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Vol. 53, Issue 6, 1089-1096, June 1998
Laboratory of Biochemistry, School of Medicine, University of
Patras, 26110 Patras, Greece
A detailed kinetic study was carried out on the inhibitory mechanisms
of two eukaryotic peptidyltransferase drugs (I), anisomycin and
sparsomycin. In an in vitro system from rabbit
reticulocytes, AcPhe-puromycin is produced in a pseudo-first-order
reaction from the preformed AcPhe-tRNA/poly(U)/80S ribosome complex
(complex C) and excess puromycin (S). This reaction is inhibited by
anisomycin and sparsomycin through different mechanisms. Anisomycin
acts as a mixed noncompetitive inhibitor. The product, AcPhe-puromycin, is derived only from C according to the puromycin reaction. On the
other hand, sparsomycin reacts with complex C in a two-step reaction, 
An
initial rapid binding of the drug produces the encounter complex CI.
During this step and before conversion of CI to C*I, sparsomycin
behaves as a competitive inhibitor. The rapidly produced CI is
isomerized slowly to a conformationally altered species C*I in which I
is bound more tightly. The rate constants of this step are
k6 = 2.1 min
1 and
k7 = 0.095 min1.
Moreover, the low value of the association rate constant
k7/Ki' (2 × 105
M1
sec1), provides insight into the rates of
possible conformational changes occurring during protein synthesis and
supports the proposal that sparsomycin is the first example of a
slow-binding inhibitor of eukaryotic peptidyltransferase. When complex
C is preincubated with concentrations of sparsomycin of >8
Ki and then reacts with a mixture of
puromycin and sparsomycin, the inhibition becomes linear mixed
noncompetitive and involves C*I instead of CI. During this phase,
AcPhe-puromycin is produced from a new, modified ribosomal complex with
a lower catalytic rate constant. Thus, sparsomycin also acts as a
modifier of eukaryotic peptidyltransferase activity.
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