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Enzymatic Detoxication, Conformational Selection, and the Role of Molten Globule Active Sites
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.ORCID-id: 0000-0002-6416-064X
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2013 (engelsk)Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, nr 25, s. 18599-18611Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The role of conformational ensembles in enzymatic reactions remains unclear. Discussion concerning induced fit versus conformational selection has, however, ignored detoxication enzymes, which exhibit catalytic promiscuity. These enzymes dominate drug metabolism and determine drug-drug interactions. The detoxication enzyme glutathione transferase A1-1 (GSTA1-1), exploits a molten globule-like active site to achieve remarkable catalytic promiscuity wherein the substrate-free conformational ensemble is broad with barrierless transitions between states. A quantitative index of catalytic promiscuity is used to compare engineered variants of GSTA1-1 and the catalytic promiscuity correlates strongly with characteristics of the thermodynamic partition function, for the substrate-free enzymes. Access to chemically disparate transition states is encoded by the substrate-free conformational ensemble. Pre-steady state catalytic data confirm an extension of the conformational selection model, wherein different substrates select different starting conformations. The kinetic liability of the conformational breadth is minimized by a smooth landscape. We propose that local molten globule behavior optimizes detoxication enzymes.

sted, utgiver, år, opplag, sider
2013. Vol. 288, nr 25, s. 18599-18611
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Identifikatorer
URN: urn:nbn:se:su:diva-92653DOI: 10.1074/jbc.M112.445767ISI: 000320721900059OAI: oai:DiVA.org:su-92653DiVA, id: diva2:640883
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AuthorCount:5;

Tilgjengelig fra: 2013-08-14 Laget: 2013-08-14 Sist oppdatert: 2017-12-06bibliografisk kontrollert

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