Kedarcidin chromophore: an enediyne that cleaves DNA in a sequence-specific manner.

Zein, Nada; Colson, Kimberly L.; Leet, John E.; Schroeder, Daniel R.; Solomon, Wyle; Doyle, Terrence W.; Casazza, Anna Maria

doi:10.1073/pnas.90.7.2822

Cited by 44 publications

(33 citation statements)

References 44 publications

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“…2-Hydroxy-1-naphthoic acid (12), 3,5-dihydroxy-2-naphthoic acid (13), 3,7-dihydroxy-2-naphthoic acid (14), and 1,4-dihydroxy-2-naphthoic acid (15) were purchased from Sigma. Chemicals from standard commercial sources were used directly without further purification.…”

Section: Methodsmentioning

confidence: 99%

Regiospecific O-Methylation of Naphthoic Acids Catalyzed by NcsB1, an O-Methyltransferase Involved in the Biosynthesis of the Enediyne Antitumor Antibiotic Neocarzinostatin

Luo

Lin

Zhang

et al. 2008

Journal of Biological Chemistry

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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. Neocarzinostatin (NCS),3 a clinical anticancer drug used to treat leukemia and cancers of the bladder, stomach, pancreas, liver, and brain, is an archetypal member of the chromoprotein family of enediyene antitumor antibiotics that are composed of a nonprotein chromophore and an apoprotein (1-3). NCS was originally isolated from Streptomyces carzinostaticus in 1965 (1-3). Its apoprotein NcsA is encoded by the ncsA gene and protects, carries, and delivers the reactive NCS chromophore (4). The NCS chromophore (1, Fig. 1B) is composed of a ninemembered enediyne core, a deoxyaminosugar, and a naphthoic acid moiety (2, 5). As a member of the enediyne family, the biological activity of NCS is derived from its ability to cleave DNA (6). The NCS chromophore undergoes Myers-Saito cycloaromatization to form a 2,6-indacene diradical species that subsequently abstracts hydrogen atoms from the deoxyribose of DNA, leading to single-and double-stranded DNA breaks (2, 7). For NCS, a thiol is often required to trigger the cycloaromatization, although a few enediynes have been reported to form diradicals via the cycloaromatization in a thiol-independent manner, likely the result of the intrinsic reactivity of the nine-membered ring enediyne core (1, 2, 7). The mechanism of action for NCS also invo...

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Section: Methodsmentioning

confidence: 99%

Regiospecific O-Methylation of Naphthoic Acids Catalyzed by NcsB1, an O-Methyltransferase Involved in the Biosynthesis of the Enediyne Antitumor Antibiotic Neocarzinostatin

Luo

Lin

Zhang

et al. 2008

Journal of Biological Chemistry

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“…Cytotoxicity assays on the HCT116 colon carcinoma cell line result in an IC 50 value of 1 nM. In vitro experiments with ΦX174, pM2 DNA, and 32 P-end-labeled restriction fragments demonstrate that this chromophore binds and cleaves duplex DNA with remarkable sequence selectivity, producing single-strand breaks (133).…”

Section: Enediyne Alkaloidal Antibioticsmentioning

confidence: 99%

Astonishing diversity of natural surfactants: 6. Biologically active marine and terrestrial alkaloid glycosides

Dembitsky

2005

Lipids

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This review article presents 209 alkaloid glycosides isolated and identified from plants, microorganisms, and marine invertebrates that demonstrate different biological activities. They are of great interest, especially for the medicinal and/or pharmaceutical industries. These biologically active glycosides have good potential for future chemical preparation of compounds useful as antioxidants, anticancer, antimicrobial, and antibacterial agents. These glycosidic compounds have been subdivided into several groups, including: acridone; aporphine; benzoxazinoid; ergot; indole; enediyne alkaloidal antibiotics; glycosidic lupine alkaloids; piperidine, pyridine, pyrrolidine, and pyrrolizidine alkaloid glycosides; glycosidic quinoline and isoquinoline alkaloids; steroidal glycoalkaloids; and miscellaneous alkaloid glycosides.

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“…1(b)) produced from Streptoalloteichus sp. [17] and N1999A2 (Fig. 1(c)) produced from Streptomyces sp.…”

Section: Introductionmentioning

confidence: 99%

Neocarzinostatin naphthoate synthase: an unique iterative type I PKS from neocarzinostatin producer Streptomyces carzinostaticus

Sthapit

Lamichhane

et al. 2004

FEBS Letters

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Enediyne antibiotics are known for their potent antitumor activities. One such enediyne, neocarzinostatin (NCS), consists of a 1:1 complex of non-peptide chromophore (1a), and peptide apoprotein. The structurally diverse nonpeptide chromophore is responsible for its biological activity. One of its structural components, the naphthoic acid moiety (2,7-dihydroxy-5-methyl-1-naphthoic acid, 1d) is synthesized by a polyketide synthase (PKS) pathway through condensing six intact acetate units. The 5.45 kb iterative type I PKS, neocarzinostatin naphthoate synthase (NNS), responsible for naphthoic acid moiety biosynthesis, shares sequence homology with 6-methyl salicylic acid synthase of fungi and orsellinic acid synthases (AviM and CalO5) of Streptomyces origin. Cultures of S. lividans TK24 and S. coelicolor YU105 containing plasmids with NNS were able to produce 2-hydroxy-5-methyl-1-naphthoic acid (2a), a key intermediate of naphthoic acid moiety in NCS. In addition to 2a, a novel product, 2-hydroxy-5-hydroxymethyl-1-naphthoic acid (2d) was isolated. This is the first report of a bacterial iterative type I PKS from an enediyne producer which enables the biosynthesis of bicyclic aromatic compounds.

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Kedarcidin chromophore: an enediyne that cleaves DNA in a sequence-specific manner.

Cited by 44 publications

References 44 publications

Regiospecific O-Methylation of Naphthoic Acids Catalyzed by NcsB1, an O-Methyltransferase Involved in the Biosynthesis of the Enediyne Antitumor Antibiotic Neocarzinostatin

Regiospecific O-Methylation of Naphthoic Acids Catalyzed by NcsB1, an O-Methyltransferase Involved in the Biosynthesis of the Enediyne Antitumor Antibiotic Neocarzinostatin

Astonishing diversity of natural surfactants: 6. Biologically active marine and terrestrial alkaloid glycosides

Neocarzinostatin naphthoate synthase: an unique iterative type I PKS from neocarzinostatin producer Streptomyces carzinostaticus

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