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Mailing List complex-science@necsi.org Message #3278 | |
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| The X-ray structures of enzyme substrate complexes have established the fact that the shape of the active site of an enzyme is complementary to that of its substrate. This complementary fit between enzymes and their substrates seems consistent with both of the following theories: 1) The lock-and-key model of Emil Fischer proposed in 1890, according to which the shape of the active site of an enzyme is already complementary to that of its substrate, so that the substrate can bind to the active site without any appreciable conformational changes, just like a key fitting into a lock. It may be convenience to refer to such a conformation of the active site of an enzyme as the 'Fischer conformation'. 2) The induced-fit model proposed by Daniel E. Koshland, Jr. in 1958, according to which the shape of the active site of an enzyme is induced to undergo marked conformational changes upon binding a substrate [see Figures 8-13 and -14 in L. Stryer's "Biochemistry", Fourth Edition, W. H. Freeman, New York, 1995, p. 191]. Let us refer to the conformation of the active site of an enzyme before binding its substrate as the 'Koshland conformation'. Stryer, in his book cited above, gives the reader the impression that, because "the shapes of the active sites of many enzymes are markedly modified by the binding of substrates" as revealed by X-ray data, the induced-fit model of Koshland is favored over the lock-and-key model of Fischer. Although Stryer's conclusion may turn out to be true, at least for some enzymes, there is an alternative way of accounting for the substrate binding-correlated conformational changes of the active site of enzymes that is suggested by the so-called generalized Franck-Condon principle. This principle states that, when a physicochemical process results from coupling two partial processes, one fast and the other slow by a factor of about 100 or more, the slow process must precede the fast one [Ann. N. Y. Acad. Sci. 227: 419-437 (1974); BioSystems 54: 107-130 (2000)]. To present this alternative view, it is necessary to use some symbols defined as follows: Koshland confromation or form = E/Koshalnd/ . . . . (1) where E stands for enzyme and /.../ indicates a subscript. Fischer conformation or form = E/Fischer/ . . . . . (2) Using these notations, we can represent the net conformational change accompanying substrate binding as follows: E/Koshland/ + S <-----> S.E/Fischer/ . . . . (3) where S is the substrate and S.E is the enzyme-substrate complex. Clearly, the volume of the active site in the Koshland conformation is significantly greater than the volume of the active site in the Fischer conformation, i.e., after binding its substrate. There are three possible mechanisms that can account for the binding reaction depicted in (1): 1) The Fischer mechanism: E/Fischer/ + S <----> S.E/Fischer/ . . . . .(4) where the conformation of the active site of an enzyme remains more or less constant through out the binding process. 2) The induced-fit mechanism: E/Koshland/ + S <---> S.E/Koshland/ . . . . . . (5) S.E/Koshland/ <---> S.E/Fischer/ . . . . . . . (6) where the conformational transition of the active site from the Koshland form to the Fischer form, Process (6), FOLLOWS (or is INDUCED by) the binding of the substrate to the active site, Process (5). 3) The Franck-Condon mechanism: E/Koshland/ <---> E/Fischer/ . . . . . . . . . (7) E/Fischer/ + S <---> S.E/Fischer/ . . . . . . . . . (8) This mechanism assumes that the conformational change of the active site of an enzyme from the Koshland form to the Fischer form, Process (7), PRECEDES the binding of the substrate to the active site, Process (8). I predict that the Franck-Condon mechanism will prevail whenever the rate of the conformational change is much slower (by a factor of about 100 or more) than the rate of substrate binding to the active site of the enzyme. If conformational changes accompanying substrate binding are extensive, involving the number of atoms far greater than the number of atoms of the substrate in question, it is highly likely that the Koshland to Fischer conformational transition of the active site of an enzyme will be much slower than the diffusion rate of the substrate to its binding site and hence the Franck-Condon mechanism will prevail. It seems eminently conceivable that these potential mechanisms of enzyme-substrate interactions can be tested experimentally, using ultrafast spectroscopic and X-ray techniques now available. The generalized Franck-Condon principle, a derivative of the Born-Oppenhimer approximation in quantum mechanics, has been used to formulate molecular mechanisms of enzymic catalysis, redox reaction-driven proton pumping, muscle contraction, and redox reaction-driven ATP synthesis [Ann. N. Y. Acad. Sci. 227: 211-226 (1974); In "Structure and Function of Biomembranes (K. Yagi, ed.), Japan Scientific Societies Press, Tokyo, 1979, pp. 25-37]. As indicated in another post on this list, the 'binding-change mechanism of ATP synthesis' in mitochondria proposed by P. D. Boyer is consistent with (and hence can be can be reformulated using) the Franck-Condon principle. I sincerely doubt that the induced-fit theory can be applied to such a wide range of energy-coupled processes. Finally, it may be pointed out that, if the Franck-Condon mechanism turns out to be valid, both the lock-and-key theory of Fischer and the induced-fit theory of Koshland must be accorded an equal validity (or invalidity, depending on your taste). Any comments or criticisms will be welcome. With all the best. Sung _________________________________________ Sungchul Ji, Ph.D. Department of Pharmacology and Toxicology Rutgers University Piscataway, N.J. 08855 |
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