carbonic anhydrase
DESCRIPTION
this document gives information about carbonic anhydrase,its background,mechanism role of zincTRANSCRIPT
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CARBONICANHYDRASE:WhyZinc?
By:AmirSafi
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WhatReactionisCatalyzed?
H2O+CO2 H+ +HCO3
CarbonicAnhydrase CatalyzestheReactionofwater+carbondioxidetoformbicarbonate.
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Rate of Catalysis
kuncat = 10-11 s-1kcat = 104 s-1
CO2 + H2O = HCO3- + H+
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Role of Zn(II) in Proteins1. Catalytic: involved directly in catalytic steps
(e.g., CA)
2. Structural: required for the stability of a protein structure, or arrangement of an active site (e.g., CuZnSOD)
3. Regulatory: Zn-free enzyme has activity, addition of Zn2+enhance or inhibit activity
(e.g., zinc finger family of proteins)
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Zinc Fingers
Jamieson, Andrew C.; Miller, Jeffrey C.; Pabo, Carl O. Nature Rev. Drug Discovery (2003), 2, 361-368.
Cys2His2 zinc fingers are found in 2% of all human genes
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Hydrolytic reactions
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Hydrolytic reactions
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BackgroundonCarbonicAnhydrase
CarbonicAnhydrase isanenzymethatislocatedinredbloodcells.
Itcontainsabout.31to.34%zinc.
Thisisimportantbecauseitsthefirstknowndirectphysiologicalfunctionofzinc.
http://www.pdb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb49_1.html
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CarbonAnhydrase Mechanism
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Step1:deprotonation
1.Berg,JeremyM.(2007).Biochemistry,6thEd.
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Step2:Carboxylation Theanionicoxygenthenperformsanucleophilicattackonthecarbon.
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Step3:FormationofRingStructure
AnionicoxygenformsabondwithZn2+tomakearinglikeresonance.
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Step4:FormationofBicarbonate
Additionofwaterdisplacesthebicarbonateion.
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CarbonicAnhydrase Mechanism
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BIGQUESTION:WHYDOESCARBONANHYDRASEUSE
ZINC?
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HistoryofZinc Zinccompoundshavebeenusedforatleast2,500years
Zincderiveditsname,supposedly,fromtheGermanword Zinke,whichmeans'toothlike'or'pointed'.
MetalliczincwasfirstproducedinIndiasometimeinthe1400sbyheatingthemineralcalamine(ZnCO3)withwool.
ZincwasrediscoveredbyAndreasSigismundMarggraf in1746byheatingcalaminewithcharcoal.
http://www.buzzle.com/articles/historyofzinc.html
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Fe,Zn,Cu:themostcommontransitionmetalionsinbiology
ELEMENT Sea Water(M)x10^8 Human Body(M)x10^8
Fe .0052 2230
Zn 8 1720
Cu 1 1650
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PropertiesofZinc
2+istheonlyaccessibleoxidationstate(d10) Bindsbothhardandsoftdonors Tetrahedralgeometrypreferred 56CNareaccessible GoodLewisacidbecausehighcharge/radiusratio
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Zincisd10 ZincIoniscolorless
NotRedox Active
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Hard/SoftAcidBaseTheory
GoodLewisacidbecausehighcharge/radiusratio
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Borderline
Metals:
Fe2+,Ni2+,Zn2+,Co2+,Cu2+
Ligands:
SR,his,X,RCO2
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ZincGeometryanddorbitalSplittingdiagrams.
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RECAPWhyZinc:
1. 2+istheonlyaccessibleoxidationstate(d10) Nocomplicationsfromredox activity.
2.Bindsbothhardandsoftdonors
3.Tetrahedralgeometrypreferred/56CNareaccessible
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MedicalApplication:TreatGlaucoma
Carbonicanhydraseinhibitorsareapplicableduringemergenciesbecausetheyareabletorapidlyreducethepressurethathasbuiltupinsidetheeyeby40%to60%.Thelessfluidthatisallowedtobuildupyieldslesspressurebehindtheeye.
http://www.pdb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb49_2.html
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Acetazolamide
Diuretic:Diureticsaredrugsthatincreasetherateofurineflow.SoldasthedrugDiamox
http://jpet.aspetjournals.org/content/115/3/251.abstract
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CarbonicAnhydrase Inhibition
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BadNewsorGoodNews
Glaucoma: Themechanismofactionto
lowerpressureisnotknown.Therouteofadministrationcanbeoral,intravenous,topical,orinhaledbysmoking,anditdictatesmanyofthebehavioralandphysiologicconsequences.Oftheseroutes,smokinghasthemorerapidonsetofpsychoactiveandotherpharmacologiceffect
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IsZincBoring?http://www.youtube.com/watch?v=99wPiMbk0o
CARBONIC ANHYDRASE:Why Zinc?What Reaction is Catalyzed?Rate of CatalysisRole of Zn(II) in ProteinsSlide Number 5Hydrolytic reactionsSlide Number 7Background on Carbonic AnhydraseCarbon Anhydrase MechanismStep 1: deprotonationStep 2: CarboxylationStep 3: Formation of Ring StructureStep 4: Formation of Bicarbonate Carbonic Anhydrase MechanismBIG QUESTION:History of ZincFe, Zn, Cu: the most common transition metal ions in biologyProperties of ZincZinc is d10Hard/ Soft Acid Base TheoryBorderlineZinc Geometry and d orbital Splitting diagrams.RECAPMedical Application: Treat GlaucomaAcetazolamideCarbonic Anhydrase InhibitionBad News or Good NewsIs Zinc Boring?