- Uncompetitive inhibitors.These bind only to the enzyme–substrate complex, not to
free enzyme. This results in a decrease in the maximum rate of reaction and means
that less enzyme is available to bind substrate. - Transition state analog inhibitors.These are compounds that resemble the substrate
portion of the hypothetical transition state of the enzymatic reaction.
Two specific enzyme-inhibitor mechanisms deserve special discussion because they are
the basis of action for several important drugs. They are the transition-state analogs and
the “suicide” substrates.
8.2.1.1 Transition-State Analogs
Transition-state analogs are inhibitors that mimic the transition-state structure of the
substrate of an enzyme, which, by definition, has the highest energy—that is, the least
stable conformation. Since the transition state of an enzyme substrate is the form that
is most tightly bound, its analog should have a higher affinity and specificity for the
enzyme than any substrate in the “ground state.” Hence, binding constants of 10−^15 M
for the transition state can be expected for substrates with KDs of only 10−^3 –10−^5 M.
There are two problems with this potentially very powerful concept. First, the mech-
anism of the enzymatic reaction must be known in order to mimic the transition state of
the substrate, since the structural specificity of the reaction is quite high. Second, a
stable analog of the labile transition state is, by implication, very difficult to prepare.
Often one must be content with a metastable intermediate analog of the substrate.
Nevertheless, there are several successful applications of this interesting principle.
Penicillin (8.11) is a transition-state analog of a distorted Gly–D–Ala–D–Ala peptide
involved in the crosslinking of glycol-peptides constituting the cell walls of bacteria.
Suicide Enzyme Inhibitors. “Suicide” substrates are irreversible enzyme inhibitors
that bind covalently. The reactive anchoring group is catalytically activated by the
enzyme itself through the enzyme–inhibitor complex. The enzyme thus produces its own
inhibitor from an originally inactive compound, and is perceived to “commit suicide.”
To design a Kcatsubstrate, the catalytic mechanism of the enzyme as well as the
nature of the functional groups at the enzyme active site must be known. Conversely,
successfulKcatinhibition provides valuable information about the structure and mecha-
nism of an enzyme. Compounds that form carbanions are especially useful in this
regard. Pyridoxal phosphate-dependent enzymes form such carbanions readily because
ENDOGENOUS MACROMOLECULES 485