CMP2) and is cleaved at the sequence RKKR by cell surface proteases (non dispo 6). This proteolytic activation leads to the oligomerization of a protective antigen heptamer corresponding to its C-terminal 63 kDa fragment. One heptamer can bind three molecules of edema factor (or lethal factor). Such a complex gets into cells by endocytosis and finally the protective antigen helps the translocation of the edema factor from late endosomes 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.	+	The edema factor is delivered into host cells thanks to the protective antigen. Indeed the protective antigen binds to cellular receptors (TEM8 or CMP2) and is cleaved at the sequence RKKR by cell surface proteases (non dispo 6). This proteolytic activation leads to the oligomerization of a protective antigen heptamer corresponding to its C-terminal 63 kDa fragment. One heptamer can bind three molecules of edema factor (or lethal factor). Such a complex gets into cells by endocytosis and finally the protective antigen helps the translocation of the edema factor from late endosomes 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.

	[[A REFORMULER :		[[A REFORMULER :
	The surface-exposed residues in L5, a6, a7, and the joining loop between a7 and a8 at the C-terminal five-helix domain of LF-PABD and EF-PABD have been mapped by mutational analysis to make the primary contacts with PA (Lacy et al, 2002). The PA binding surface of EF–PABD is richly negatively charged, which could promote interaction with the positively charged residues at EF/LF interacting surface of PA <ref>Cunningham et al, 2002</ref>]]		The surface-exposed residues in L5, a6, a7, and the joining loop between a7 and a8 at the C-terminal five-helix domain of LF-PABD and EF-PABD have been mapped by mutational analysis to make the primary contacts with PA (Lacy et al, 2002). The PA binding surface of EF–PABD is richly negatively charged, which could promote interaction with the positively charged residues at EF/LF interacting surface of PA <ref>Cunningham et al, 2002</ref>]]

-	==The molecular basis of activation and catalysis of the adenylyl cyclase activity of EF by calmodulin==	+	==The molecular basis of activation and catalysis of the adenylyl cyclase activity of EF by [[calmodulin]]==
-	Domain organisation of EF and calmodulin	+	Domain organisation of EF and [[calmodulin]].
-	The edema factor has three domains: a PA-binding domain (30 kDa at the N-terminus), a helical domain (17kDa) and acatalytic core domain (43 kDa, in the C-terminal 510 amino acid region) (Drum et al, 2002). The catalytic core domain is itself composed of two domains called CA and CB. The helical domain and the catalytic core are liked by switch C. The adenyly cylase catalytic site is located at the interface of CA and CB. In the absence of calmodulin the enzyme remains inactive thanks to a disordered catalytic loop at the interaction site between the EF helical domain and the catalytic core domain.	+
-	Calmodulin has two globular domains, the N-terminal and C-terminal domains, that are connected by a flexible a-helix. Each one of these domains can bind two calcium ions thanks to two helix-loop-helix motifs. The binding of a calcium ion induces a conformational change: the domain goes from a hydrophilic “closed” conformation to an “open” state which exposes a hydrophobic pocket. This hydrophobic pocket plays an important role in interaction of calmodulin with other molecules.	+	The edema factor has three domains: a PA-binding domain (30 kDa at the N-terminus), a helical domain (17kDa) and acatalytic core domain (43 kDa, in the C-terminal 510 amino acid region) (Drum et al, 2002). The catalytic core domain is itself composed of two domains called CA and CB. The helical domain and the catalytic core are liked by switch C. The adenyly cylase catalytic site is located at the interface of CA and CB. In the absence of [[calmodulin]] the enzyme remains inactive thanks to a disordered catalytic loop at the interaction site between the EF helical domain and the catalytic core domain.
		+	[[Calmodulin]] has two globular domains, the N-terminal and C-terminal domains, that are connected by a flexible a-helix. Each one of these domains can bind two calcium ions thanks to two helix-loop-helix motifs. The binding of a calcium ion induces a conformational change: the domain goes from a hydrophilic “closed” conformation to an “open” state which exposes a hydrophobic pocket. This hydrophobic pocket plays an important role in interaction of [[calmodulin]] with other molecules.

	==The molecular basis for the activation of anthrax EF by calmodulin==		==The molecular basis for the activation of anthrax EF by calmodulin==
	How CaM binds to and activates its effectors <ref>Hoeflich and Ikura 2002</ref>		How CaM binds to and activates its effectors <ref>Hoeflich and Ikura 2002</ref>
-	The helical domain of EF interacts with the CA domain and switch C in the absence of calmodulin. This locks EF in the inactive state. Most of those interactions are disrupted upon calmodulin binding. Four discrete regions of edema factor form a surface that recognizes calmodulin.	+	The helical domain of EF interacts with the CA domain and switch C in the absence of [[calmodulin]]. This locks EF in the inactive state. Most of those interactions are disrupted upon [[calmodulin]] binding. Four discrete regions of edema factor form a surface that recognizes [[calmodulin]].

	''The binding of calmodulin and the activation of EF requires two steps.''		''The binding of calmodulin and the activation of EF requires two steps.''
-	The calcium-free, closed N-terminal domain of calmodulin binds to EF thanks to an interaction with its helical domain. This interaction is due to hydrogen bonds and a salt bridge between helices I and II of the N-terminal domain of calmodulin and helices L and M of the helical domain of EF. When the N-terminal domain is bound to the EF helical domain, the calcium-loaded C-terminal domain in its open conformation inserts between the helical domain and the catalytic core of EF (Drum et al, 2002). This allows a conformational change of switch C that will stabilize the catalytic loop (switch B) of EF in an active state. A rigid-body rotation of CB relative to CA also occurs. This changes the pocket formed between these two domains and allows the interaction of EF with the phosphates of ATP.	+	The calcium-free, closed N-terminal domain of [[calmodulin]] binds to EF thanks to an interaction with its helical domain. This interaction is due to hydrogen bonds and a salt bridge between helices I and II of the N-terminal domain of [[calmodulin]] and helices L and M of the helical domain of EF. When the N-terminal domain is bound to the EF helical domain, the calcium-loaded C-terminal domain in its open conformation inserts between the helical domain and the catalytic core of EF (Drum et al, 2002). This allows a conformational change of switch C that will stabilize the catalytic loop (switch B) of EF in an active state. A rigid-body rotation of CB relative to CA also occurs. This changes the pocket formed between these two domains and allows the interaction of EF with the phosphates of ATP.


Line 84:		Line 85:
	Winterroth and colleagues described six antibodies of moderate affinity, including one IgM that could neutralize EF activity in CHO cells. This antibody had no significant protective effect against a Sterne strain infection in a mouse model but extended the mean time to death when combined with a subprotective dose of anti-PA antibody. <ref>Winterroth, L., J. Rivera, A. S. Nakouzi, E. Dadachova, and A. Casadevall. 2010. A neutralizing monoclonal antibody to edema toxin and its effect on murine anthrax. Infect. Immun. 78:2890–2896 </ref>		Winterroth and colleagues described six antibodies of moderate affinity, including one IgM that could neutralize EF activity in CHO cells. This antibody had no significant protective effect against a Sterne strain infection in a mouse model but extended the mean time to death when combined with a subprotective dose of anti-PA antibody. <ref>Winterroth, L., J. Rivera, A. S. Nakouzi, E. Dadachova, and A. Casadevall. 2010. A neutralizing monoclonal antibody to edema toxin and its effect on murine anthrax. Infect. Immun. 78:2890–2896 </ref>

-	Chen and colleagues developed chimpanzee antibodies that included one having very high affinity and that competes with calmodulin for binding to the helical domain of EF. This antibody was very effective at preventing ET-mediated edema in a mouse footpad model and provided significant protection in a systemic toxin challenge. <ref>Chen, Z., et al. 2009. Potent neutralization of anthrax edema toxin by a humanized monoclonal antibody that competes with calmodulin for edema factor binding. Proc. Natl. Acad. Sci. U. S. A. 106:13487–13492</ref>	+	Chen and colleagues developed chimpanzee antibodies that included one having very high affinity and that competes with [[calmodulin]] for binding to the helical domain of EF. This antibody was very effective at preventing ET-mediated edema in a mouse footpad model and provided significant protection in a systemic toxin challenge. <ref>Chen, Z., et al. 2009. Potent neutralization of anthrax edema toxin by a humanized monoclonal antibody that competes with [[calmodulin]] for edema factor binding. Proc. Natl. Acad. Sci. U. S. A. 106:13487–13492</ref>

	Leysath et al. developed and characterized four anti-EF monoclonal antibodies (MAb).		Leysath et al. developed and characterized four anti-EF monoclonal antibodies (MAb).
Line 101:		Line 102:

	====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 cyclases (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 cyclases 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 ~~calmoduline~~ or with the binding of the substrate. <ref>Lee et al. 2004</ref> <ref>Shen et al. 2004</ref> <ref>Soelaiman et al. 2003</ref>	+	There are at least six classes of adenylyl cyclases (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 cyclases 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>Lee et al. 2004</ref> <ref>Shen et al. 2004</ref> <ref>Soelaiman et al. 2003</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 both in the test tube and in cultured cells with no inhibition of the activity of endogenous host AC.		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>		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>