N. Zein et al., MADUROPEPTIN - AN ANTITUMOR CHROMOPROTEIN WITH SELECTIVE PROTEASE ACTIVITY AND DNA-CLEAVING PROPERTIES, Biochemistry, 34(36), 1995, pp. 11591-11597
Maduropeptin (MDP) is a recently isolated antitumor antibiotic, consis
ting of an enediyne-containing chromophore embedded in a highly acidic
protein. This holoantibiotic damages duplex DNA in vitro, producing a
mixture of single- and double-strand breaks at selected sites. The ch
romophore, isolated as the methanol adduct from the protein-containing
holoantibiotic, exhibits the same selectivity and cleavage chemistry
as the chromoprotein complex. Preliminary evidence suggests that the p
rimary DNA breaks involve 4'-H abstraction from the deoxyribose sugars
at the cleavage sites. Unlike most other enediyne antitumor antibioti
cs, DNA strand scission is not bioreductively induced by MDP or the me
thanol adduct of the chromophore. This was also observed for the C1027
chromophore. DNA cleavage is inhibited in the presence of certain cat
ions (Ca2+, Mg2+) as was observed with the kedarcidin chromophore. H-1
NMR spectroscopy studies on the methanol adduct of the maduropeptin c
hromophore in the presence of calcium chloride provide clues regarding
its activation and give insight as to the regions of the chromophore
important for DNA binding. Our results suggest that the solvent artifa
ct of the chromophore may in essence be a prodrug and it regenerates t
he parent chromophore as in the holoantibiotic prior to cleaving DNA.
As with kedarcidin and neocarzinostatin, maduropeptin exhibits a high
affinity for histones, in vitro, cleaving them to low molecular mass p
eptides. Histone H1, the most opposite in net charge, is cleaved most
readily. This latter activity may serve to disrupt the chromatin super
structure in vivo, prior to exposing the DNA to the chromophore.