A Ribonuclease A Variant with Low Catalytic Activity but High Cytotoxicity

OnconaseTM, a homolog of ribonuclease A (RNase A) with low ribonucleolytic activity, is cytotoxic and has efficacy as a cancer chemotherapeutic. Here variants of RNase A were used to probe the interplay between ribonucleolytic activity and evasion of the cytosolic ribonuclease inhibitor protein (RI)...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-04, Vol.275 (14), p.9893-9896
Main Authors: Bretscher, Lynn E., Abel, Richele L., Raines, Ronald T.
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Antineoplastic Agents - toxicity
Cell Division - drug effects
DNA, Neoplasm - biosynthesis
Egg Proteins - metabolism
Egg Proteins - toxicity
Enzyme Stability
Genetic Variation
Humans
K562 Cells
Kinetics
Models, Molecular
Onconase
Protein Conformation
Protein Structure, Secondary
Recombinant Proteins - chemistry
Recombinant Proteins - metabolism
Recombinant Proteins - toxicity
Ribonuclease A
Ribonuclease, Pancreatic - genetics
Ribonuclease, Pancreatic - metabolism
Ribonuclease, Pancreatic - toxicity
Ribonucleases - metabolism
Ribonucleases - toxicity
Thymidine - metabolism
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Summary:OnconaseTM, a homolog of ribonuclease A (RNase A) with low ribonucleolytic activity, is cytotoxic and has efficacy as a cancer chemotherapeutic. Here variants of RNase A were used to probe the interplay between ribonucleolytic activity and evasion of the cytosolic ribonuclease inhibitor protein (RI) in the cytotoxicity of ribonucleases. K41R/G88R RNase A is a less active catalyst than G88R RNase A but, surprisingly, is more cytotoxic. Like OnconaseTM, the K41R/G88R variant has a low affinity for RI, which apparently compensates for its low ribonucleolytic activity. In contrast, K41A/G88R RNase A, which has the same affinity for RI as does the K41R/G88R variant, is not cytotoxic. The nontoxic K41A/G88R variant is a much less active catalyst than is the toxic K41R/G88R variant. These data indicate that maintaining sufficient ribonucleolytic activity in the presence of RI is a requirement for a homolog or variant of RNase A to be cytotoxic. This principle can guide the design of new chemotherapeutics based on homologs and variants of RNase A.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.275.14.9893