Biological actions of the oligomers of ribonuclease A

Natural and engineered ribonucleases as potential cancer therapeutics

“…3) similarly to monomeric RNase A. Therefore, an improved interaction of the oligomers with the polyanionic cell surface followed by an efficient endocytosis was proposed for the nonetheless observed cytotoxicity (Libonati 2004). Like ?S-RNase, however, these artificial oligomers can dissociate which leads to the loss of their cytotoxic activity.…”

“…Artificial oligomerization of RNase A molecules as the consequence of an intermolecular exchange of their N-and/or C-termini ('domain swapping') results in higher-order, linear or cyclic multimers, which display antitumor and aspermatogenic but no embryotoxic activity (Libonati 2004). Analogously to BS-RNase one would expect that a disturbance of the RNase-RI interaction is responsible for the acquired cytotoxicity.…”

“…Even though tandemization obviously did not result in an improved RI evasion in vitro, the constructs showed pronounced cytotoxicity (Leich et al 2006). An improved endocytosis as proposed for domain swapped RNase A oligomers (Libonati 2004) might be the reason for the increased cytotoxicity.…”

The Buried Diversity of Bovine Seminal Ribonuclease: Shape and Cytotoxicity of the Swapped Non-covalent Form of the Enzyme

“…7,8 Thus, despite some notable exceptions, such as that provided by a human-frog ribonuclease chimera, 9 RI action and cytotoxicity appear to be strongly anticorrelated. 6,10 In keeping with this indication, the production of aggregated forms of ribonucleases that are not amenable to RI binding for steric hindrance [11][12][13][14] may provide a way to produce proteins possessing enhanced cytotoxic effects. In this scenario, bovine seminal ribonuclease (BS-RNase) occupies a special position (Fig.…”

“…25 Surprisingly, these dimers display a detectable cytotoxic activity, although significantly smaller in comparison to BS-RNase. [11][12][13] However, it should be pointed out that the two units of NDRNaseA molecule 23,26 are not related by a 2-fold symmetry. Therefore, while the binding of one chain in the RI binding site can easily occur, the binding of the second subunit gives rise to severe interpenetration of the partner chain on the inhibitor molecule.…”