SB-203207 and SB-203208, Two Novel Isoleucyl tRNA Synthetase Inhibitors from a Streptomyces sp. I. Fermentation, Isolation and Properties.

Stefanska, Anna L.; Cassels, Robert; Ready, Sarah J.; Warr, S. R. C.

doi:10.7164/antibiotics.53.357

Cited by 45 publications

(28 citation statements)

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“…These genes may have physiological roles in dealing with harsh environments or be directly involved in biosynthetic pathways given the huge metabolic potential of this group of bacteria. For example, several structurally complex natural products from actinomycetes are potent aaRS inhibitors, and functional genomic analyses of the corresponding strains can offer a means to explore the relationship between duplicated aaRSs and identify antibiotic biosynthetic gene clusters (12,29,30). The identification of two serS genes in the antibiotic albomycin producer Streptomyces sp.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Two Seryl-tRNA Synthetases in Albomycin-Producing Streptomyces sp. Strain ATCC 700974

Zeng

Roy

Patil

et al. 2009

Antimicrob Agents Chemother

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The Trojan horse antibiotic albomycin, produced by Streptomyces sp. strain ATCC 700974, contains a thioribosyl nucleoside moiety linked to a hydroxamate siderophore through a serine residue. The seryl nucleoside structure (SB-217452) is a potent inhibitor of seryl-tRNA synthetase (SerRS) in the pathogenic bacterium Staphylococcus aureus, with a 50% inhibitory concentration (IC 50 ) of ϳ8 nM. In the albomycinproducing Streptomyces sp., a bacterial SerRS homolog (Alb10) was found to be encoded in a biosynthetic gene cluster in addition to another serRS gene (serS1) at a different genetic locus. Alb10, named SerRS2 herein, is significantly divergent from SerRS1, which shows high homology to the housekeeping SerRS found in other Streptomyces species. We genetically and biochemically characterized the two genes and the proteins encoded. Both genes were able to complement a temperature-sensitive serS mutant of Escherichia coli and allowed growth at a nonpermissive temperature. serS2 was shown to confer albomycin resistance, with specific amino acid residues in the motif 2 signature sequences of SerRS2 playing key roles. SerRS1 and SerRS2 are comparably efficient in vitro, but the K m of serine for SerRS2 measured during tRNA aminoacylation is more than 20-fold higher than that for SerRS1. SB-217452 was also enzymatically generated and purified by two-step chromatography. Its IC 50 against SerRS1 was estimated to be 10-fold lower than that against SerRS2. In contrast, both SerRSs displayed comparable inhibition kinetics for serine hydroxamate, indicating that SerRS2 was specifically resistant to SB-217452. These data suggest that mining Streptomyces genomes for duplicated aminoacyltRNA synthetase genes could provide a novel approach for the identification of natural products targeting aminoacyl-tRNA synthetases.

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Section: Discussionmentioning

confidence: 99%

Characterization of Two Seryl-tRNA Synthetases in Albomycin-Producing Streptomyces sp. Strain ATCC 700974

Zeng

Roy

Patil

et al. 2009

Antimicrob Agents Chemother

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“…In the presence of Pb(OAc)4, amide 15 evolved into the final isocyanate 16 through the Baumgarten variant of the Hoffmann rearrangement. SB-203207 (25), an alkaloid isolated from a Streptomices species by researchers in the SmithKline Beecham group, was found to show marked isoleucyl tRNA synthetase inhibition activity [39,40]. Very recently, Kan and co-workers described a total synthesis of this compound starting from lactam 22, in which the primary amide unit was generated by catalytic hydration of nitrile intermediate 23 with complex 1 (Scheme 8) [41].…”

Section: Preparation Of Complex [Pth{(pme 2 O) 2 H}(pme 2 Oh)] Firstmentioning

confidence: 99%

Synthetic Applications of the Parkins Nitrile Hydration Catalyst [PtH{(PMe2O)2H}(PMe2OH)]: A Review

Cadierno

2015

Applied Sciences

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Abstract:The air-stable hydride-platinum(II) complex [PtH{(PMe2O)2H}(PMe2OH)], reported by Parkins and co-workers in 1995, is the most versatile catalyst currently available for the hydration of C≡N bonds. It features remarkable activity under relatively mild conditions and exceptionally high functional group compatibility, facts that have allowed the implementation of this complex in the synthesis of a large number of structurally complex, biologically active molecules and natural products. In this contribution, synthetic applications of the Parkins catalyst are reviewed.

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“…Aminoacyl-tRNA synthetases have gained attention recently as potential targets for antibiotics (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Identifying differences in the catalytic mechanisms of bacterial and human aminoacyl-tRNA synthetases will facilitate the development of antibiotics that selectively target the bacterial aminoacyltRNA synthetases.…”

mentioning

confidence: 99%

Potassium Functionally Replaces the Second Lysine of the KMSKS Signature Sequence in Human Tyrosyl-tRNA Synthetase

Austin¹,

First

2002

Journal of Biological Chemistry

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Unlike their bacterial homologues, a number of eukaryotic tyrosyl-tRNA synthetases require potassium to catalyze the aminoacylation reaction. In addition, the second lysine in the class I-specific KMSKS signature motif is absent from all known eukaryotic tyrosyl-tRNA synthetase sequences, except those of higher plants. This lysine, which is the most highly conserved residue in the class I aminoacyl-tRNA synthetase family, has been shown to interact with the pyrophosphate moiety of the ATP substrate in the Bacillus stearothermophilus tyrosyl-tRNA synthetase. Equilibrium dialysis and presteady-state kinetic analyses were used to determine the role that potassium plays in the tyrosine activation reaction in the human tyrosyl-tRNA synthetase and whether it can be replaced by any of the other alkali metals. Kinetic analyses indicate that potassium interacts with the pyrophosphate moiety of ATP, stabilizing the E⅐Tyr⅐ATP and E⅐[Tyr-ATP] ‡ complexes by 2.3 and 4.3 kcal/mol, respectively. Potassium also appears to stabilize the asymmetric conformation of the human tyrosyltRNA synthetase dimer by 0.7 kcal/mol. Rubidium is the only other alkali metal that can replace potassium in catalyzing tyrosine activation, although the forward rate constant is half of that observed when potassium is present. The above results are consistent with the hypothesis that potassium functionally replaces the second lysine in the KMSKS signature sequence. Possible implications of these results with respect to the design of antibiotics that target bacterial aminoacyl-tRNA synthetases are discussed.Aminoacyl-tRNA synthetases have gained attention recently as potential targets for antibiotics (1-10). Identifying differences in the catalytic mechanisms of bacterial and human aminoacyl-tRNA synthetases will facilitate the development of antibiotics that selectively target the bacterial aminoacyltRNA synthetases. We are currently investigating the catalytic mechanisms of the human and Bacillus stearothermophilus tyrosyl-tRNA synthetases to elucidate the differences between these two enzymes.Tyrosyl-tRNA synthetase catalyzes the attachment of tyrosine to tyrosine tRNA (tRNA Tyr ) 1 by an ATP-dependent twostep reaction mechanism. In the first step, tyrosine is activated by MgATP to form an enzyme-bound tyrosyl-adenylate intermediate. The second step consists of the transfer of tyrosine to the 3Ј end of tRNA Tyr .TyrRS ϩ Tyr ϩ MgATP^TyrRS ⅐ Tyr-AMP ϩ PP i (Eq. 1)Tyrosyl-tRNA synthetase is a homodimer that displays "halfof-the-sites" reactivity, with only one tyrosyl-adenylate molecule formed per dimer (11-13). Although most of the active site amino acids are conserved between the human and B. stearothermophilus tyrosyl-tRNA synthetases, several differences exist between the two enzymes, including the inability of the human and bacterial tyrosyl-tRNA synthetases to aminoacylate each other's tRNA Tyr (14,15). In addition, sequence analyses indicate that the human tyrosyl-tRNA synthetase is Ͻ16% identical to the B. stearothermophilus enzyme and that four...

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SB-203207 and SB-203208, Two Novel Isoleucyl tRNA Synthetase Inhibitors from a Streptomyces sp. I. Fermentation, Isolation and Properties.

Abstract: Two novel inhibitors of isoleucyl tRNA synthetase designated SB-203207 and SB-203208 have been detected in the culture of a new Streptomyces species. The fermentation, isolation and someproperties of the inhibitors are described.

Cited by 45 publications

References 9 publications

Characterization of Two Seryl-tRNA Synthetases in Albomycin-Producing Streptomyces sp. Strain ATCC 700974

Characterization of Two Seryl-tRNA Synthetases in Albomycin-Producing Streptomyces sp. Strain ATCC 700974

Synthetic Applications of the Parkins Nitrile Hydration Catalyst [PtH{(PMe2O)2H}(PMe2OH)]: A Review

Potassium Functionally Replaces the Second Lysine of the KMSKS Signature Sequence in Human Tyrosyl-tRNA Synthetase

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