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Abstract
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-mefhyl-10-[4′-[3″-hydroxy-3″,5″-dimethyl-4″ (Z- 2′″,4″′-dimethyl-2′″-heptenoyloxy) tetrahydropyran-l″-yloxy]-5′-methylcyclohexan-l′-yloxy] -1,4,6,7,9-pentaoxo-l,4,6,6a,7,8,9,10,10a,ll-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 iV6-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.