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The Journal of biochemistry v.119 no.3, 1996년, pp.572 - 576  

Differential Inhibition of Calpain and Proteasome Activities by Peptidyl Aldehydes of Di-Leucine and Tri-Leucine

Tsubuki, S. ; Saito, Y. ; Tomioka, M. ; Ito, H. ; Kawashima, S. ;
  • 초록  

    To explore membrane-permeable synthetic inhibitors that discriminate between endogenous calpain and proteasome in cells, we examined the inhibition profiles against calpain and proteasome in vitro and in vivo of peptidyl aldehydes possessing di-leucine and tri-leucine. The tripeptide aldehyde benzyloxycarbonyl-leucyl-leucyl-leucinal (ZLLLal) strongly inhibited calpain and proteasome activities in vitro. The concentration required for 50% inhibition (IC/sub 50/) of the casein-degrading activity of calpain was 1.25 .mu.M, and the IC/sub 50/s for the succinyl-leucyl-leucyl-valyl-tyrosine-4-methylcoumaryl-7-amide (SucLLVY-MCA)- and benzyloxycarbonyl-leucyl-leucyl-leucine-4-methylcoumaryl-7-amide (ZLLL-MCA)-degrading activities of proteasome were 850 and 100 nM, respectively. On the other hand, the synthetic dipeptide aldehyde benzyloxycarbonyl-leucyl-leucinal (ZLLal) strongly inhibited the casein degrading activity of calpain (IC/sub 50/ 1.20 .mu.M), but the inhibition of proteasome was weak (IC/sub 50/s for SucLLVY-MCA- and ZLLL-MCA-degrading activities were 120 and 110 .mu.M, respectively). Thus, while calpain was inhibited by similar concentrations of ZLLal and ZLLLal, the inhibitory potencies of ZLLLal against the ZLLL-MCA- and SucLLVY-MCA-degrading activities in proteasome were 1,100 and 140 times stronger than those of ZLLal, respectively. To evaluate the effectiveness of these inhibitors on intracellular proteasome, the induction of neurite outgrowth in PC12 cells caused by proteasome inhibition was examined. ZLLLal and ZLLal initiated neurite outgrowth with optimal concentrations of 20 nM and 10 .mu.M, respectively, again showing a big difference in the effective concentrations for the proteasome inhibition as in vitro. As for the effect on intracellular calpain, the concentrations of ZLLLal and ZLLal required for the inhibition of the autolytic activation of calpain in rabbit erythrocytes were 100 and 100 .mu.M or more, respectively. The almost equal inhibitory potencies of ZLLLal and ZLLal were in agreement with the inhibition of calpain in vitro. These differential effects of inhibitors against calpain and proteasome are potentially useful for identifying the functions of calpain and proteasome in cell physiology and pathology.


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