Enzymes are biological molecules which accelerate the rate, and often direct the specificity, of a chemical reaction. Like all catalysts, they are not themselves consumed in the reactions in which they participate but are regenerated to take part in multiple cycles. Transformations which are very slow, such as the breakdown of DNA, can be accelerated by many orders of magnitude by an appropriate enzyme. Enzymes cannot catalyze reactions that are not thermodynamically favorable, but they can facilitate and accelerate those that are favorable but slow and can couple unfavorable reactions to even more favorable ones. Most enzymes are proteins and thus are made up of amino acids. Recently it was discovered that RNA molecules can also be enzymes; this type of enzyme activity will not be discussed in this article. For the purposes of this discussion, we will explore how protein molecules, sometimes in conjunction with cofactors, use chemistry to convert substrates to products. The availability within a protein, or through cofactors, of nucleophiles or electrophiles, acid or base residues, redox centers, or other features associated with chemical catalysts, when coupled to the selective pressure of evolution, has afforded selective and efficient catalysts. The study of enzyme mechanisms aims to define as precisely as possible the nature of the chemical steps that effect these conversions.
A logical starting point is to consider the structures of four of the representative enzymes depicted in this article: chymotrypsin, dihydrofolate reductase, aspartate aminotransferase, and cytochrome P450. In general, one observes a well-defined binding site for capturing the substrate and executing the chemical transformation through various polar and nonpolar interactions between the substrate and the amino acids that line the active site. Much of the rate acceleration (up to 108-fold) for enzymatic catalysis can often be attributed to the juxtaposition of substrates and catalytic residues within the active site cavity. There are currently available X-ray crystallographic structures of enzymes, many with active sites occupied with inhibitors and determined to a resolution of less than 2.5 Å , which permit inferences as to the mechanism of the chemical transformation. Nuclear magnetic resonance (NMR) and optical spectroscopic methods provide important, complementary data on solution structure. Despite considerable differences in the primary amino acid sequence, the overall protein fold with its α- helical and β-sheet secondary structural elements is often retained for classes of transformations that are related through a common mechanistic species and thus constitute members of a protein superfamily. One implication is that the entire tertiary structure, not merely the active site, is important in the efficiency and selectivity of the chemical transformation. The structures we have chosen will serve to illustrate how the convergence of the knowledge of structure with the output from other experimental tools provides arguments for probable mechanisms of catalysis.
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