Famous Koshland theory was developed for water-soluble enzymes (99% of all)/ Some vital enzymes, like cytochrome P450s (CYPs), are embedded into phospholipid matrix of microsomal (endoplasmic reticulum) membranes. By definition, hydrophobic substrates of CYP (mainly, medicinal drugs), has to reach CYP active center thru lipid barrier and plasticity of CYP is still a question to answer.
Dear Ilya
This is a very interesting question but a quite complicated one to answer, unfortunately.
Obviously, for those P450 enzymes that are membrane-bound, the question is how does the substrate reach the active center. James Halpert and his colleagues on CYP2B enzymes and others on CYP3A enzymes have shown that protein plasticity is important and that Koshland theory holds since it seems that theenzyme 3D structure fits to the substrate (if I may say so).
The problem is dual: on one hand, the active center in P450 enzymes is buried within the protein core so that the substrate has to reach it through channels, on the other hand the membrane-bound P450 enzyme has to deal with highly hydrophobic substrate that have a quite high LogP values and that stickswithin the membarne bilayer instead of going freely in the surrounding cytosol.
There are a few papers on that, especially those form Michel Otyepka and his colleagues (J Phys Chem B. 2013 Oct 3;117(39):11556-11564)... and there is one from my group showing that for CYP1A enzymes what is important for P450 substrate specifciity with PAH substrates is NOT LOgP but the substrate size (Biochim Biophys Acta Gen Subjects 2015, 1850: 696-707).
Best reagrds,
Philippe Urban
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