Hydroxyquinone O-methylation in mitomycin biosynthesis.

Hydroxyquinone O-methylation in mitomycin biosynthesis. Research Abstract Details 

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Hydroxyquinone O-methylation in mitomycin biosynthesis. Abstract Text:

Sabine ,Leng-Chee Chang,Yingqing Mao,David H Sherman,

Mitomycins are bioreductively activated DNA-alkylating agents. One member of this family, mitomycin C, is in clinical use as part of combination therapy for certain solid tumors. The cytotoxicity displayed by mitomycins is dependent on their electrochemical potential which, in turn, is governed in part by the substituents of the quinone moiety. In this paper we describe studies on the biogenesis of the quinone methoxy group present in mitomycins A and B. An engineered Streptomyces lavendulae strain in which the mmcR methyltransferase gene had been deleted failed to produce the three mitomycins (A, B, and C) that are typically isolated from the wild type organism. Analysis of the culture extracts from the mmcR-deletion mutant strain revealed that two new metabolites, 7-demethylmitomycin A and 7-demethylmitomycin B, had accumulated instead. Production of mitomycins A and C or mitomycin B was selectively restored upon supplementing the culture medium of a S. lavendulae strain unable to produce the key precursor 3-amino-5-hydroxybenzoate with either 7-demethylmitomycin A or 7-demethylmitomycin B, respectively. MmcR methyltransferase obtained by cloning and overexpression of the corresponding mmcR gene was shown to catalyze the 7-O-methylation of both C9beta- and C9alpha-configured 7-hydroxymitomycins in vitro. This study provides direct evidence for the catalytic role of MmcR in formation of the 7-OMe group that is characteristic of mitomycins A and B and demonstrates the prerequisite of 7-O-methylation for the production of the clinical agent mitomycin C.

Hydroxyquinone O-methylation in mitomycin biosynthesis. Publishing Authors By Initials

S ,LC Chang,Y Mao,DH Sherman,

For similar bacteria: endospore-forming bacteria: gram-positive endospore-forming bacteria: gram-positive endospore-forming rods: streptomycetaceae: streptomyces research abstracts see: bacteria: endospore-forming bacteria: gram-positive endospore-forming bacteria: gram-positive endospore-forming rods: streptomycetaceae: streptomyces research

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Hydroxyquinone O-methylation in mitomycin biosynthesis. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Journal of the American Chemical Society

VOLUME: 129

Page Numbers: 6470-6

Journal Abbreviation: J. Am. Chem. Soc.

ISSN: 0002-7863

DAY: 27

MONTH: 04

YEAR: 2007

Hydroxyquinone O-methylation in mitomycin biosynthesis. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7503056

Hydroxyquinone O-methylation in mitomycin biosynthesis. Keywords Mesh Terms:

KEYWORDS: Streptomyces

MESH TERMS: metabolism

Chemical & Substance for Abstract: Hydroxyquinone O-methylation in mitomycin biosynthesis. Information

Substance Name: Methyltransferases

Registry Number: EC 2.1.1.-

Grant and Affiliation Information for Hydroxyquinone O-methylation in mitomycin biosynthesis.

AFFILIATION: Life Sciences Institute, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.

Country: United States

AGENCY: United States NCI

GRANT: R01 CA 81172

ACRONYM: CA

MEDLINETA: J Am Chem Soc

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