Cisplatin mediates selective downstream hydrolytic cleavage of Met-(Gly)(n)-His segments (n=1,2) in methionine- and histidine-containing peptides: the role of ammine loss trans to the initial Pt-S(Met) anchor in facilitating amide hydrolysis.
The pH- and time-dependent reactions of the antitumor drug cisplatin, cis-[PtCl(2)(NH(3))(2)], with the methionine- and histidine-containing pentapeptides Ac-Met-Gly-His-Gly-Gly-OH, Ac-Met-Gly-Gly-His-Gly-OH and Ac-Gly-Met-Gly-His-Gly-OH (Gly=glycyl, Met=L-methionyl, His=L-histidyl) at 313K have been investigated by high performance liquid chromatography, mass spectrometry and nuclear magnetic resonance. Cisplatin mediates a rapid "downstream" hydrolytic cleavage of the Met-Gly amide bond in weakly acid solution (pH < or =5) for all three peptides, leading to release of H-Gly-His-Gly-Gly-OH, H-Gly-Gly-His-Gly-OH and H-Gly-His-Gly-OH, respectively, and formation of kappa(2)S,N(M) chelate complexes of the methionine-containing residuals Ac-Met-OH or Ac-Gly-Met-OH. An alternative reaction pathway affords tridentate kappa(3)S,N(M),N(imidazole) macrochelates of the original pentapeptide following ammine loss. The downstream cleavage pathway is competitive with the likewise cisplatin-mediated upstream cleavage of the Ac-Gly linkage in the pentapeptide Ac-Gly-Met-Gly-His-Gly-OH. This leads to formation of both the kappa(3)S,N(M),N(G1) complex of H-Gly-Met-Gly-His-Gly-OH due to upstream cleavage and the analogous tridentate complex for H-Gly-Met-OH due to initial downstream loss of H-Gly-His-Gly-OH followed by upstream loss of acetic acid. As downstream cleavage is not observed for Ac-(Gly)(2)-Met-(Gly)(2)-OH under similar conditions, it may be concluded that rapid histidine imidazole substitution of the ammine ligand in trans-position to an anchoring methionine S atom must assist hydrolytic cleavage of the Met-Gly amide bond.
Hohage
Oliver
O
Lehrstuhl für Analytische Chemie, Ruhr-Universität Bochum, Universitätsstrasse 150, D-44780 Bochum, Germany.
Sheldrick
William S
WS
D000577:Amides / Q000737:chemistry*; D000595:Amino Acid Sequence; D002945:Cisplatin / Q000737:chemistry*; D005998:Glycine; D006639:Histidine; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D008715:Methionine; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D010984:Platinum / Q000737:chemistry*
D000577:Amides; D009944:Organoplatinum Compounds; D010455:Peptides; D010984:Platinum; D006639:Histidine; D008715:Methionine; D002945:Cisplatin; D005998:Glycine