EFFECTS OF LINKAGE ISOMERISM AND OF ACID-BASE EQUILIBRIA ON REACTIVITY AND CATALYTIC TURNOVER IN HYDROLYTIC CLEAVAGE OF HISTIDYL PEPTIDES COORDINATED TO PALLADIUM(II) - IDENTIFICATION OF THE ACTIVE COMPLEX BETWEEN PALLADIUM(II) AND THE HISTIDYL RESIDUE

This is a quantitative study of hydrolysis of the His-Gly bond in the peptide AcHis-Gly catalyzed by cis-[Pd(en)(H2O)(2)](2+). We exploit th e diverse coordinating abilities and acid-base properties of histidyl residue to interpret the kinetics and explain the mechanism of this ne w reaction. We compare peptides selectively methylated at the N-1 or N -3 atom of imidazole and study effects of solution acidity on the abun dance of different pepride-catalyst complexes and on the late constant for hydrolysis. Only the catalyst bound to the N-3 atom of imidazole can effect this reaction; none of the four other modes of coordination is effective. The necessary approach of the palladium(II) aqua comple x to the scissile peptide bond and the rate constant of hydrolysis are unaffected by the remote methyl group that merely controls the mode o f peptide coordination to the catalyst. Acid in solution affects hydro lysis only by controlling the concentration of the reactive complex, n ot by catalyzing the reaction itself. Weakly acidic solution is requir ed to suppress oligomerization of the catalyst. Hydrolytic cleavage oc curs with a turnover greater than 4. With the halflife of 5.1 h at pH 5.0, the cleavage is fast enough at relatively mild conditions to be p ractical for various applications in biochemistry and structural biolo gy. This study is an important step in our development of palladium(TI ) complexes as artificial metallopeptidases.