Peptide inhibitors of mammalianribonucleotide reductase

摘要

Ribonucleotide reductases (RRs) form a family of allosterically regulated enzymesthat catalyze the conversion of ribonucleotides to 2'-deoxyribonucleotides and areessential for de novo DNA biosynthesis (Eklund et al., 2001). As such, RR is a well-recognized target for cancer chemotherapeutic and antiviral agents (Weber, 1983;Cory, 1988; Szekeres et al., 1997; Robins, 1999), with activity levels that are morethan 100-fold higher in rapidly growing hepatoma cells than in normal liver cells(Weber, 1983). Two compounds are currently in clinical use, targeting either theactive site (gemcitabine) (Robins, 1999, van Moorsel et al., 2000) or the stable tyrosylfree radical that is required for enzyme activity (hydroxyurea) (Nocentini, 1996). Mammalian RR (mRR) belongs to Class Ia of the four known classes of RRs.Class Ia RRs accept the four common nucleoside diphosphates (NDPs) assubstrates, with enzymatic activity dependent upon the formation of a complexbetween two different subunits, R1 and R2 (Eklund et al., 2001). The mammaliancell contains one gene product for R1 but two gene products for R2, mR2 andp53R2, which are 80% identical in sequence and functionally similar.