Stereochemistry and absolute configuration of the antibiotic spectinomycin: an X-ray diffraction study

Cochran, Todd G.; Abraham, Donald J.; Martin, Lawrence L.

doi:10.1039/c39720000494

Cited by 33 publications

(7 citation statements)

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“…However, it was initially difficult to obtain definitive chemical shift assignments. An examination of the spectinomycin structure (24) indicated that the proton on C-7 had an equatorial geometry, whereas all the others were axial. The multiplet that contained only small coupling constants ( 3 J ϭ 2.8 Hz) was the doublet of doublets at 4.636 ppm, and this signal was therefore assigned to H-7.…”

Section: Overexpression and Purification Of Aph(9)-ia-thementioning

confidence: 99%

Spectinomycin Kinase from Legionella pneumophila

Thompson

Hughes

Cianciotto

et al. 1998

Journal of Biological Chemistry

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The bacterium Legionella pneumophila is the responsible agent for Legionnaires' disease and has recently been shown to harbor a gene encoding a kinase that confers resistance to the aminoglycoside antibiotic spectinomycin (Suter, T. M., Viswanathan, V. K., and Cianciotto, N. P. (1997) Antimicrob. Agents Chemother. 41, 1385-1388). We report the overproduction, purification, and characterization of this spectinomycin kinase from an expressing system in Escherichia coli. The purified protein shows stringent substrate specificity for spectinomycin with K m ‫؍‬ 21.5 M and k cat ‫؍‬ 24.2 s ؊1 and does not bind other aminoglycosides including kanamycin, amikacin, neomycin, butirosin, streptomycin, or apramycin. Purification of spectinomycin phosphate followed by characterization by mass spectrometry and 1 H, 13 C, and 31 P NMR established the site of phosphorylation to be at the hydroxyl group at position 9. Thus this enzyme is designated APH(9)-Ia (where APH is aminoglycoside kinase). The enzyme was inactivated by the electrophilic ATP analogue 5-[p-(fluorosulfonyl)benzoyl]adenosine, consistent with a nucleophilic residue such as Lys lining the nucleotide binding pocket. Sitedirected mutagenesis of Lys-52 and Asp-212 to Ala confirmed that these residues were important for catalysis, with Lys-52 playing a potential role in ATP binding and Asp-212 in phosphoryl transfer. Thio and solvent isotope effect experiments in the presence of either Mg 2؉ or Mn 2؉ were consistent with a kinetic mechanism in which phosphate transfer does not contribute significantly to the rate-limiting step. These results establish that APH(9)-Ia is a highly specific antibiotic resistance kinase and provides the requisite mechanistic information for future structural studies.

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Section: Overexpression and Purification Of Aph(9)-ia-thementioning

confidence: 99%

Spectinomycin Kinase from Legionella pneumophila

Thompson

Hughes

Cianciotto

et al. 1998

Journal of Biological Chemistry

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“…During our study, aglain derivative 7 a was isolated as a solid material, encouraging us to separate the major endo diastereomer by crystallization. [13] Interestingly, the aglain core was found to exist preferentially as a hydrated bridgehead ketone (also observed for other aglain derivatives) which may result from double hydrogen-bond stabilization of the hydrate with the benzopyran ether oxygen atom and tertiary hydroxyl (Figure 4). [14] Such stabilization highlights the high degree of electrophilicity of the bridgehead ketone and may be of importance for additional manipulations such as stereocontrolled reduction to access aglain natural products including ponapensin 3.…”

mentioning

confidence: 72%

“…The structure of 7 v was determined by single-crystal X-ray structure analysis and indicated the presence of a bridgehead ketone moiety. [13] The utility of stilbene as dipolarophile and our results from the overall dipolarophile screening suggest the involvement of the triplet biradicaloid [17] form of phototautomer 6 in the photocycloaddition. [18] Indeed, photocycloaddition of methyl cinnamate 5 a and 4 in the presence of the triplet quencher 9,10-dibromoanthracene did not lead to cycloadduct formation.…”

mentioning

confidence: 91%

Biomimetic Photocycloaddition of 3‐Hydroxyflavones: Synthesis and Evaluation of Rocaglate Derivatives as Inhibitors of Eukaryotic Translation

et al. 2010

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“…It is an important antibiotic for treatment and control of veterinary pathogens including certain Gram-negative bacteria (Mortensen et al 1996). Spectinomycin has a 1,3-diamino-cyclitol embedded within an unusual tricyclic ring system in which the two cyclitol-amino groups are N-methylated (Cochran et al 1972). It is still an important antibiotic for treating gonorrhea including infections by some resistant strains of gonococci (Lo et al 2012).…”

Section: Miscellaneous Natural Aminoglycosidesmentioning

confidence: 99%

Aminoglycoside Antibiotics

Kirst

Marinelli

2013

Antimicrobials

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Aminoglycosides were the second major antibiotic class to be discovered from fermentation of microorganisms. They are structurally characterized by an aminocyclitol that is substituted in several different patterns by amino-and/or neutral sugar moieties. They are potent, bactericidal, water-soluble compounds that are given by parenteral administration. They are especially useful for treatment of infections caused by Gram-negative bacteria, including Pseudomonas aeruginosa. Limitations of the class include the development of microbial resistance by a variety of mechanisms and patient toxicity, especially nephrotoxicity and ototoxicity. Several semi-synthetic derivatives have been developed that have improved features, especially increased activity against resistant strains of bacteria. The newest aminoglycoside, plazomicin, is a semi-synthetic derivative of sisomicin that is undergoing further evaluation in clinical trials.

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Stereochemistry and absolute configuration of the antibiotic spectinomycin: an X-ray diffraction study

Cited by 33 publications

References 0 publications

Spectinomycin Kinase from Legionella pneumophila

Spectinomycin Kinase from Legionella pneumophila

Biomimetic Photocycloaddition of 3‐Hydroxyflavones: Synthesis and Evaluation of Rocaglate Derivatives as Inhibitors of Eukaryotic Translation

Aminoglycoside Antibiotics

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