Maduropeptin: an antitumor chromoprotein with selective protease activity and DNA cleaving properties.
Maduropeptin (MDP) is a recently isolated antitumor antibiotic, consisting 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 chromophore, 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 primary DNA breaks involve 4'-H abstraction from the deoxyribose sugars at the cleavage sites. Unlike most other enediyne antitumor antibiotics, DNA strand scission is not bioreductively induced by MDP or the methanol adduct of the chromophore. This was also observed for the C1027 chromophore. DNA cleavage is inhibited in the presence of certain cations (Ca2+, Mg2+) as was observed with the kedarcidin chromophore. 1H NMR spectroscopy studies on the methanol adduct of the maduropeptin chromophore 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 artifact of the chromophore may in essence be a prodrug and it regenerates the 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 peptides. Histone H1, the most opposite in net charge, is cleaved most readily. This latter activity may serve to disrupt the chromatin superstructure in vivo, prior to exposing the DNA to the chromophore.
Zein
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Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
Solomon
W
W
Colson
K L
KL
Schroeder
D R
DR
D000480:Alkynes / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism*; D023181:Antimicrobial Cationic Peptides; D010584:Bacteriophage phi X 174 / Q000235:genetics; D001483:Base Sequence; D002122:Calcium Chloride / Q000737:chemistry; D002417:Cattle; D003516:Cycloparaffins / Q000737:chemistry / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D053281:Enediynes; D006657:Histones / Q000378:metabolism; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009281:Naphthalenes / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides; D013379:Substrate Specificity; D013950:Thymus Gland / Q000378:metabolism
D000480:Alkynes; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D023181:Antimicrobial Cationic Peptides; D003516:Cycloparaffins; D053281:Enediynes; D006657:Histones; D009281:Naphthalenes; D010455:Peptides; C075998:maduropeptin A1; C080542:kedarcidin chromophore; D004247:DNA; D010450:Endopeptidases; D002122:Calcium Chloride