Nagao K, Suzuki K, Tokunaga J, Miyazaki H, Katayama N, Mitsuyama R, Uyeda M
Laboratory of Medicinal Microbiology, Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
J Enzyme Inhib. 1996;10(2):115-24. doi: 10.3109/14756369609020164.
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.
链霉菌属菌株560在培养滤液中产生几种类型的DNA甲基转移酶抑制剂。其中两种，DMI - 2和DMI - 3，通过它们对DNA甲基转移酶的抑制谱和抑制特性与先前报道的DMI - 1区分开来。DMI - 2和DMI - 3的分子量分别为854和435。DMI - 2的结构被确定为4"'R,6aR,10S,10aS - 8 - 乙酰基 - 6a,10a - 二羟基 - 2 - 甲氧基 - 12 - 甲基 - 10 - [4'-[3"-羟基 - 3",5"-二甲基 - 4" (Z - 2"',4"'-二甲基 - 2"'-庚烯酰氧基)四氢吡喃 - 1"- 氧基]-5'-甲基环己烷 - 1'- 氧基]-1,4,6,7,9 - 五氧代 - 1,4,6,6a,7,8,9,10,10a,11 - 十氢萘并四苯。DMI - 2的化学结构被确定为土霉素的互变异构体，土霉素是链霉菌属菌株1725产生的一种抗肿瘤抗生素。DMI - 2和DMI - 3对N6 - 甲基腺嘌呤 - DNA甲基转移酶（M. Eco RI）表现出强烈抑制作用。DMI - 2以竞争方式抑制M. Eco RI，相对于用作DNA底物的质粒pUC19；以非竞争方式抑制M. Eco RI，相对于用作甲基供体的S - 腺苷甲硫氨酸（SAM）。DMI - 3以竞争方式抑制M. Eco RI，相对于质粒pUC19和SAM。两种抑制剂的抑制活性均取决于测定介质中的pH和温度。
