A Homology Model for Rat Mu Class Glutathione S-Transferase 4-4
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- 作者：Marcel J. de Groot ; Nico P. E. Vermeulen ; Diana L. J. Mullenders ; and Gabrië ; lle M. Donné ; -Op den Kelder
- 刊名：Chemical Research in Toxicology
- 出版年：1996
- 出版时间：January 1996
- 年：1996
- 卷：9
- 期：1
- 页码：28 - 40
- 全文大小：487K
- 年卷期：v.9,no.1(January 1996)
- ISSN：1520-5010
文摘
Glutathione S-transferases (GSTs) are an importantclass of phase II (de)toxifying enzymes,catalyzing the conjugation of glutathione (GSH) to electrophilicspecies. Recently, a numberof cytosolic GSTs was crystallized. In the present study,molecular modeling techniques havebeen used to derive a three-dimensional homology model for rat GST 4-4based upon the crystalstructure of rat GST 3-3, both members of the mu class. GST 3-3and GST 4-4 isoenzymesshare a sequence homology of 88%. GST 4-4 distinguishes itselffrom GST 3-3 in being muchmore efficient and stereoselective in the nucleophilic addition of GSHto epoxides and 
,
-unsaturated ketones. GST 3-3, however, is much more efficient incatalyzing nucleophilicaromatic substitution reactions. In this study, several knownsubstrates of GST 4-4 wereselected and their GSH conjugates docked into the active site of GST4-4. GSH conjugates ofphenanthrene 9(S),10(R)-oxide and4,5-diazaphenanthrene 9(S),10(R)-oxide weredocked intothe active site of both GST 3-3 and GST 4-4. From these homologymodeling and dockingdata, the difference in stereoselectivity between GST 3-3 and GST 4-4for the R- andS-configured carbons of the oxirane moiety could berationalized. The data acquired from arecently derived small molecule model for GST 4-4 substrates werecompared with the resultsof the present protein homology model of GST 4-4. The energyoptimized positions of theconjugates in the protein model agreed very well with the originalrelative positions of thesubstrates within the substrate model, confirming the usefulness ofsmall molecule models inthe absence of structural protein data. The protein homologymodel, together with the substratemodel, will be useful to further rationalize the substrate selectivityof GST 4-4, and to identifynew potential GST 4-4 substrates.
,-unsaturated ketones. GST 3-3, however, is much more efficient incatalyzing nucleophilicaromatic substitution reactions. In this study, several knownsubstrates of GST 4-4 wereselected and their GSH conjugates docked into the active site of GST4-4. GSH conjugates ofphenanthrene 9(S),10(R)-oxide and4,5-diazaphenanthrene 9(S),10(R)-oxide weredocked intothe active site of both GST 3-3 and GST 4-4. From these homologymodeling and dockingdata, the difference in stereoselectivity between GST 3-3 and GST 4-4for the R- andS-configured carbons of the oxirane moiety could berationalized. The data acquired from arecently derived small molecule model for GST 4-4 substrates werecompared with the resultsof the present protein homology model of GST 4-4. The energyoptimized positions of theconjugates in the protein model agreed very well with the originalrelative positions of thesubstrates within the substrate model, confirming the usefulness ofsmall molecule models inthe absence of structural protein data. The protein homologymodel, together with the substratemodel, will be useful to further rationalize the substrate selectivityof GST 4-4, and to identifynew potential GST 4-4 substrates.