S. Di Gaetano et al., Second generation antitumour human RNase: significance of its structural and functional features for the mechanism of antitumour action, BIOCHEM J, 358, 2001, pp. 241-247
A second generation mutant of dimeric human pancreas RNase (HHP2-RNase), wa
s obtained by a single residue mutation (Glu(111)--> Gly) of the previously
described dimeric human pancreas RNase variant (HHP-RNase). HHP2-RNase was
found to be a highly specific antitumour agent, with an enhanced cytotoxic
activity compared with HHP-RNase. The structural and functional requisites
of the antitumour action of HHP2-RNase were investigated and compared with
those of other dimeric antitumour RNases. The stability of the dimeric str
ucture, i.e. the resistance of human dimeric RNase variants to reductive cl
eavage of the two intersubunit disulphide bonds that bridge the subunits, w
as determined to be an essential feature of antitumour dimeric RNases. The
stability of the dimeric structure is in turn responsible for the resistanc
e to inhibition by the cytosolic RNase inhibitor (cRI). Both the stability
of the dimeric structure and the resistance to cRI inhibition appeared to b
e highly enhanced by an RNase substrate, This suggests a possible role for
RNA in the amplification of the antitumour potential of dimeric RNases.