|
Figure 7.
Proposed scheme for the catalytic inactivation of caspase-3
by isoquinoline-1,3,4-trione derivatives through redox cycling.
In the presence of DTT in vitro and possibly dihydrolipoic acid
in vivo, isoquinoline-1,3,4-trione derivatives rapidly undergo
reduction to the corresponding semiquinone anion radicals
(RQ^-). The reaction is reversible in the presence of
atmospheric oxygen by reduction oxygen to ROS. The farther
oxidation of DTT and dihydrolipoic acid intermediate also could
generate ROS (38, 39). The produced ROS catalyzes the step by
step oxidation of the active site cysteine of caspase-3 to the
sulfonic acid. The semiquinone anion radicals may also
contribute to the specific oxidation of the catalytic cysteine
via a intermediate (Caspase-SH/RQ^-). Caspase-SH, caspase-SOH,
caspase-SO[2]H, and caspase-SO[3]H represent the thiol,
sulfenic, sulfinic, and sulfonic acid states of the catalytic
cysteine.
|
