X hits on this document





16 / 22

1060 Chemical Reviews, 1998, Vol. 98, No. 3


onconase377 Figure 10. Amino acid sequences of RNase A , ), and five human homologues (RNase 1, 52,53 388

RNase 2,391,393 RNase 3,392,394 two cytotoxic homologues (bovine seminal ribonuclease RNase 4,395 and angiogenin 390 389 ). The and

sequences were aligned by using the program PILEUP (Genetics Computer GroupsVersion 9; Madison, WI) with GapWeight 1.000 and GapLengthWeight 0.100. Boxes are drawn around cysteine residues and completely conserved residues.

contain a protein that is identical to RNase 2, with residue 7 being an unusual C2-R-mannosyltryptophan

401-403 404 RNase 1,42,404 RNase 2,404,405 RNase 3,406 (8). 198,407 408 RNase 4, by human and angiogenin RI. Angiogeni are all bound tightly and the eosinophilic n

ribonucleases409,410 reviews.

have been the objects of recent

The crystalline structures of several homologues of RNase A have been determined by X-ray diffrac- tion analysis. These homologues include bovine seminal ribonuclease,411,412 Rana pipiens ribonuclease (which is also known as onconase),413 human angio- genin,414 bovine angiogenin,415 and human RNase 2.416 The crystalline structures of RI200 and an RI

RNase A complex,201,202 are also known.

which is not ribonucleolytic,

All of the RNase A homologues described above catalyze the cleavage of RNA. Wild-type levels of ribonucleolytic activity are essential for the cytotoxic and other biological activities of bovine seminal ribonuclease,417 onconase,377 RNase 2,404 and angio- genin.418 In surprising contrast, the wild-type ribo- nucleolytic activity of RNase 3 is not essential for its antibacterial activity.419 Revealing the mechanism by which the ribonucleolytic activity of these RNase A homologues is manifested in their unusual biologi-

cal activities is now a frutiful area for research that spans the chemistry-biology interface.420

XIII. Conclusion

RNase A has been the most studied enzyme of the 20th century. Methods now exist to produce unlim- ited quantities of RNase A (and its homologues) in which any amino acid residue is changed to any other. Methods also exist to synthesize informative and useful nucleotides and nucleotide analogues. These methods leave us poised to reveal in even more detail the precise role of enzymic residues, and to exploit further the use of RNase A in biotechnology and medicine. Work on RNase A will continue to provide a chemical framework for work on other ribonucleases, on ribozymes, and on synthetic cata- lysts of nucleic acid cleavage.

XIV. Acknowledgments

Work on RNase A in the Raines laboratory has been supported by the National Institutes of Health. I thank B. M. Fisher, B. R. Kelemen, P. A. Leland, C. Park, L. W. Schultz, and K. J. Woycechowsky for comments on the manuscript. Major international conferences on the structure and function of ribonu- cleases have been held in Moscow, U.S.S.R. (1988); San Feliu de Gu─▒´xols, Spain (1990); Capri, Italy (1993); Groningen, The Netherlands (1996); and Warrenton, VA (planned for May 1999). I am grate- ful to the organizers of these conferences for facilitat- ing the wide dissemination of up-to-date information on the enchanting world of ribonucleases.

  • XV.


    • (1)

      The RNA World; Gesteland, R. F.; Atkins, J. F., Eds.; Cold Spring Harbor Laboratory Press: Plainview, NY, 1993.

Document info
Document views56
Page views56
Page last viewedWed Oct 26 02:48:21 UTC 2016