shannon hoon river phoenix chris farley what did they have in common? they were all cocaine addicts...
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Shannon Hoon
River Phoenix
Chris Farley
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What did they What did they have in have in
common?common?
They were all cocaine They were all cocaine addicts and they died of addicts and they died of
cocaine overdose!cocaine overdose!
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COCAINE ESTERASE (cocE)COCAINE ESTERASE (cocE)The story of the ‘dope The story of the ‘dope fiend’ fiend’ Rhodococcus Rhodococcus bacteria.bacteria.
By: Gladys de LeonBy: Gladys de Leon
Department of Chemistry and Department of Chemistry and BiochemistryBiochemistry
University of GuelphUniversity of Guelph
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OverviewOverview
general description of Cocainegeneral description of Cocaine Brain mechanism under influence of Brain mechanism under influence of
cocainecocaine Effects and dependencyEffects and dependency CocE overviewCocE overview Structural and biochemical analysis of Structural and biochemical analysis of
cocEcocE Concluding remarksConcluding remarks
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Structure of cocaineStructure of cocaine
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What is cocaine?What is cocaine?
C, coke, snow, nose, candy, crackC, coke, snow, nose, candy, crack powerful central nervous system powerful central nervous system
(CNS) stimulant (CNS) stimulant provides intense feelings of pleasure provides intense feelings of pleasure Derived from leaves of South Derived from leaves of South
American coca bush (American coca bush (erythroxylon erythroxylon cocacoca and erythroxylon and erythroxylon novogranatense)novogranatense)
Addictive and can cause deathAddictive and can cause death
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Erythroxylon cocaErythroxylon coca
cultivated in Bolivia, cultivated in Bolivia, Peru and Ecuador Peru and Ecuador
grows to a height of grows to a height of up to eight feetup to eight feet
rich in vitamins, rich in vitamins, protein, calcium, iron protein, calcium, iron and fibreand fibre
cocaine content of cocaine content of the leaves ranges the leaves ranges from O.1% to 0.9%from O.1% to 0.9%
http://cocaine.org/cokleaf.html
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History of cocaineHistory of cocaine Used by man since 800 A.D.Used by man since 800 A.D. Cultivated by the Incan Cultivated by the Incan 1500s - Coca chewing of the South American 1500s - Coca chewing of the South American
IndiansIndians 1860s - Isolated from coca leaf by Albert Nieman1860s - Isolated from coca leaf by Albert Nieman 1880s - Sigmund Freud’s 1880s - Sigmund Freud’s Uber CocaUber Coca 1886 - 1886 - Coca ColaCoca Cola a a non-alcoholic medicinal non-alcoholic medicinal
tonictonic from Atlanta Georgia from Atlanta Georgia 1890s – Cocaine containing medicine1890s – Cocaine containing medicine 1922 – Narcotic Drug Import and Export Act 1922 – Narcotic Drug Import and Export Act
restricted coca importsrestricted coca imports
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Word from our sponsors:
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Coke in the 20Coke in the 20thth CenturyCentury
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1 Kg of Cocaine
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Tools of Trade
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How does Cocaine affect How does Cocaine affect the brain?the brain?
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The Dopamine HypothesisThe Dopamine Hypothesis
F. I. Carroll et al, Journal of Medical Chemistry 42, 2721-36 (1999)
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The brainThe brain
F. I. Carroll et al, Journal of Medical Chemistry 42, 2721-36 (1999)
NA – nucleus accumbensVT – ventral tegmentalFC – frontal cortexCB – cerebellerPT – putamenCN- caudate nucleus
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What are the What are the effects of cocaine effects of cocaine on the mind?on the mind?
Thinking and feeling brainThinking and feeling brain Racing thoughtsRacing thoughts RewardReward Felling of well beingFelling of well being
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!! EUPHORIA !!!! EUPHORIA !!Negative effects:Negative effects:
Increased heart rateIncreased heart rate
Hyperthermia Hyperthermia
Dilated pupilsDilated pupils
DiaphoresisDiaphoresis
IrritabilityIrritability
Decrease appetiteDecrease appetite
SleeplessnessSleeplessness
DepressionDepression
Over dose:Over dose: respiratory arrest respiratory arrest
Myocardial infarctionMyocardial infarction
ArrhythmiaArrhythmia
SeizuresSeizures
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Cocaine Dependency : Cocaine Dependency : Three classical clinical Three classical clinical characteristics that define characteristics that define addictionaddiction
1.1. Psychological Psychological dependencedependence
2.2. ToleranceTolerance
3.3. Physical withdrawalPhysical withdrawal
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1. Psychological 1. Psychological dependencedependence
Compulsive drug seeking behavior Compulsive drug seeking behavior despite negative consequencesdespite negative consequences
Drug becomes the highest priority Drug becomes the highest priority in the individual’s lifein the individual’s life
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2. Tolerance2. Tolerance
As time goes on, more and more As time goes on, more and more of the drug is needed to produce of the drug is needed to produce the same highthe same high
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3. Physical withdrawal3. Physical withdrawal
Constellation signs and symptoms Constellation signs and symptoms that occur following cessation of that occur following cessation of drug usedrug use
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Emergency Emergency SituationSituation
COCAINE COCAINE OVERDOSEOVERDOSE
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So what is an ideal So what is an ideal cocaine antidote in an cocaine antidote in an emergency setting?emergency setting?
High catalytic proficiencyHigh catalytic proficiency Lack of observable product Lack of observable product
inhibitioninhibition Ability to hydrolyze both cocaine Ability to hydrolyze both cocaine
and cocaethyleneand cocaethylene
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Cocaine Esterase Cocaine Esterase (cocE) is an (cocE) is an attractive candidate attractive candidate for rapid cocaine for rapid cocaine detoxification in an detoxification in an emergency setting.emergency setting.
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Overview of cocE:Overview of cocE:
Identified in the bacteria Identified in the bacteria RhodococcusRhodococcus sp. Strain MB1 (sp. Strain MB1 (Rhodococcus Rhodococcus thrives in thrives in the rhizosphere soil of the cocaine-the rhizosphere soil of the cocaine-producing plant Erythroxylum coca)producing plant Erythroxylum coca)
Cocaine degrading enzymeCocaine degrading enzyme First enzyme in the metabolic pathway First enzyme in the metabolic pathway
leading to cocaine catabolismleading to cocaine catabolism Inducible and specific for cocaineInducible and specific for cocaine
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Hydrolysis of cocaine by Hydrolysis of cocaine by cocEcocE
D. W. Landry et al, Science, 259, 1899-1901
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Structural and Structural and Biochemical Biochemical Characterization of Characterization of Cocaine Esterase (cocE)Cocaine Esterase (cocE)
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Structural Overview of Structural Overview of cocEcocE
Belongs to the Belongs to the // hydrolase hydrolase superfamilysuperfamily
574 amino acids574 amino acids ~65,000 Daltons~65,000 Daltons 3 domains – (DOM 1, DOM 2, DOM 3 domains – (DOM 1, DOM 2, DOM
3)3) 30 % 30 % -sheet-sheet 23 % 23 % -helix-helix
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What is the structure of What is the structure of cocE?cocE?
N. A. Larsen et al., Nature Structural Biology 9, 17-21 (2002)
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Domain Domain Structure Structure
and and AssociationAssociation
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Domain 1: Domain 1: // sandwich sandwich
Residues 1-144 and Residues 1-144 and residues 241-354residues 241-354
Hydrolase fold Hydrolase fold (repeating (repeating --- - motifs)motifs)
Central Central -sheet is -sheet is predominantly predominantly parallelparallel
Contains the active Contains the active site His-287site His-287
N. A. Larsen et al., Nature Structural Biology 9, 17-21 (2002)
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REVIEWREVIEW
N. A. Larsen et al., Nature Structural Biology 9, 17-21 (2002)
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Domain 2: The Domain 2: The -helical -helical domaindomain
95 amino acids95 amino acids Compose of 7 Compose of 7
heliceshelices Inserted between Inserted between
6 and 6 and 7 of 7 of Domain 1Domain 1
Five helix core – Five helix core – helices H2-H6helices H2-H6
N. A. Larsen et al., Nature Structural Biology 9, 17-21 (2002)
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REVIEWREVIEW
N. A. Larsen et al., Nature Structural Biology 9, 17-21 (2002)
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Domain 3: jelly-roll Domain 3: jelly-roll --barrelbarrel
221 amino acids221 amino acids Overall fold has a jelly-Overall fold has a jelly-
roll-like topology ( i.e. roll-like topology ( i.e. Hgg-Haemagglutinin)Hgg-Haemagglutinin)
Mostly Mostly -structure-structure -barrel-like core-barrel-like core Strands connected by Strands connected by
6 cross over loops6 cross over loops Important role in the Important role in the
overall tertiary overall tertiary structurestructureN. A. Larsen et al., Nature Structural Biology 9, 17-21 (2002)
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Active site of cocEActive site of cocE
Located in a cleft Located in a cleft formed at the formed at the interface of the interface of the three domainsthree domains
Catalytic triad – Catalytic triad – Ser 117, Asp 259 Ser 117, Asp 259 and His 287and His 287
Oxyanion hole – Oxyanion hole – backbone amide backbone amide of Y118 and Y44of Y118 and Y44
N. A. Larsen et al., Nature Structural Biology 9, 17-21 (2002)
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Proposed Mechanism for Proposed Mechanism for acyl intermediate acyl intermediate hydrolysishydrolysis
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Biochemical Biochemical Characterization and Characterization and Structural Analysis of cocEStructural Analysis of cocE
cocE hydrolyzes cocaine faster than any cocE hydrolyzes cocaine faster than any other reported cocaine esteraseother reported cocaine esterase
Follows Michaelis-Menten kinetics with Follows Michaelis-Menten kinetics with kcat= 7.8 s-1 and Km 640 nm.kcat= 7.8 s-1 and Km 640 nm.
Similar rate for cocaethyleneSimilar rate for cocaethylene Validated the proposed mechanismValidated the proposed mechanism Reveal contributions of active site Reveal contributions of active site
towards substrate recognition and towards substrate recognition and catalysiscatalysis
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J.M. Turner et al. Biochemistry, 41, 12297-12307 ( 2002)
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In conclusion:In conclusion:
cocE enzyme itself has therapeutic cocE enzyme itself has therapeutic potential as an enzyme-based potential as an enzyme-based treatment for cocaine overdose, treatment for cocaine overdose, furthermore, the crystal structure furthermore, the crystal structure of the bacterial cocaine esterase of the bacterial cocaine esterase provides a basis for further provides a basis for further antibody engineeringantibody engineering..
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http://cocaine.org/cokehell.html
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ReferencesReferences1.1. W.F. Borson and T.D. Hurley, W.F. Borson and T.D. Hurley, Nat Struct Biol.Nat Struct Biol. 99, 4-5 (2002)., 4-5 (2002).2.2. N.A. Larsen et al., N.A. Larsen et al., Nat Struct BiolNat Struct Biol. . 99, 17-21 (2002)., 17-21 (2002).3.3. J.M. Turner J.M. Turner et alet al., ., BiochemistryBiochemistry, , 4141, 12297-12307 (2002)., 12297-12307 (2002).4.4. Larsen, N. A., Zhou, B., Heine, A., Wirsching, P., Janda, K. D., and Wilson, I. A. Larsen, N. A., Zhou, B., Heine, A., Wirsching, P., Janda, K. D., and Wilson, I. A.
J. Mol. Biol. J. Mol. Biol. 311311, 9-15 (2001) , 9-15 (2001) 5.5. F.I. Carroll, L.L. Howell, and M.J. Kuhar, F.I. Carroll, L.L. Howell, and M.J. Kuhar, J Med ChemJ Med Chem. . 4242, 2721-2736 (1999)., 2721-2736 (1999).6.6. L.L. Howell and K.M. Wilcox, L.L. Howell and K.M. Wilcox, Perspectives in PharmacologyPerspectives in Pharmacology, , 298298, 1- 6 (2000)., 1- 6 (2000).7.7. A. M. Washton and M.S. Gold. “Cocaine: A clinician’s handbook”, The Guilford A. M. Washton and M.S. Gold. “Cocaine: A clinician’s handbook”, The Guilford
Press, New York. 1987. Pp. 73-79.Press, New York. 1987. Pp. 73-79.8.8. D.W. Landry D.W. Landry et al., Scienceet al., Science, , 259259, 1899- 1901 (1993)., 1899- 1901 (1993).9.9. P.H. Earley. “The Cocaine Recovery Book”, Sage Publications, London. 1991, P.H. Earley. “The Cocaine Recovery Book”, Sage Publications, London. 1991,
pp.9-35.pp.9-35.10.10. L.M. Kamendulis et al., L.M. Kamendulis et al., Jour. Phar. Exp. TherJour. Phar. Exp. Ther., ., 279279, 713-717 (1996)., 713-717 (1996).11.11. M.R. Brzezinski et al., M.R. Brzezinski et al., Drug Metab DisposDrug Metab Dispos., ., 99, 1089-1096 (1997)., 1089-1096 (1997).12.12. C. E. Mattes et al., C. E. Mattes et al., Addict BiolAddict Biol., ., 22, 171-188 (1998)., 171-188 (1998).13.13. http://www.cocaine.org/cokeleaf.htmlhttp://www.cocaine.org/cokeleaf.html14.14. http://www.hc-sc.gc.ca/hppb/alcohol-otherdrugs/pube/straight/stimulants.htmhttp://www.hc-sc.gc.ca/hppb/alcohol-otherdrugs/pube/straight/stimulants.htm15.15. http://www.a1b2c3.com/drugs/coc03.htmhttp://www.a1b2c3.com/drugs/coc03.htm