【摘 要】
：
Myocardial ischemia causes rapid depletion of ATP in part due to inefficient hydrolysis of ATP when the mitochondrial F1F0 ATP synthase switches to a hydrolase,which serves no useful work.The amount o
【机 构】
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Physiology and Biophysics Robert Wood Johnson Medical School USA
【出 处】
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中国上海第七届国际新药发明科技年会
论文部分内容阅读
Myocardial ischemia causes rapid depletion of ATP in part due to inefficient hydrolysis of ATP when the mitochondrial F1F0 ATP synthase switches to a hydrolase,which serves no useful work.The amount ofATP hydrolyzed by this enzyme during myocardial ischemia represents a substantial fraction of that used during an ischemic event.Studies with oligomycin (inhibits both F1F0 ATP synthase and hydrolase activities) done previously showed that it conserved ATP during ischemia and its efficacy varied with species.A peptide,IF-l,activated by low pH and conditions similar to those seen during ischemia,inhibits F1F0 ATP hydrolase activity and is highly expressed in "slow heart rate species" (dog,rabbit) and poorly expressed in rat.Upon restoration of normal pH,IF-1 loses its activity,therefore giving it selectivity for inhibiting hydrolase activity and serves as a form of endogenous protection.Development of a peptide mimetic of IF-1 is impossible and a small molecule selective for the hydrolase would be difficult if the switch from synthase to hydrolase is merely a chemical reversal,but it has been suggested that this reversal may be a conformational change.The focus of this review is on BMS-199264 that is a small molecule F1F0 ATP hydrolase selective inhibitor that protects ischemic myocardium by conserving ATP during the ischemic episode.
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