期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 276, 期 46, 页码 43095-43102出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M106636200
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资金
- NCI NIH HHS [CA73808] Funding Source: Medline
- NIGMS NIH HHS [T32 GM07215] Funding Source: Medline
Onconase(R) is an amphibian protein that is now in Phase IH clinical trials as a cancer chemotherapeutic. Human pancreatic ribonuclease (RNase 1) is homologous to Onconase(R) but is not cytotoxic. Here, ERDD RNase 1, which is the L86E/N88R/G89D/R91D variant of RNase 1, is shown to have conformational. stability and ribonucleolytic activity similar to that of the wild-type enzyme but >10(3)-fold less affinity for the endogenous cytosolic ribonuclease inhibitor protein. Most significantly, ERDD RNase 1 is toxic to hum an leukemia cells. The addition of a non-native disulfide bond to ERDD RNase I not only increases the conformational stability of the enzyme but also increases its cytotoxicity such that its IC(50) value is only 8-fold greater than that of Onconase(R). Thus, only a few amino acid substitutions are necessary to make a human protein toxic to human cancer cells. This finding has significant implications for human cancer chemotherapy.
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