| pubmed-article:12130672 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:12130672 | lifeskim:mentions | umls-concept:C0009170 | lld:lifeskim |
| pubmed-article:12130672 | lifeskim:mentions | umls-concept:C0020289 | lld:lifeskim |
| pubmed-article:12130672 | lifeskim:mentions | umls-concept:C0728810 | lld:lifeskim |
| pubmed-article:12130672 | pubmed:issue | 2 | lld:pubmed |
| pubmed-article:12130672 | pubmed:dateCreated | 2002-7-19 | lld:pubmed |
| pubmed-article:12130672 | pubmed:abstractText | To address the problem of acute cocaine overdose, we undertook molecular engineering of butyrylcholinesterase (BChE) as a cocaine hydrolase so that modest doses could be used to accelerate metabolic clearance of this drug. Molecular modeling of BChE complexed with cocaine suggested that the inefficient hydrolysis (k(cat) = 4 min(-1)) involves a rotation toward the catalytic triad, hindered by Tyr332. To eliminate rotational hindrance and retain substrate affinity, we introduced two amino acid substitutions (Ala328Trp/Tyr332Ala). The resulting mutant BChE reduced cocaine burden in tissues, accelerated plasma clearance by 20-fold, and prevented cocaine-induced hyperactivity in mice. The enzyme's kinetic properties (k(cat) = 154 min(-1), K(M) = 18 microM) satisfy criteria suggested previously for treating cocaine overdose (k(cat) >120 min(-1), K(M) < 30 microM). This success demonstrates that computationally guided mutagenesis can generate functionally novel enzymes with clinical potential. | lld:pubmed |
| pubmed-article:12130672 | pubmed:grant | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:12130672 | pubmed:language | eng | lld:pubmed |
| pubmed-article:12130672 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:12130672 | pubmed:citationSubset | IM | lld:pubmed |
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| pubmed-article:12130672 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:12130672 | pubmed:month | Aug | lld:pubmed |
| pubmed-article:12130672 | pubmed:issn | 0026-895X | lld:pubmed |
| pubmed-article:12130672 | pubmed:author | pubmed-author:HarhJ YJY | lld:pubmed |
| pubmed-article:12130672 | pubmed:author | pubmed-author:LockridgeOksa... | lld:pubmed |
| pubmed-article:12130672 | pubmed:author | pubmed-author:PangYuan-Ping... | lld:pubmed |
| pubmed-article:12130672 | pubmed:author | pubmed-author:BrimijoinStep... | lld:pubmed |
| pubmed-article:12130672 | pubmed:issnType | Print | lld:pubmed |
| pubmed-article:12130672 | pubmed:volume | 62 | lld:pubmed |
| pubmed-article:12130672 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:12130672 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:12130672 | pubmed:pagination | 220-4 | lld:pubmed |
| pubmed-article:12130672 | pubmed:dateRevised | 2007-11-14 | lld:pubmed |
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| pubmed-article:12130672 | pubmed:year | 2002 | lld:pubmed |
| pubmed-article:12130672 | pubmed:articleTitle | Re-engineering butyrylcholinesterase as a cocaine hydrolase. | lld:pubmed |
| pubmed-article:12130672 | pubmed:affiliation | Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic & Foundation for Medical Education and Research, Rochester, Minnesota 55905, USA. | lld:pubmed |
| pubmed-article:12130672 | pubmed:publicationType | Journal Article | lld:pubmed |
| pubmed-article:12130672 | pubmed:publicationType | Research Support, U.S. Gov't, P.H.S. | lld:pubmed |
| pubmed-article:12130672 | pubmed:publicationType | Research Support, Non-U.S. Gov't | lld:pubmed |
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