Document Detail


Regiospecific O-methylation of naphthoic acids catalyzed by NcsB1, an O-methyltransferase involved in the biosynthesis of the enediyne antitumor antibiotic neocarzinostatin.
MedLine Citation:
PMID:  18387946     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Neocarzinostatin, a clinical anticancer drug, is the archetypal member of the chromoprotein family of enediyne antitumor antibiotics that are composed of a nonprotein chromophore and an apoprotein. The neocarzinostatin chromophore consists of a nine-membered enediyne core, a deoxyaminosugar, and a naphthoic acid moiety. We have previously cloned and sequenced the neocarzinostatin biosynthetic gene cluster and proposed that the biosynthesis of the naphthoic acid moiety and its incorporation into the neocarzinostatin chromophore are catalyzed by five enzymes NcsB, NcsB1, NcsB2, NcsB3, and NcsB4. Here we report the biochemical characterization of NcsB1, unveiling that: (i) NcsB1 is an S-adenosyl-L-methionine-dependent O-methyltransferase; (ii) NcsB1 catalyzes regiospecific methylation at the 7-hydroxy group of its native substrate, 2,7-dihydroxy-5-methyl-1-naphthoic acid; (iii) NcsB1 also recognizes other dihydroxynaphthoic acids as substrates and catalyzes regiospecific O-methylation; and (iv) the carboxylate and its ortho-hydroxy groups of the substrate appear to be crucial for NcsB1 substrate recognition and binding, and O-methylation takes place only at the free hydroxy group of these dihydroxynaphthoic acids. These findings establish that NcsB1 catalyzes the third step in the biosynthesis of the naphthoic acid moiety of the neocarzinostatin chromophore and further support the early proposal for the biosynthesis of the naphthoic acid and its incorporation into the neocarzinostatin chromophore with free naphthoic acids serving as intermediates. NcsB1 represents another opportunity that can now be exploited to produce novel neocarzinostatin analogs by engineering neocarzinostatin biosynthesis or applying directed biosynthesis strategies.
Authors:
Yinggang Luo; Shuangjun Lin; Jian Zhang; Heather A Cooke; Steven D Bruner; Ben Shen
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2008-04-03
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  283     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2008 May 
Date Detail:
Created Date:  2008-05-19     Completed Date:  2008-07-18     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  14694-702     Citation Subset:  IM    
Affiliation:
Division of Pharmaceutical Sciences, University of Wisconsin National Cooperative Drug Discovery Group, Department of Chemistry, University of Wisconsin, Madison, WI 53705, USA.
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MeSH Terms
Descriptor/Qualifier:
Anti-Bacterial Agents / biosynthesis*,  chemistry
Antineoplastic Agents / chemistry,  metabolism*
Catalysis
Cloning, Molecular
Gene Expression
Methylation
Methyltransferases / genetics,  isolation & purification,  metabolism*
Molecular Structure
Naphthalenesulfonates / metabolism*
Substrate Specificity
Zinostatin / biosynthesis*,  chemistry
Grant Support
ID/Acronym/Agency:
CA 113297/CA/NCI NIH HHS; CA 78747/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Antineoplastic Agents; 0/Naphthalenesulfonates; 84-86-6/naphthionic acid; 9014-02-2/Zinostatin; EC 2.1.1.-/Methyltransferases
Comments/Corrections

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