Document Detail

Biosynthesis of 3-methoxy-5-methyl naphthoic acid and its incorporation into the antitumor antibiotic azinomycin B.
MedLine Citation:
PMID:  20485749     Owner:  NLM     Status:  MEDLINE    
Azinomycin B is a potent antitumor antibiotic that features a set of unusual, densely assembled functionalities. Among them, the 3-methoxy-5-methylnaphthoic acid (NPA) moiety provides an important noncovalent association with DNA, and may, therefore, contribute to the specificity of DNA alkylation for biological activity exhibition. We have previously cloned and sequenced the azinomycin B biosynthetic gene cluster, and proposed that four enzymes: AziB, AziB1, AziB2, and AziA1, are involved in the naphthoate moiety formation and incorporation. In this study, we report in vivo and/or in vitro characterizations of the P450 hydroxylase AziB1, the O-methyltransferase AziB2, and the substrate specificity of the non-ribosomal peptide synthetase (NRPS) AziA1, providing insights into the timing of individual steps in the late-stage modification of 5-methyl-NPA synthesized by the iterative type I polyketide synthase AziB. AziB1 catalyzes a regiospecific hydroxylation at the C3 position of the free naphthoic acid 5-methyl-NPA to produce 3-hydroxy-5-methyl-NPA, and the resulting hydroxyl group is subsequently O-methylated by AziB2 to furnish the methoxy functionality. The di-domain NRPS AziA1 specifically incorporates 3-methoxy-5-methyl-NPA via an unusual A domain to initiate the backbone formation of azinomycin B. AziA1 activates several analogues of the natural starter unit, suggesting a potential for production by metabolic engineering of new azinomycin analogues differing in their NPA moieties.
Wei Ding; Wei Deng; Mancheng Tang; Qi Zhang; Gongli Tang; Yurong Bi; Wen Liu
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-16
Journal Detail:
Title:  Molecular bioSystems     Volume:  6     ISSN:  1742-2051     ISO Abbreviation:  Mol Biosyst     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-05-20     Completed Date:  2010-08-30     Revised Date:  2011-05-16    
Medline Journal Info:
Nlm Unique ID:  101251620     Medline TA:  Mol Biosyst     Country:  England    
Other Details:
Languages:  eng     Pagination:  1071-81     Citation Subset:  IM    
School of Life Science, Lanzhou University, 222 South Tianshui Rd, Lanzhou 730000, China.
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MeSH Terms
Anti-Bacterial Agents / chemistry,  metabolism
Antibiotics, Antineoplastic / chemistry,  metabolism
Bacterial Proteins / genetics,  metabolism
Biosynthetic Pathways*
Carboxylic Acids / chemistry,  metabolism*
Cytochrome P-450 Enzyme System / genetics,  metabolism
Hydrogen-Ion Concentration
Methyltransferases / genetics,  metabolism
Molecular Structure
Naphthalenes / chemistry,  metabolism*
Peptide Synthases / genetics,  metabolism
Peptides / chemistry,  metabolism*
Polyketide Synthases / genetics,  metabolism
Streptomyces / genetics,  metabolism
Substrate Specificity
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Antibiotics, Antineoplastic; 0/Bacterial Proteins; 0/Carboxylic Acids; 0/Naphthalenes; 0/Peptides; 106486-76-4/azinomycin B; 79956-01-7/Polyketide Synthases; 86-55-5/1-naphthoic acid; 9035-51-2/Cytochrome P-450 Enzyme System; EC 2.1.1.-/Methyltransferases; EC 6.3.2.-/Peptide Synthases

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