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Enzyme Mechanisms 639

often accelerate, by large factors, the reaction over that in
aqueous media.
For DHFR in particular, molecular dynamics calcula-
tions, NMR measurements of solution structure, and ki-
netics measurements of mutant forms of the enzyme ap-
pear to support the importance of dynamic motions of
the protein fold to trigger the reaction of an enzyme–
substrate NAC. The mutations in question (for exam-
ple Gly120 in Fig. 7) are well removed from the active
site and underscore the role of the entire protein fold.
The contribution of dynamic motions to the overall cat-
alytic rate remains to be elucidated for the majority of
enzymes. Their existence may explain why more rigid
molecules such as imprinted polymers and catalytic anti-
bodies do not generally exhibit the large rate accelerations
noted with enzymes despite the fact that they too have
converted an intermolecular process to an intramolecular
process.

FIGURE 10 A currently accepted version of the catalytic cycle of
cytochrome P450. The iron porphyrin is drawn as a parallelogram, SEE ALSO THE FOLLOWING ARTICLES
the substrate is designated as SH and the product as SOH. See
the text for a description. [Adapted from Mueller, E. J., Loida, P. J.,
and Sligar, S. G. (1995). Twenty-five years of P450 cam research. BIOCONJUGATE CHEMISTRY • BIOENERGETICS •
In “Cytochrome P450: Structure, Mechanism, and Biochemistry” BIOINORGANIC CHEMISTRY • BIOREACTORS • FIBER-
(P. R. Ortiz de Montellano, ed.), 2nd ed., pp. 83–124, Plenum, OPTIC CHEMICAL SENSORS • GENE EXPRESSION,REGU-
New York.]
LATION OF • LIPOPROTEIN/CHOLESTEROL METABOLISM
• TRANSLATION OF RNA TO PROTEIN • VITAMINS AND
populated with cofactors that are poised for reaction. COENZYMES
These structures, or NACs (near attack conformers), are
similar in structure to the transition state so that only slight
changes in bond distances and angles within the structures BIBLIOGRAPHY
through the normal dynamic motions of the protein are
sufficient to trigger the crossing of the reaction barrier. The Bugg, T. (1997). “An Introduction to Enzyme and Coenzyme Chemistry,”
enzyme’s active site is also preorganized in the sense that Blackwell Sci., London.
Fersht, A. (1999). “Structure and Mechanism in Protein Science,”
the locus of general acids/bases, nucleophiles, solvents,
Freeman, New York.
dipoles, hydrogen bonds, and so forth arefixed by the NAC Hammes, G. G. (1982). “Enzyme Catalysis and Regulation,” Academic
to interact with the transition state. Molecular dynamic Press, New York.
calculations sampling several enzyme classes suggest that Ortiz de Montellano, P. R., ed. (1995). “Cytochrome P450: Structure,
the affinity of these enzymes for their transition states is Mechanism, and Biochemistry,” 2nd ed., Plenum, New York.
Page, M. I. (1984). “The Chemistry of Enzyme Action,” Elsevier, New
little changed from that for the substrate. The enzyme-
York.
catalyzed reaction also benefits in many cases due to the Price, N. C., and Stephens, L. (1989). “Fundamentals of Enzymology,”
nonaqueous interaction of the active site cavity, which can Oxford Univ. Press, New York.