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7682 Biochemistry 1988, 27, 7682-7688 Kinetic Properties of the Binding of a-Lytic Protease to Peptide Boronic Acids
 

Summary: 7682 Biochemistry 1988, 27, 7682-7688
Kinetic Properties of the Binding of a-Lytic Protease to Peptide Boronic Acids
Charles A. Kettner,*st Roger Bone,$ David A. Agard,f and William W. Bachovchinll
Central Research and Development Department, E. I. du Pont de Nemours and Company, Experimental Station, Wilmington,
Delaware 19898, Department of Biochemistry and Biophysics and Howard Hughes Medical Institute, University of California,
San Francisco, San Francisco, California 94142-0448, and Department of Biochemistry, Tufts University School of Medicine,
Boston, Massachusetts 02111
Received October 27, 1987; Revised Manuscript Received July 7, 1988
ABSTRACT: The kinetic parameters for peptide boronic acids in their interaction with a-lytic protease were
determined and found to be similar to those of other serine proteases [Kettner, C., & Shenvi, A. B. (1984)
J.Biol. Chem. 259, 15106-151 141. a-Lytic protease hydrolyzes substrates with either alanine or valine
in the P, site and has a preference for substrate with a P1alanine. The most effective inhibitors are tri-
and tetrapeptide analogues that have a -boroVal-OH residue in the P, site. At pH 7.5, MeOSuc-Ala-
Ala-Pro-boroVal-OH has a Kiof 6.4 nM and Boc-Ala-Pro-boroVal-OH has a Kiof 0.35nM. Ac-boroVal-OH
and Ac-Pro-boroVal-OH are 220000- and 500-fold less effective, respectively, than the tetrapeptide analogue.
The kinetic properties of the tri- and tetrapeptide analogues are consistent with the mechanism for slow-binding
inhibition, E + I + E1 + EI*, while the less effective inhibitors are simple competitive inhibitors. MeO-
Suc-Ala-Ala-Pro-boroAla-OHis a simple competitive inhibitor with a Kiof 67 nM at pH 7.5. Other peptide
boronic acids, which are analogues of nonsubstrates, are less effective than substrate analogues but still
are effective competitive inhibitors. For example, MeOSuc-Ala-Ala-Pro-boroPhe-OHhas a Kiof 0.54 p M

  

Source: Agard, David - Department of Biochemistry and Biophysics, University of California at San Francisco

 

Collections: Biotechnology; Biology and Medicine