Active Site of Ribonuclease A

Ribonuclease A (RNase A; EC 3.1.27.5) was perhaps the most studied enzyme of the 20th century and is the best characterized ribonuclease. The “A” in its name refers not to its substrate specificity, but to the predominant form of the enzyme produced by the bovine pancreas. RNase A is unmodified, whereas RNase B, RNase C, and RNase D are mixtures of glycoforms. Because of its availability in large quantity and high purity, RNase A has been the object of landmark work in protein chemistry and enzymology (see Cuchillo et al. 1997; Raines 1998 and references therein). In addition, cytotoxic RNase A variants and homologues have demonstrated utility as chemotherapeutic agents (Leland and Raines 2001). Recognition of the seminal role of RNase A in the chemical sciences reached a pinnacle in 1972, when all three Nobel Prizes in chemistry were awarded for work on this enzyme. Stein and Moore were acknowledged “for their contribution to the understanding of the connection between chemical structure and catalytic activity of the active center of the ribonuclease molecule” (Moore and Stein 1973). Anfinsen was recognized “for his work on ribonuclease, especially concerning the connection between the amino acid sequence and the biologically active conformation” (Anfinsen 1973). Another Nobel Prize in chemistry was added in 1984. In that year, Merrifield was acknowledged “for his development of methodology for chemical synthesis on a solid matrix” (Merrifield 1984). He too chose RNase A as his model system, making it the first protein to succumb to total synthesis.