The Structure of Novobiocin<sup>1,2</sup>

Hinman, J. W.; Caron, Eddy; Hoeksema, Herman

doi:10.1021/ja01571a047

Cited by 92 publications

(34 citation statements)

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“…Preliminary assays to reconstitute SimL activity contained 1 mM aminocoumarin 5 (17,20) For the determination of kinetic parameters for the carboxylic acids accepted by SimL, the concentration of the aminocoumarin substrate was kept constant at 200 µM while the concentration of the acid substrates was varied in the above-described reaction buffer. Each reaction was analyzed as described above, and the product concentration was calculated by comparison with the product standard curves described below.…”

Section: Methodsmentioning

confidence: 99%

“…Fractions containing the desired product were pooled and concentrated under reduced pressure, yielding yellowish solids. Products were confirmed by LC-MS: decatetraenoic acid SimL product 7 [ESI for C 20 Standard curves were generated for each product using analytical reverse-phase HPLC over specific concentration ranges: decatetraenoic acid SimL product (0.009-0.4 nmol), fumagillin SimL product (0.009-1.08 nmol), trans-retinoic SimL product (0.025-2 nmol), and the decatetraenedioic monomethyl ester SimL product (0.25-5 nmol).…”

Section: Methodsmentioning

confidence: 99%

“…The appearance of product was accompanied by a corresponding decrease in the free carboxylate substrate, and the reaction was monitored by RP-HPLC and confirmed by LC-MS [ESI for C 20 On the other hand, SimL is unable to catalyze amide bond formation for either the NovL or CouL substrates 3-prenyl-4-hydroxybenzoic acid and 3-methylpyrrole-2,4-dicarboxylic acid. In addition, neither NovL nor CouL exhibits any activity on any of the acyl SimL substrates tested here.…”

Section: +mentioning

confidence: 98%

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Characterization of the Aminocoumarin Ligase SimL from the Simocyclinone Pathway and Tandem Incubation with NovM,P,N from the Novobiocin Pathway

et al. 2005

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Simocyclinone D 8 consists of an anguicycline C-glycoside tethered by a tetraene diester linker to an aminocoumarin. Unlike the antibiotics novobiocin, clorobiocin, and coumermycin A 1 , the phenolic hydroxyl group of the aminocoumarin in simocyclinone is not glycosylated with a decorated noviosyl moiety that is the pharmacophore for targeting bacterial DNA gyrase. We have expressed the Streptomyces antibioticus simocyclinone ligase SimL, purified it from Escherichia coli, and established its ATP-dependent amide bond forming activity with a variety of polyenoic acids including retinoic acid and fumagillin. We have then used the last three enzymes from the novobiocin pathway, NovM, NovP, and NovN, to convert a SimL product to a novel novobiocin analogue, in which the 3-prenyl-4-hydroxybenzoate of novobiocin is replaced with a tetraenoate moiety, to evaluate antibacterial activity.The aminocoumarin antibiotics novobiocin 1, clorobiocin 2, and coumermycin A 1 3, produced by various Streptomyces species (Figure 1), contain a bicyclic 3-amino-4,7-dihydroxycoumarin ring system, which serves as an essential scaffold for targeting them to the bacterial type II topoisomerases DNA gyrase and topoisomerase IV (1-5). Coumermycin A 1 is a pseudosymmetric dimer, containing elements of novobiocin (the 8-methylaminocoumarin) and clorobiocin (the 3′-O-methylpyrrolyl acyl group). Cocrystals of the N-terminal 24 kDa subfragment of the DNA gyrase B subunit (GyrB) 1 with 1 and 2 (1, 2) reveal that this family of antibiotics uses the aminocoumarin as a planar scaffold to present the decorated 4′-O-methyl-3′-O-acyl noviosyl moiety as the pharmacophore for inhibiting ATP hydrolysis in GyrB. These decorations of the L-deoxy sugar noviose include 4′-Omethylation and 3′-O-acylation with either a carbamoyl or methylpyrrolyl group. This 3′-O-acyl substituent is in intimate contact with GyrB active site residues and/or bound water molecules.Recently, another antibiotic containing the conserved aminocoumarin moiety, simocyclinone D 4 from Streptomyces antibioticus, has been discovered (6, 7). Simocyclinone D is a structurally unique antibiotic containing an aromatic anguicycline polyketide nucleus, the deoxy sugar D-olivose, and either the 8-chloro or 8-desmethyl version of the 3-amino-4,7-dihydroxycoumarin (8). The anguicycline Cglycoside and the aminocoumarin elements are linked by a tetraene dicarboxylic acid moiety. Simocyclinone possesses antimicrobial activity against Gram-positive bacteria, as well as exhibiting cytostatic effects against human tumor cell lines (6). However, its lack of a decorated noviosyl moiety at the 7-hydroxy position of the aminocoumarin scaffold suggests a molecular mechanism of action different than that of 1 and 2 given the X-ray information on GyrB complexes noted above for 1 and 2 (1, 2). Indeed, recent studies reveal that simocyclinone D8 is a potent inhibitor of gyrase, albeit through a novel mode of action by preventing the initial binding of gyrase to DNA (Anthony Maxwell, personal communicatio...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: +mentioning

confidence: 98%

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Characterization of the Aminocoumarin Ligase SimL from the Simocyclinone Pathway and Tandem Incubation with NovM,P,N from the Novobiocin Pathway

et al. 2005

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“…The reactants which were used in feeding experiments (Table 1) were supplied by Sigma-Aldrich and Roth. Novobiocic acid was synthesized as already described (22). Two chemical compounds, 1-amino-4-chloranthraquinone (23) and 1,2,5,8-tetrahydroxyanthraquinone (24), were synthesized as described previously.…”

Section: Methodsmentioning

confidence: 99%

Tracking Down Biotransformation to the Genetic Level: Identification of a Highly Flexible Glycosyltransferase from Saccharothrix espanaensis

Strobel

Schmidt

Linnenbrink

et al. 2013

Appl Environ Microbiol

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e Saccharothrix espanaensis is a member of the order Actinomycetales. The genome of the strain has been sequenced recently, revealing 106 glycosyltransferase genes. In this paper, we report the detection of a glycosyltransferase from Saccharothrix espanaensis which is able to rhamnosylate different phenolic compounds targeting different positions of the molecules. The gene encoding the flexible glycosyltransferase is not located close to a natural product biosynthetic gene cluster. Therefore, the native function of this enzyme might be not the biosynthesis of a secondary metabolite but the glycosylation of internal and external natural products as part of a defense mechanism.

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“…As a part of our work concerning structure-activity relationships for novobiocin and hsp90, new noviose-free novobiocin analogs have been prepared. Cyclonovobiocinic acid, obtained after acidic hydrolysis of novobiocin [3], was studied by X-ray crystallography. The title compound is an amide having a 3-amino-4,7-dihydroxy-8-methylcoumarin (A) and 3,4-dihydro-2,2-dimethyl-2f/-lbenzopyran-6-carboxylic acid (B).…”

mentioning

confidence: 99%

Crystal structure of cyclonovobiocin , C44H42N2O12

Bras¹,

Bekaert²,

Viossat³

et al. 2006

Zeitschrift Für Kristallographie - New Crystal Structures

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Source of materialNovobiocin (0.613 g, 0.001 mol) and dibromozinc (1.126 g, 0.005 mol) were carefully dissolved in 20 mL of hot ethanoic acid and maintained 24 hours at 50 °C. Cyclonovobiocin crystallized as translucent needles. A suitable crystal was taken for diffraction studies. DiscussionNovobiocin is a coumarin antibiotic first discovered in Streptomyces spheroides [1]. The biological activity is due to the inhibition of bacterial DNA gy rase [ 1 ]. Recent works demonstrated that novobiocin can bind to the C-terminal nucleotide-binding region of hsp90 leading to decrease in hsp90 client proteins in various cancer cell lines [2]. However, novobiocin exhibits a weak inhibitory activity against hsp90. As a part of our work concerning structure-activity relationships for novobiocin and hsp90, new noviose-free novobiocin analogs have been prepared. Cyclonovobiocinic acid, obtained after acidic hydrolysis of novobiocin [3], was studied by X-ray crystallography. The title compound is an amide having a 3-amino-4,7-dihydroxy-8-methylcoumarin (A) and 3,4-dihydro-2,2-dimethyl-2f/-lbenzopyran-6-carboxylic acid (B). The coumarin entity (A) has a planar conformation with a largest deviation of 0.045(2) A for C12 from the best plane PI (C2-C7/09/C10/C12/C13), defined by two six-member rings P2 (C2/C7) and P3 (C5/C6/09/C10/ C12/C13) which make a dihedral angle of 3.1(1)°. Electron localization was found at the short C12-C13 bond with a length of 1.367(3) Ä. The wide angle of C12-C13-014 and the narrow angle of 014-C1J-C5 give the hydroxy group a tilt to the C4 direction. In Β entity, the atoms C25 and C26 are displaced out of the

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The Structure of Novobiocin^1,2

Cited by 92 publications

References 0 publications

Characterization of the Aminocoumarin Ligase SimL from the Simocyclinone Pathway and Tandem Incubation with NovM,P,N from the Novobiocin Pathway

Characterization of the Aminocoumarin Ligase SimL from the Simocyclinone Pathway and Tandem Incubation with NovM,P,N from the Novobiocin Pathway

Tracking Down Biotransformation to the Genetic Level: Identification of a Highly Flexible Glycosyltransferase from Saccharothrix espanaensis

Crystal structure of cyclonovobiocin , C44H42N2O12

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The Structure of Novobiocin1,2

Cited by 92 publications

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Characterization of the Aminocoumarin Ligase SimL from the Simocyclinone Pathway and Tandem Incubation with NovM,P,N from the Novobiocin Pathway

Characterization of the Aminocoumarin Ligase SimL from the Simocyclinone Pathway and Tandem Incubation with NovM,P,N from the Novobiocin Pathway

Tracking Down Biotransformation to the Genetic Level: Identification of a Highly Flexible Glycosyltransferase from Saccharothrix espanaensis

Crystal structure of cyclonovobiocin , C44H42N2O12

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The Structure of Novobiocin^1,2