DMI-2 and DMI-3, DNA methyltransferase inhibitors produced by Streptomyces sp. strain no. 560.
Streptomyces sp. strain No. 560 produces several types of DNA methyltransferase inhibitors in the culture filtrate. Two of them, DMI-2 and DMI-3, were distinguished from the previously reported DMI-1 by their inhibitory spectrum and inhibition characteristics against DNA methyltransferase. The molecular weights of DMI-2 and DMI-3 were 854 and 435, respectively. The structure of DMI-2 was determined to be 4"'R,6aR,10S,10aS-8-acetyl-6a, 10a-dihydroxy-2-methoxy-12-methyl-10-[4'-[3"-hydroxy-3",5"-dimethyl-4" (Z-2"',4"'-dimethyl-2"'-heptenoyloxy) tetrahydropyran-1"-yloxy]-5'-methylcyclohexan-1'-yloxy ]-1,4,6, 7,9-pentaoxo-1,4,6,6a,7,8,9,10,10a,11-decahydronaphthacene. The chemical structure of DMI-2 was established as a tautomer of dutomycin which is an antitumor antibiotic produced by Streptomyces sp. 1725. DMI-2 and DMI-3 showed strong inhibition against N6-methyladenine-DNA methyltransferase (M. Eco RI). DMI-2 inhibited M. Eco RI in a competitive manner with respect to plasmid pUC19 used as DNA substrate and in an uncompetitive manner with respect to S-adenosylmethionine (SAM) used as methyl donor. DMI-3 inhibited M. Eco RI in a competitive manner with respect to plasmid pUC19 and SAM. The inhibitory activities of both inhibitors depended upon the pH and temperature in the assay media.
Nagao
K
K
Laboratory of Medicinal Microbiology, Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Suzuki
K
K
Tokunaga
J
J
Miyazaki
H
H
Katayama
N
N
Mitsuyama
R
R
Uyeda
M
M
D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D005227:Fatty Acids / Q000037:antagonists & inhibitors; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D008970:Molecular Weight; D009279:Naphthacenes / Q000737:chemistry / Q000494:pharmacology; D012436:S-Adenosylmethionine / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013302:Streptomyces / Q000737:chemistry*; D013696:Temperature
C098700:8-methylpentadecanoic acid; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D009279:Naphthacenes; D012436:S-Adenosylmethionine; D015254:DNA Modification Methylases