Sandbox Reserved 987 - Revision history

David Buck at 05:31, 6 April 2015

David Buck — Mon, 06 Apr 2015 05:31:55 GMT

←Older revision		Revision as of 05:31, 6 April 2015
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	== Mutations ==		== Mutations ==
-	The wild-type cocaine esterase is not stable at physiological temperature, which poses a problem for its use as a pharmaceutical drug. Mutations have been conducted in order to increase its thermostability. In vivo testing showed the wild-type having a 11 min half-life. A mutant having its threonine swapped for a arginine at position 172 (T172R) was found to last 9 times as long, and a mutant that further had its glycine swapped for a glutamine (T172R/G173Q) was found to last 24 times as long (~4h 20m)<sup><ref>Gao D., Narasimhan D. L., Macdonald J., Brim R., Ko M., Landry D. W., Woods J. H., Sunahara R. K., Zhan C. (2009) Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity. Mol. Pharmacol. 75, 318-323.</ref></sup> Another mutant that has been explored is the L169K/G173Q mutant. This showed an in vivo half life of ~2h 20m.<sup><ref>Brim R. L., Nance M. R., Youngstrom D. W., Narasimhan D., Zhan C. G., Tesmer J. J. G., Sunahara, R. K., Woods J. W. (2010) A Thermally Stable Form of Bacterial Cocaine Esterase: A Potential Therapeutic Agent for Treatment of Cocaine Abuse. Mol. Pharmacol. 77(4), 593-600.</ref></sup>	+	The wild-type cocaine esterase is not stable at physiological temperature, which poses a problem for its use as a pharmaceutical drug. Mutations have been conducted in order to increase its thermostability. In vivo testing showed the wild-type having a 11 min half-life. A mutant having its threonine swapped for a arginine at position 172 (T172R) was found to last 9 times as long, and a mutant that further had its glycine swapped for a glutamine (T172R/G173Q) was found to last 24 times as long (~4h 20m)<sup><ref>Gao D., Narasimhan D. L., Macdonald J., Brim R., Ko M., Landry D. W., Woods J. H., Sunahara R. K., Zhan C. (2009) Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity. Mol. Pharmacol. 75, 318-323.</ref></sup> Another mutant that has been explored is the L169K/G173Q mutant. This showed an in vivo half life of ~2h 20m.<sup><ref>Brim R. L., Nance M. R., Youngstrom D. W., Narasimhan D., Zhan C. G., Tesmer J. J. G., Sunahara, R. K., Woods J. W. (2010) A Thermally Stable Form of Bacterial Cocaine Esterase: A Potential Therapeutic Agent for Treatment of Cocaine Abuse. Mol. Pharmacol. 77(4), 593-600.</ref></sup> L169K causes a large increase in half life up to 9h 30m, but reduced catalytic efficiency 4.5 fold.<sup><ref>Narasimhan D., Nance M.R., Gao D., Ko M.C., Macdonald J., Tamburi P., Yoon D., Landry D.M., Woods J.H., Zhan C.G., Tesmer J.J., Sunahara R.K. (2009) Structural analysis of thermostabilizing mutations of cocaine esterase. Protein Eng. Des. Sel. 23:537-547.</ref></sup>
-		+
-	L169K causes a large increase in half life up to 9h 30m, but reduced catalytic efficiency 4.5 fold.<sup><ref>Narasimhan D., Nance M.R., Gao D., Ko M.C., Macdonald J., Tamburi P., Yoon D., Landry D.M., Woods J.H., Zhan C.G., Tesmer J.J., Sunahara R.K. (2009) Structural analysis of thermostabilizing mutations of cocaine esterase. Protein Eng. Des. Sel. 23:537-547.</ref></sup>	+

	== Medical Relevance ==		== Medical Relevance ==

David Buck at 05:31, 6 April 2015

David Buck — Mon, 06 Apr 2015 05:31:15 GMT

←Older revision		Revision as of 05:31, 6 April 2015
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	== Mutations ==		== Mutations ==
	The wild-type cocaine esterase is not stable at physiological temperature, which poses a problem for its use as a pharmaceutical drug. Mutations have been conducted in order to increase its thermostability. In vivo testing showed the wild-type having a 11 min half-life. A mutant having its threonine swapped for a arginine at position 172 (T172R) was found to last 9 times as long, and a mutant that further had its glycine swapped for a glutamine (T172R/G173Q) was found to last 24 times as long (~4h 20m)<sup><ref>Gao D., Narasimhan D. L., Macdonald J., Brim R., Ko M., Landry D. W., Woods J. H., Sunahara R. K., Zhan C. (2009) Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity. Mol. Pharmacol. 75, 318-323.</ref></sup> Another mutant that has been explored is the L169K/G173Q mutant. This showed an in vivo half life of ~2h 20m.<sup><ref>Brim R. L., Nance M. R., Youngstrom D. W., Narasimhan D., Zhan C. G., Tesmer J. J. G., Sunahara, R. K., Woods J. W. (2010) A Thermally Stable Form of Bacterial Cocaine Esterase: A Potential Therapeutic Agent for Treatment of Cocaine Abuse. Mol. Pharmacol. 77(4), 593-600.</ref></sup>		The wild-type cocaine esterase is not stable at physiological temperature, which poses a problem for its use as a pharmaceutical drug. Mutations have been conducted in order to increase its thermostability. In vivo testing showed the wild-type having a 11 min half-life. A mutant having its threonine swapped for a arginine at position 172 (T172R) was found to last 9 times as long, and a mutant that further had its glycine swapped for a glutamine (T172R/G173Q) was found to last 24 times as long (~4h 20m)<sup><ref>Gao D., Narasimhan D. L., Macdonald J., Brim R., Ko M., Landry D. W., Woods J. H., Sunahara R. K., Zhan C. (2009) Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity. Mol. Pharmacol. 75, 318-323.</ref></sup> Another mutant that has been explored is the L169K/G173Q mutant. This showed an in vivo half life of ~2h 20m.<sup><ref>Brim R. L., Nance M. R., Youngstrom D. W., Narasimhan D., Zhan C. G., Tesmer J. J. G., Sunahara, R. K., Woods J. W. (2010) A Thermally Stable Form of Bacterial Cocaine Esterase: A Potential Therapeutic Agent for Treatment of Cocaine Abuse. Mol. Pharmacol. 77(4), 593-600.</ref></sup>
		+
		+	L169K causes a large increase in half life up to 9h 30m, but reduced catalytic efficiency 4.5 fold.<sup><ref>Narasimhan D., Nance M.R., Gao D., Ko M.C., Macdonald J., Tamburi P., Yoon D., Landry D.M., Woods J.H., Zhan C.G., Tesmer J.J., Sunahara R.K. (2009) Structural analysis of thermostabilizing mutations of cocaine esterase. Protein Eng. Des. Sel. 23:537-547.</ref></sup>

	== Medical Relevance ==		== Medical Relevance ==

David Buck at 04:22, 6 April 2015

David Buck — Mon, 06 Apr 2015 04:22:53 GMT

←Older revision		Revision as of 04:22, 6 April 2015
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	== Mutations ==		== Mutations ==
-	The wild-type cocaine esterase is not stable at physiological temperature, which poses a problem for its use as a pharmaceutical drug. Mutations have been conducted in order to increase its thermostability. In vivo testing showed the wild-type having a 11 min half-life. A mutant having its threonine swapped for a arginine at position 172 was found to last 9 times as long, and a mutant that further had its glycine swapped for a glutamine was found to last 24 times as long (~~~4hr 20min~~)<sup><ref>Gao D., Narasimhan D. L., Macdonald J., Brim R., Ko M., Landry D. W., Woods J. H., Sunahara R. K., Zhan C. (2009) Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity. Mol. Pharmacol. 75, 318-323.</ref></sup> ~~Further research was conducted to~~	+	The wild-type cocaine esterase is not stable at physiological temperature, which poses a problem for its use as a pharmaceutical drug. Mutations have been conducted in order to increase its thermostability. In vivo testing showed the wild-type having a 11 min half-life. A mutant having its threonine swapped for a arginine at position 172 (T172R) was found to last 9 times as long, and a mutant that further had its glycine swapped for a glutamine (T172R/G173Q) was found to last 24 times as long (~4h 20m)<sup><ref>Gao D., Narasimhan D. L., Macdonald J., Brim R., Ko M., Landry D. W., Woods J. H., Sunahara R. K., Zhan C. (2009) Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity. Mol. Pharmacol. 75, 318-323.</ref></sup> Another mutant that has been explored is the L169K/G173Q mutant. This showed an in vivo half life of ~2h 20m.<sup><ref>Brim R. L., Nance M. R., Youngstrom D. W., Narasimhan D., Zhan C. G., Tesmer J. J. G., Sunahara, R. K., Woods J. W. (2010) A Thermally Stable Form of Bacterial Cocaine Esterase: A Potential Therapeutic Agent for Treatment of Cocaine Abuse. Mol. Pharmacol. 77(4), 593-600.</ref></sup>

	== Medical Relevance ==		== Medical Relevance ==

David Buck at 03:24, 6 April 2015

David Buck — Mon, 06 Apr 2015 03:24:48 GMT

←Older revision		Revision as of 03:24, 6 April 2015
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	== Mutations ==		== Mutations ==
-	The wild-type cocaine esterase is not stable at physiological temperature, which poses a problem for its use as a pharmaceutical drug. Mutations have been conducted in order to increase its thermostability. In vivo testing showed the wild-type having a 11 min half-life. A mutant having its threonine swapped for a arginine at position 172 was found to last 9 times as long, and a mutant that further had its glycine swapped for a glutamine was found to last 24 times as long (~4hr 20min)<sup><ref>Gao D., Narasimhan D. L., Macdonald J., Brim R., Ko M., Landry D. W., Woods J. H., Sunahara R. K., Zhan C. (2009) Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity. Mol. Pharmacol. 75, 318-323.</ref></sup>	+	The wild-type cocaine esterase is not stable at physiological temperature, which poses a problem for its use as a pharmaceutical drug. Mutations have been conducted in order to increase its thermostability. In vivo testing showed the wild-type having a 11 min half-life. A mutant having its threonine swapped for a arginine at position 172 was found to last 9 times as long, and a mutant that further had its glycine swapped for a glutamine was found to last 24 times as long (~4hr 20min)<sup><ref>Gao D., Narasimhan D. L., Macdonald J., Brim R., Ko M., Landry D. W., Woods J. H., Sunahara R. K., Zhan C. (2009) Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity. Mol. Pharmacol. 75, 318-323.</ref></sup> Further research was conducted to

	== Medical Relevance ==		== Medical Relevance ==

David Buck at 03:14, 6 April 2015

David Buck — Mon, 06 Apr 2015 03:14:11 GMT

←Older revision		Revision as of 03:14, 6 April 2015
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-	==Cocaine Esterase==
-
	<Structure load='4P08' size='400' frame ='true' align='right' caption='Cocaine Esterase' scene='69/691529/Cocaineesterase/1' />		<Structure load='4P08' size='400' frame ='true' align='right' caption='Cocaine Esterase' scene='69/691529/Cocaineesterase/1' />

David Buck at 02:35, 6 April 2015

David Buck — Mon, 06 Apr 2015 02:35:13 GMT

←Older revision		Revision as of 02:35, 6 April 2015
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	== Medical Relevance ==		== Medical Relevance ==

-	Cocaine is a tropane alkaloid produced by the South American plant Erythroxylon coca.<sup><ref>Benowitz NL. Clinical pharmacology and toxicology of cocaine. Pharmacol. Toxicol. 1993; 72(1): 3–12. [PubMed: 8441738]</ref></sup> Cocaine’s psychological effects occur via binding to neurotransmitter reuptake transporters in the presynaptic nerve termini and blocking them, leading to prolonged presence of neurotransmitters in the synapse.<sup><ref>Johanson CE, Fischman MW. The pharmacology of cocaine related to its abuse. Pharmacol. Rev. 1989; 41(1):3–52. [PubMed: 2682679]</ref></sup> Large amounts of dopamine and serotonin in the synapse results in feelings of euphoria and wellbeing. This lingering increase in neurotransmitters within the synapse can lead to self-administration and, therefore, addiction. When cocaine is bound to noradrenergic transporters, elevated noradrenergic signaling occurs, resulting in increased heart rate (HR), blood pressure and vasoconstriction which are often seen in cocaine users.<sup><ref>Crumb WJ Jr, Kadowitz PJ, Xu YQ, Clarkson CW. Electrocardiographic evidence for cocaine cardiotoxicity in cat. Can. J. Physiol. Pharmacol. 1990; 68(5):622–625. [PubMed: 2340451]</ref></sup> Cocaine also binds cardiac and neuronal sodium channels leading to profound cardiovascular and central nervous system alterations that are frequently lethal.<sup><ref>Zimmerman JL. Cocaine intoxication. Crit Care Clin 2012; 28: 517–526</ref></sup> Cocaine abuse is a serious public health problem. 50% of emergency room visits are due to illicit drug use, cocaine accounts for the majority of those cases.<sup><ref>Ball, JK.; Albright, V. National Estimates of Drug-Related Emergency Department Visits. Rockville, MD, USA: Substance Abuse and Mental Health Services Administration, Office of Applied Studies; 2008</ref></sup> Interestingly, despite cocaine’s broad use and ~~high addictiveness~~, there is no US FDA-approved medication for the treatment of cocaine abuse or toxicity. Physicians treat patients enduring cocaine toxicity with standard emergency room agents that control arrhythmias, convulsions and high blood pressure but not with drugs that directly address the toxic levels of cocaine present in the patient.	+	Cocaine is a tropane alkaloid produced by the South American plant Erythroxylon coca.<sup><ref>Benowitz NL. Clinical pharmacology and toxicology of cocaine. Pharmacol. Toxicol. 1993; 72(1): 3–12. [PubMed: 8441738]</ref></sup> Cocaine’s psychological effects occur via binding to neurotransmitter reuptake transporters in the presynaptic nerve termini and blocking them, leading to prolonged presence of neurotransmitters in the synapse.<sup><ref>Johanson CE, Fischman MW. The pharmacology of cocaine related to its abuse. Pharmacol. Rev. 1989; 41(1):3–52. [PubMed: 2682679]</ref></sup> Large amounts of dopamine and serotonin in the synapse results in feelings of euphoria and wellbeing. This lingering increase in neurotransmitters within the synapse can lead to self-administration and, therefore, addiction. When cocaine is bound to noradrenergic transporters, elevated noradrenergic signaling occurs, resulting in increased heart rate (HR), blood pressure and vasoconstriction which are often seen in cocaine users.<sup><ref>Crumb WJ Jr, Kadowitz PJ, Xu YQ, Clarkson CW. Electrocardiographic evidence for cocaine cardiotoxicity in cat. Can. J. Physiol. Pharmacol. 1990; 68(5):622–625. [PubMed: 2340451]</ref></sup> Cocaine also binds cardiac and neuronal sodium channels leading to profound cardiovascular and central nervous system alterations that are frequently lethal.<sup><ref>Zimmerman JL. Cocaine intoxication. Crit Care Clin 2012; 28: 517–526</ref></sup> Cocaine abuse is a serious public health problem. 50% of emergency room visits are due to illicit drug use, cocaine accounts for the majority of those cases.<sup><ref>Ball, JK.; Albright, V. National Estimates of Drug-Related Emergency Department Visits. Rockville, MD, USA: Substance Abuse and Mental Health Services Administration, Office of Applied Studies; 2008</ref></sup> Interestingly, despite cocaine’s broad use and addictive effects, there is no US FDA-approved medication for the treatment of cocaine abuse or toxicity. Physicians treat patients enduring cocaine toxicity with standard emergency room agents that control arrhythmias, convulsions and high blood pressure but not with drugs that directly address the toxic levels of cocaine present in the patient.

	Finding a therapeutic agent to combat cocaine, such as small molecules has proven difficult. For this reason, the focus has been switched to cocaine esterases. For over a decade, cocaine esterases have been studied and numerous findings strongly suggest that bacterial cocaine esterases should provide a safe and effective method to rapidly eliminate the symptoms of acute cocaine intoxication in humans, as well as reducing addictiveness to the drug.		Finding a therapeutic agent to combat cocaine, such as small molecules has proven difficult. For this reason, the focus has been switched to cocaine esterases. For over a decade, cocaine esterases have been studied and numerous findings strongly suggest that bacterial cocaine esterases should provide a safe and effective method to rapidly eliminate the symptoms of acute cocaine intoxication in humans, as well as reducing addictiveness to the drug.

David Buck at 02:33, 6 April 2015

David Buck — Mon, 06 Apr 2015 02:33:23 GMT

←Older revision		Revision as of 02:33, 6 April 2015
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	== Background ==		== Background ==
-	Cocaine use is ~~still~~ a problem with approximately 21 million people ~~using~~ worldwide. <sup><ref>"200 Million People Use Illicit Drugs, Study Finds" Katie Moisse. abcNews Medical Unit. 6 January 2012</ref></sup> Cocaine mostly affects the brain by inhibiting reuptake of norepinephrine, serotonin, and dopamine <sup><ref>"Cocaine Use and Its Effects" Joseph Goldberg. WebMD Substance Abuse and Addiction Health Center. 23 June 2013</ref></sup> With these neurotransmitters inhibited from reabsorbing it creates a sense of a "high" for the person using but the "crash" can lead to paranoia, restlessness, and anxiety.	+	Cocaine use is a problem with approximately 21 million people abusing it worldwide. <sup><ref>"200 Million People Use Illicit Drugs, Study Finds" Katie Moisse. abcNews Medical Unit. 6 January 2012</ref></sup> Cocaine mostly affects the brain by inhibiting reuptake of norepinephrine, serotonin, and dopamine <sup><ref>"Cocaine Use and Its Effects" Joseph Goldberg. WebMD Substance Abuse and Addiction Health Center. 23 June 2013</ref></sup> With these neurotransmitters inhibited from reabsorbing it creates a sense of a "high" for the person using but the "crash" can lead to paranoia, restlessness, and anxiety.
-	Cocaine Esterase (CocE) is the most efficient protein to hydrolyze the cocaine domain known to date ''in vivo''.<sup><ref>"Effects of cocaine esterase following its repeated administration with cocaine in mice" Mei-Chaun Ko, Diwahar Narasimhan, Aaron A. Berlin, Nicholas W. Lukacs, Roger K. Sunahara, James H. Woods. Drug and Alcohol Dependence 1 May 2009;101:202-09. doi: 10.1016/j.drugalcdep.2009.01.002</ref></sup> Cocaine Esterase is used in bacterium ''Rhodococcus'' which hydrolyzes the cocaine that it uptakes and uses it for carbons and nitrogens. Although this protein metabolizes cocaine in bacterium, it is sure to induce an immune response as it is foreign to the human body. This could mitigate the effects of CocE if a person had suffered from cocaine toxicity.	+	Cocaine Esterase (CocE) is the most efficient protein to hydrolyze the cocaine domain known to date ''in vivo''.<sup><ref>"Effects of cocaine esterase following its repeated administration with cocaine in mice" Mei-Chaun Ko, Diwahar Narasimhan, Aaron A. Berlin, Nicholas W. Lukacs, Roger K. Sunahara, James H. Woods. Drug and Alcohol Dependence 1 May 2009;101:202-09. doi: 10.1016/j.drugalcdep.2009.01.002</ref></sup> Cocaine Esterase is used in bacterium ''Rhodococcus'', which hydrolyzes the cocaine that it uptakes and uses it for carbons and nitrogens. Although this protein metabolizes cocaine in bacterium, it is sure to induce an immune response as it is foreign to the human body. This could mitigate the effects of CocE if a person had suffered from cocaine toxicity.

	== Structure ==		== Structure ==
	<scene name='69/691529/Cocaine_esterase/1'>Cocaine Esterase</scene>		<scene name='69/691529/Cocaine_esterase/1'>Cocaine Esterase</scene>

-	Cocaine Esterase is a globular protein that is expressed in the cytosol of ''Rhodococcus'' strain of bacteria, containing 574 residues divided into three domains. Domain I is a α/β hydrolase fold-containing domain consisting of residues 1-144 and residues 241-354 with the active site His-287. Domain II is a α-helical consisting of residues 145-240, making up seven helices inserted between β6 and β7 of Domain I. Helices two through six together form a five helix core with helices two and three combine to make a lid-like structure over the active site, His-287. Domain III is made up of residues 355-574 with mostly β-structure ~~and~~ a β-barrel-like core connected by 6 cross over loops, forming a jelly roll-like topology.<sup><ref>Narasimhan, D.; Woods, J.H.; Sunahara, R.K. “Bacterial cocaine esterase: a protein-based therapy for cocaine overdose and addiction.” ''Future Med Chem.'' 2012, 4, 2: 137-150.</ref></sup>	+	Cocaine Esterase is a globular protein that is expressed in the cytosol of ''Rhodococcus'' strain of bacteria, containing 574 residues divided into three domains. Domain I is a α/β hydrolase fold-containing domain consisting of residues 1-144 and residues 241-354 with the active site His-287. Domain II is α-helical, consisting of residues 145-240, making up seven helices inserted between β6 and β7 of Domain I. Helices two through six together form a five helix core with helices two and three combine to make a lid-like structure over the active site, His-287. Domain III is made up of residues 355-574 with mostly β-structure including a β-barrel-like core connected by 6 cross over loops, forming a jelly roll-like topology.<sup><ref>Narasimhan, D.; Woods, J.H.; Sunahara, R.K. “Bacterial cocaine esterase: a protein-based therapy for cocaine overdose and addiction.” ''Future Med Chem.'' 2012, 4, 2: 137-150.</ref></sup>

	<scene name='69/691529/Domain_i/2'>Domain I</scene> is highlighted in blue		<scene name='69/691529/Domain_i/2'>Domain I</scene> is highlighted in blue
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	== Mutations ==		== Mutations ==
-	The wild-type cocaine esterase is not stable at physiological temperature, which poses a problem for its use as a pharmaceutical drug. Mutations have been conducted in order to increase its thermostability. In vivo testing showed the wild-type having a ~~11min~~ half-life. A mutant having its threonine swapped for a arginine at position 172 was found to last 9 times as long and a mutant that further had its glycine swapped for a glutamine was found to last 24 times as long (~4hr 20min)<sup><ref>Gao D., Narasimhan D. L., Macdonald J., Brim R., Ko M., Landry D. W., Woods J. H., Sunahara R. K., Zhan C. (2009) Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity. Mol. Pharmacol. 75, 318-323.</ref></sup>	+	The wild-type cocaine esterase is not stable at physiological temperature, which poses a problem for its use as a pharmaceutical drug. Mutations have been conducted in order to increase its thermostability. In vivo testing showed the wild-type having a 11 min half-life. A mutant having its threonine swapped for a arginine at position 172 was found to last 9 times as long, and a mutant that further had its glycine swapped for a glutamine was found to last 24 times as long (~4hr 20min)<sup><ref>Gao D., Narasimhan D. L., Macdonald J., Brim R., Ko M., Landry D. W., Woods J. H., Sunahara R. K., Zhan C. (2009) Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity. Mol. Pharmacol. 75, 318-323.</ref></sup>

	== Medical Relevance ==		== Medical Relevance ==

-	Cocaine is a tropane alkaloid produced by the South American plant Erythroxylon coca.<sup><ref>Benowitz NL. Clinical pharmacology and toxicology of cocaine. Pharmacol. Toxicol. 1993; 72(1): 3–12. [PubMed: 8441738]</ref></sup> Cocaine’s psychological effects occur via binding to neurotransmitter reuptake transporters in the presynaptic nerve termini and blocking them, leading to prolonged presence of neurotransmitters in the synapse.<sup><ref>Johanson CE, Fischman MW. The pharmacology of cocaine related to its abuse. Pharmacol. Rev. 1989; 41(1):3–52. [PubMed: 2682679]</ref></sup> Large amounts of dopamine and serotonin in the synapse results in feelings of euphoria and wellbeing. This lingering increase in neurotransmitters within the synapse can lead to self-administration and, therefore, addiction. When cocaine is bound to noradrenergic transporters, elevated noradrenergic signaling occurs, resulting in increased heart rate (HR), blood pressure and vasoconstriction which are often seen in cocaine users.<sup><ref>Crumb WJ Jr, Kadowitz PJ, Xu YQ, Clarkson CW. Electrocardiographic evidence for cocaine cardiotoxicity in cat. Can. J. Physiol. Pharmacol. 1990; 68(5):622–625. [PubMed: 2340451]</ref></sup> Cocaine also binds cardiac and neuronal sodium channels leading to profound cardiovascular and central nervous system alterations that are frequently lethal.<sup><ref>Zimmerman JL. Cocaine intoxication. Crit Care Clin 2012; 28: 517–526</ref></sup> Cocaine abuse is a serious public health problem. ~~Emergency room visits due to cocaine abuse is greater than any other drug with nearly~~ 50% of emergency room visits ~~involving an~~ illicit drug.<sup><ref>Ball, JK.; Albright, V. National Estimates of Drug-Related Emergency Department Visits. Rockville, MD, USA: Substance Abuse and Mental Health Services Administration, Office of Applied Studies; 2008</ref></sup> Interestingly, despite cocaine’s broad use and high addictiveness, there is no US FDA-approved medication for the treatment of cocaine abuse or toxicity. Physicians treat patients enduring cocaine toxicity with standard emergency room agents that control arrhythmias, convulsions and high blood pressure but not with drugs that directly address the toxic levels of cocaine present in the patient.	+	Cocaine is a tropane alkaloid produced by the South American plant Erythroxylon coca.<sup><ref>Benowitz NL. Clinical pharmacology and toxicology of cocaine. Pharmacol. Toxicol. 1993; 72(1): 3–12. [PubMed: 8441738]</ref></sup> Cocaine’s psychological effects occur via binding to neurotransmitter reuptake transporters in the presynaptic nerve termini and blocking them, leading to prolonged presence of neurotransmitters in the synapse.<sup><ref>Johanson CE, Fischman MW. The pharmacology of cocaine related to its abuse. Pharmacol. Rev. 1989; 41(1):3–52. [PubMed: 2682679]</ref></sup> Large amounts of dopamine and serotonin in the synapse results in feelings of euphoria and wellbeing. This lingering increase in neurotransmitters within the synapse can lead to self-administration and, therefore, addiction. When cocaine is bound to noradrenergic transporters, elevated noradrenergic signaling occurs, resulting in increased heart rate (HR), blood pressure and vasoconstriction which are often seen in cocaine users.<sup><ref>Crumb WJ Jr, Kadowitz PJ, Xu YQ, Clarkson CW. Electrocardiographic evidence for cocaine cardiotoxicity in cat. Can. J. Physiol. Pharmacol. 1990; 68(5):622–625. [PubMed: 2340451]</ref></sup> Cocaine also binds cardiac and neuronal sodium channels leading to profound cardiovascular and central nervous system alterations that are frequently lethal.<sup><ref>Zimmerman JL. Cocaine intoxication. Crit Care Clin 2012; 28: 517–526</ref></sup> Cocaine abuse is a serious public health problem. 50% of emergency room visits are due to illicit drug use, cocaine accounts for the majority of those cases.<sup><ref>Ball, JK.; Albright, V. National Estimates of Drug-Related Emergency Department Visits. Rockville, MD, USA: Substance Abuse and Mental Health Services Administration, Office of Applied Studies; 2008</ref></sup> Interestingly, despite cocaine’s broad use and high addictiveness, there is no US FDA-approved medication for the treatment of cocaine abuse or toxicity. Physicians treat patients enduring cocaine toxicity with standard emergency room agents that control arrhythmias, convulsions and high blood pressure but not with drugs that directly address the toxic levels of cocaine present in the patient.

	Finding a therapeutic agent to combat cocaine, such as small molecules has proven difficult. For this reason, the focus has been switched to cocaine esterases. For over a decade, cocaine esterases have been studied and numerous findings strongly suggest that bacterial cocaine esterases should provide a safe and effective method to rapidly eliminate the symptoms of acute cocaine intoxication in humans, as well as reducing addictiveness to the drug.		Finding a therapeutic agent to combat cocaine, such as small molecules has proven difficult. For this reason, the focus has been switched to cocaine esterases. For over a decade, cocaine esterases have been studied and numerous findings strongly suggest that bacterial cocaine esterases should provide a safe and effective method to rapidly eliminate the symptoms of acute cocaine intoxication in humans, as well as reducing addictiveness to the drug.

Lawrence Tran at 02:20, 6 April 2015

Lawrence Tran — Mon, 06 Apr 2015 02:20:14 GMT

←Older revision		Revision as of 02:20, 6 April 2015
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-	{{Sandbox_gvsu_chm463}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE -->
	==Cocaine Esterase==		==Cocaine Esterase==

	<Structure load='4P08' size='400' frame ='true' align='right' caption='Cocaine Esterase' scene='69/691529/Cocaineesterase/1' />		<Structure load='4P08' size='400' frame ='true' align='right' caption='Cocaine Esterase' scene='69/691529/Cocaineesterase/1' />
-	This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
-	You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

	== Background ==		== Background ==

David Buck: /* Mechanism */

David Buck — Mon, 06 Apr 2015 01:53:43 GMT

Mechanism

←Older revision		Revision as of 01:53, 6 April 2015
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	Cocaine esterase works in a four step mechanism.<sup><ref>Liu J., Zhao X., Yang W., Zhan G. C. (2011) Reaction mechanism for cocaine esterase-catalyzed hydrolysis of (+)- and (-)-cocaine: unexpected common rate-determining step. J. Phys. Chem. B. 115(17), 5017-5025.</ref></sup>		Cocaine esterase works in a four step mechanism.<sup><ref>Liu J., Zhao X., Yang W., Zhan G. C. (2011) Reaction mechanism for cocaine esterase-catalyzed hydrolysis of (+)- and (-)-cocaine: unexpected common rate-determining step. J. Phys. Chem. B. 115(17), 5017-5025.</ref></sup>
		+
	1. The lone pair on from Ser117 attacks the ester.		1. The lone pair on from Ser117 attacks the ester.
		+
	2. The extra pair of electrons on the oxygen reform the double bond and ecgonine methyl ester leaves.		2. The extra pair of electrons on the oxygen reform the double bond and ecgonine methyl ester leaves.
		+
	3. A water molecules, stabilized by His287, attacks the ester again.		3. A water molecules, stabilized by His287, attacks the ester again.
		+
	4. The extra pair of electrons reform the double bond again and this time break the bond to Ser117, regenerating the catalyst.		4. The extra pair of electrons reform the double bond again and this time break the bond to Ser117, regenerating the catalyst.

David Buck: /* Mechanism */

David Buck — Mon, 06 Apr 2015 01:53:02 GMT

Mechanism

←Older revision		Revision as of 01:53, 6 April 2015
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	From Wikipedia, the free encyclopedia</ref></sup>		From Wikipedia, the free encyclopedia</ref></sup>

-	Cocaine esterase works in a ~~three~~ step mechanism ~~shown below:~~<sup><ref>Liu J., Zhao X., Yang W., Zhan G. C. (2011) Reaction mechanism for cocaine esterase-catalyzed hydrolysis of (+)- and (-)-cocaine: unexpected common rate-determining step. J. Phys. Chem. B. 115(17), 5017-5025.</ref></sup>	+	Cocaine esterase works in a four step mechanism.<sup><ref>Liu J., Zhao X., Yang W., Zhan G. C. (2011) Reaction mechanism for cocaine esterase-catalyzed hydrolysis of (+)- and (-)-cocaine: unexpected common rate-determining step. J. Phys. Chem. B. 115(17), 5017-5025.</ref></sup>
		+	1. The lone pair on from Ser117 attacks the ester.
		+	2. The extra pair of electrons on the oxygen reform the double bond and ecgonine methyl ester leaves.
		+	3. A water molecules, stabilized by His287, attacks the ester again.
		+	4. The extra pair of electrons reform the double bond again and this time break the bond to Ser117, regenerating the catalyst.

	[[Image:Cocaine_esterase_mechanism.jpg]]		[[Image:Cocaine_esterase_mechanism.jpg]]