Sandbox Reserved 964

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==1f2w: Carbonic Anhydrase II==
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<StructureSection load='1f2w' size='340' side='right' caption='Caption for this structure' scene=''>
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==1f2w Cyanamide-Carbonic Anhydrase II EC 4.2.1.1==
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<StructureSection load='1f2w' size='340' side='right' caption='Structure of carbonic anhydrase II' scene=''>
==Introduction==
==Introduction==
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Carbonic anhydrase II (gene name CA2), is one of fourteen forms of human α carbonic anhydrases. Carbonic anhydrase catalyzes reversible hydration of carbon dioxide. Defects in this enzyme are associated with osteopetrosis and renal tubular acidosis. Renal carbonic anhydrase allows the reabsorption of sodium ions in the proximal tubule
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1f2w is a human protein from the Carbonic anhydrase II (gene name CA2) sub-sub-family, which is one of the fourteen isoforms of human α carbonic anhydrases.
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This enzyme is a lyase, which is able to break C-N links, and needs its cofactor, the zinc ion, to be activated.
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Carbonic anhydrase II is located in the cytosol, and normally catalyzes the reversible hydration of CO2 into bicarbonate:
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[[Image:D7423ca6daa1149f361c10b977acad36.png]]
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But in this representation, we observe the carbonic anhydrase II bound to its suicide substrate, the cyanamide, which is hydrated by the enzyme, forming urea. The urea-carbonic anhydrase II complex leads to the inactivation of the enzyme.
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Cyanamide is an organic compound, which formula is :
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[[Image:620px-Cyanamide.svg.png|300px]]
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Cyanamide is a toxic compound mainly found in pesticides or drugs. It exists as two tautomers, the NCNH2 form dominating the other one. Cyanamide is produced by hydrolysis of calcium cyanamide.
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==Structure==
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The carbonic anhydrase II is composed of 259 amino acids, and its dimensions are 42Å x 42Å x 72Å.
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The protein is composed of :
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- 5 <scene name='60/604483/Alpha_helix/2'>α helix</scene>
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- 15 <scene name='60/604483/Beta_sheets/2'>β sheets</scene>
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The protein's '''active site''' is formed of <scene name='60/604483/Zinc_binding_site/2'>three histidines</scene> (residues 94,96 and 119) that can bind a zinc ion. The active site is located in an '''hydrophobic hole''' :
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[[Image:Znnn.png|500px]]
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There are two binding sites for mercury :
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- <scene name='60/604483/Hg_binding_site/1'>Hg binding site</scene>.
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- <scene name='60/604483/Hgb_binding_site/1'>HgB binding site</scene>.
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We can see here the conservation of the residues: <jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/f2/1f2w_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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</jmolCheckbox>
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</jmol>
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[[Image:Consurf_key_small.gif|200px]]
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The most conserved residues are located in the active site's cavity.
== Function ==
== Function ==
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Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye
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In this complex, 1f2w catalyzes the hydration of cyanamide into urea according to the equation :
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[[Image:D7423ca6daa1149f361c10b977acad36.jpg]]
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==Mechanism of Action==
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[[Image:Cyanamide.png]]
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The three-dimensional structure of a possible intermediate in the hydration reaction of cyanamide to urea catalyzed by human carbonic anhydrase II (hCAII) has been determined by cryocrystallographic techniques. The crystal structure shows that two different adducts are formed under the experimental conditions and that they have different occupancy in the crystal. The high occupancy form consists of a binary hCAII-cyanamide complex where the substrate has replaced the zinc-bound hydroxide anion present in the native enzyme, maintaining the tetrahedral geometry around the metal ion. The second, low-occupancy form consists of a hCAII-cyanamide-water ternary complex where the catalytic zinc ion, still being bound to cyanamide, is approached by a water molecule in a five-coordinate adduct. While the first form can be considered a nonproductive complex, the second form may represent an intermediate state of the catalyzed reaction where the water molecule is about to perform a nucleophilic attack on the zinc-activated cyanamide substrate. The structural evidence is consistent with the kinetic data previously reported about this recently described hydrolytic reaction catalyzed by hCAII, and indicates that a different mechanism with respect to that generally accepted for the physiologic carbon dioxide hydration reaction may be adopted by the enzyme, depending on the substrate chemical properties.
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Cyanamide is a toxic compound, and is an analog of CO2. It can thereby bind the active site of the carbonic anhydrase II thanks to the zinc ion.
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== Headline text ==
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The reaction is a '''suicide inhibition''': the enzyme binds an suicide substrate (here cyanamide), and this substrate is modified by the enzyme (here into urea) and produces a reactive group that forms a '''stable inhibitor-enzyme complex'''.
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Ceci sont les <scene name='60/604483/Ligands/1'>ligands</scene>.
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The inactivation of the carbonic anhydrase II leads to health issues. In fact, it can cause several diseases, such as osteopetrosis autosomal recessive type 3 (also known as Guibaud-Vainsel syndrome). This syndrome is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation.
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== Disease ==
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==Mechanism of Action==
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[CAH2_HUMAN] Defects in CA2 are the cause of osteopetrosis autosomal recessive type 3 (OPTB3) [MIM:259730]; also known as osteopetrosis with renal tubular acidosis, carbonic anhydrase II deficiency syndrome, Guibaud-Vainsel syndrome or marble brain disease. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. The disorder occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Autosomal recessive osteopetrosis is usually associated with normal or elevated amount of non-functional osteoclasts. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation.[1] [2] [3] [4] [5]
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== Relevance ==
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== Structural highlights ==
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The <scene name='60/604483/Cnn_binding_site/2'>Cyanamide</scene> can bind the metal ion and two threonine residues (THR 199 and 200), it is thereby adding to the coordination sphere. The cyanamid attacks the zinc ion (nucleophilic attack). Afertwards the water molecule performs a nucleophilic attack on the zinc-activated cyanamide substrate forming urea which remains bound to the zinc ion.
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Urea is tightly linked to the carbonic anhydrase II, acting in this way as an inhibitor.
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
 
</StructureSection>
</StructureSection>
== References ==
== References ==
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1. Briganti F, Mangani S, Scozzafava A, Vernaglione G, Supuran CT (1999) "Carbonic anhydrase catalyzes cyanamide hydration
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to urea: is it mimicking the physiological reaction?" J. Biol. Chem 528-36.
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2. Guerri A, Briganti F, Scozzafava A, Supuran CT, Mangani S (2000) "Mechanism of cyanamide hydration catalyzed by carbonic
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anhydrase II suggested by cryogenic X-ray diffraction" Biochemistry 12391-7
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3. RCBS: http://www.rcsb.org/pdb/explore.do?structureId=1f2w consulted the 2/01/2015 [online]
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4. PDJB: http://pdbj.org/mine/summary/1f2w consulted the 2/01/2014 [online]
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5. Jennalib: http://jenalib.fli-leibniz.de/cgi-bin/ImgLib.pl?CODE=1f2w consulted the 3/01/2015 [online]
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6. Wikipedia "Carbonic anhydrase" http://en.wikipedia.org/wiki/Carbonic_anhydrase consulted the 27/12/2014 [online]
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7. Wikipedia "Cyanamide" http://en.wikipedia.org/wiki/Cyanamide consulted the 27/12/2014 [online]
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<references/>
<references/>
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==Editors==
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Flinois Arielle
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Hubschwerlin Jean

Current revision

This Sandbox is Reserved from 15/11/2014, through 15/05/2015 for use in the course "Biomolecule" taught by Bruno Kieffer at the Strasbourg University. This reservation includes Sandbox Reserved 951 through Sandbox Reserved 975.
To get started:
  • Click the edit this page tab at the top. Save the page after each step, then edit it again.
  • Click the 3D button (when editing, above the wikitext box) to insert Jmol.
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More help: Help:Editing

1f2w Cyanamide-Carbonic Anhydrase II EC 4.2.1.1

Structure of carbonic anhydrase II

Drag the structure with the mouse to rotate

References

1. Briganti F, Mangani S, Scozzafava A, Vernaglione G, Supuran CT (1999) "Carbonic anhydrase catalyzes cyanamide hydration

to urea: is it mimicking the physiological reaction?" J. Biol. Chem 528-36.


2. Guerri A, Briganti F, Scozzafava A, Supuran CT, Mangani S (2000) "Mechanism of cyanamide hydration catalyzed by carbonic

anhydrase II suggested by cryogenic X-ray diffraction" Biochemistry 12391-7


3. RCBS: http://www.rcsb.org/pdb/explore.do?structureId=1f2w consulted the 2/01/2015 [online]


4. PDJB: http://pdbj.org/mine/summary/1f2w consulted the 2/01/2014 [online]


5. Jennalib: http://jenalib.fli-leibniz.de/cgi-bin/ImgLib.pl?CODE=1f2w consulted the 3/01/2015 [online]


6. Wikipedia "Carbonic anhydrase" http://en.wikipedia.org/wiki/Carbonic_anhydrase consulted the 27/12/2014 [online]


7. Wikipedia "Cyanamide" http://en.wikipedia.org/wiki/Cyanamide consulted the 27/12/2014 [online]


Editors

Flinois Arielle

Hubschwerlin Jean

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