MISC

基本情報

氏名 河手 久弥
氏名(カナ) カワテ ヒサヤ
氏名(英語) HISAYA KAWATE
所属 中村学園大学 栄養科学部 栄養科学科
職名 教授

題名

Substrate specificity of human O-6-methylguanine-DNA methyltransferase for O-6-benzylguanine derivatives in oligodeoxynucleotides

単著・共著の別

 

著者

Terashima, I
H Kawate
K Sakumi
M Sekiguchi
K Kohda

担当区分

 

概要

To investigate the substrate specificity of human O-6-methylguanine-DNA methyltransferase (MGMT) for O-6-benzylguanine (6BG) derivatives incorporated in oligodeoxynucleotides, we prepared 25-mer lengths of sequences containing various 6BG derivatives and their related compounds and then measured the ability of these derivatives to inactivate MGMT in vitro. Oligodeoxynucleotides containing a 6BG, O-6-(2-fluorobenzyl)guanine (2F-6BG), O-6-(3-fluorobenzyl)guanine (3F-6BG), O-6-(4-fluorobenzyl)guanine (4F-6BG), O-6-benzylhypoxanthine (6BH), or O-6-methylguanine (6MG) were all good substrates for MGMT, and no obvious differences were observed among them. Oligodeoxynucleotides containing N-2-isobutyrylated 6BG and 6MG showed only a slightly reduced capacity for inactivating MGMT compared to N-2-nonmodified forms of these derivatives. No obvious differences were observed in the corresponding double-stranded and single-stranded oligodeoxynucleotides. MGMT substrate specificity for the 6BG derivatives in the oligodeoxynucleotide was found to be quite different from that seen in our previous study [Mineura, K., et al. (1994) Int. J. Cancer 58, 706-712; (1995) Int. J. Cancer 63, 148-151. Kohda, K., et al. (1995) Biol. Pharm. Bull. 18, 424-430] and others [Moschel, R. C., et al. (1992) J. Med. Chem. 35, 4486-4491. Chae, M.-Y., et al. (1994) J. Med. Chem. 37, 342-347] using the corresponding free bases. In brief, (i) 6BG, 3F-6BG, and 4F-6BG greatly inhibited human MGMT, whereas 2F-6BG, 6BH, and 6MG displayed much weaker activity; (ii) any modifications at the 2-amino group of the 6BG resulted in severe reductions in the ability to inactivate MGMT. These results obtained by the experiments using oligodeoxynucleotides and free bases suggest that human MGMT has low substrate specificity for 6BGs in oligodeoxynucleotides. Conformational changes in human MGMT which favor binding to oligodeoxynucleotides containing 6BG derivatives and the subsequent transfer of their benzyl groups may account for the difference in substrate specificity between the incorporated 6BG derivatives and their free base form.

発表雑誌等の名称

CHEMICAL RESEARCH IN TOXICOLOGY

出版者

AMER CHEMICAL SOC

10

11

開始ページ

1234

終了ページ

1239

発行又は発表の年月

1997-11

査読の有無

無し

依頼の有無

無し

記述言語

英語

掲載種別

 

国際・国内誌

 

国際共著

 

ISSN

 

eISSN

 

DOI

10.1021/tx9700580

Cinii Articles ID

 

Cinii Books ID

 

Pubmed ID

 

PubMed Central 記事ID

 

形式

無償ダウンロード

JGlobalID

 

arXiv ID

 

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DBLP ID