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Substrate Specificity of Human Renin: The Effect of Substitutions at the Amino Terminus and P3 Position of the Substrate

  • David W. Green
  • Meheryar N. Rivetna
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 306)

Abstract

Renin (E.C. 3.4.23.15) regulates the initial step in the generation of the potent pressor octapeptide angiotensin II by cleaving the decapeptide angiotensin I from the amino terminus of angiotensinogen (Ondetti & Cushman, 1982). In contrast to structurally homologous cellular aspartic proteases, renin specificity is restricted to angiotensinogen and little variation from the substrate sequence is tolerated. Inspection of the crystal structure (Sielecki et al., 1989) indicates substrate residues P4 to P3′ (nomenclature of Schechter & Berger, 1967, where P1−P1′ is the scissile peptide bond) interact directly with renin. We have determined the steady-state kinetic parameters of human renin with substrates (Table 1) that differ in the amino terminal P7 to P10 residues (PTDP and KIHPFHLLVYS) and P3 residue (KIHPXHLLVYS). Our results are consistent with the structural predictions; that is, substitutions outside of the P4 to P3′ sequence have no significant effect on renin activity but substituting p-nitro-phenylalanine (pNF, X) for phenylalanine at the P3 position decreases the reactivity of renin.

Keywords

Human Renin Scissile Bond Substrate Residue 1040A Diode Array Scissile Peptide Bond 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Baranay, G. & Merrifield, R. B., 1979, in: “The Peptides”, E. Gross & J. Meienhofer, eds., Vol. 2, pp.1–284, Academic Press, New York.Google Scholar
  2. Bradford, M., 1976, Anal. Biochem. 72: 248–254.PubMedCrossRefGoogle Scholar
  3. Burton, J. & Quinn, T., 1988, Biochim. Biophys. Acta 952: 8–12.PubMedCrossRefGoogle Scholar
  4. Fruton, J. S., 1976, Adv. Enzymology 44: 1–36.Google Scholar
  5. Green, D. W., Aykent, S., Gierse, J. K. & Zupec, M. E., 1990, Biochemistry 29: 3126–3133.PubMedCrossRefGoogle Scholar
  6. Ondetti, M. A. & Cushman, D. W., 1982, Ann. Rev. Biochem. 51: 283–308.PubMedCrossRefGoogle Scholar
  7. Poorman, R. A., Palmero, D. P., Post, L. E., Murakami, K., Kinner, J. H., Smith, C. W., Reardon, H. & Heinrickson, R. L., 1987, Proteins: Struct. Funct. Genet. 1: 139–145.Google Scholar
  8. Sali, A., Veerapandian, B., Cooper, J. B., Foundling, S. L, Hoover, D. J. & Blundell, T. L., 1989, EMBO J. 8: 2179–2188.PubMedGoogle Scholar
  9. Schechter, I. & Berger, A., 1967, Biochem. Biophys. Res. Commun. 27: 157–162.PubMedCrossRefGoogle Scholar
  10. Sielecki, A. R., Hayakawa, K., Fujiaga, M., Murphy, M. E. P., Fraser, M., Muir, A. K., Carilli, C. T., Lewicki, J. A., Baxter, J. D. & James, M. N. G., 1989, Science 243: 1346–1351.PubMedCrossRefGoogle Scholar
  11. Suguna, K., Padlan, E. A., Smith, C. W., Carlson, W. D. & Davies, D. R., 1987, Proc. Natl. Acad. Sci. U.S.A. 84: 7009–7013.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • David W. Green
    • 1
  • Meheryar N. Rivetna
    • 1
  1. 1.Department of Biological SciencesCorporate Research and Development, Monsanto CompanyChesterfieldUSA

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