5-Lipoxygenase
(5-LOX) reacts with arachidonic acid (AA) to first
generate 5(S)-hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic
acid [5(S)-HpETE] and then an epoxide from 5(S)-HpETE to form leukotriene A4, from a single
polyunsaturated fatty acid. This work investigates the kinetic mechanism
of these two processes and the role of ATP in their activation. Specifically,
it was determined that epoxidation of 5(S)-HpETE
(dehydration of the hydroperoxide) has a rate of substrate capture
(Vmax/Km)
significantly lower than that of AA hydroperoxidation (oxidation of
AA to form the hydroperoxide); however, hyperbolic kinetic parameters
for ATP activation indicate a similar activation for AA and 5(S)-HpETE. Solvent isotope effect results for both hydroperoxidation
and epoxidation indicate that a specific step in its molecular mechanism
is changed, possibly because of a lowering of the dependence of the
rate-limiting step on hydrogen atom abstraction and an increase in
the dependency on hydrogen bond rearrangement. Therefore, changes
in ATP concentration in the cell could affect the production of 5-LOX
products, such as leukotrienes and lipoxins, and thus have wide implications
for the regulation of cellular inflammation.
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