6 Chemical and Biological Aspects of Sparsomycin, an Antibiotic, from Streptomyces

Hc, Ottenheijm; La, van den Broek; Jp, Ballesta; Żylicz, Zbigniew

doi:10.1016/s0079-6468(08)70344-8

Cited by 27 publications

(29 citation statements)

References 76 publications

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“…Sparsomycin has been derivatized extensively to improve its clinical properties (1). Whereas all attempts to alter the modified uracil base, except for removal of the methyl group (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This provides a basis for its antitumor activity, although its selectivity for some human tumors must depend on the preferential membrane permeability of the active sparsomycin derivatives (1). The identification of a ribosomal binding site for sparsomycin on 23S-like rRNA provides an important insight into a conserved feature of the catalytic center of peptide bond formation.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the antibiotic and some of its derivatives selectively act on several different human tumors (1). Although some side effects can occur, including eye toxicity, active testing programs with sparsomycin and its derivatives continue, and it has been used successfully as a potentiate of cis-platinum treatment of tumors (1). Sparsomycin is one of several antibiotics that interfere with peptide bond formation, a process that is central to protein biosynthesis and takes place on the large ribosomal subunit (reviewed in refs.…”

Section: Sparsomycin (mentioning

confidence: 99%

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Direct crosslinking of the antitumor antibiotic sparsomycin, and its derivatives, to A2602 in the peptidyl transferase center of 23S-like rRNA within ribosome-tRNA complexes

Porse

Kirillov²,

Awayez³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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The antitumor antibiotic sparsomycin is a universal and potent inhibitor of peptide bond formation and selectively acts on several human tumors. It binds to the ribosome strongly, at an unknown site, in the presence of an N-blocked donor tRNA substrate, which it stabilizes on the ribosome. Its site of action was investigated by inducing a crosslink between sparsomycin and bacterial, archaeal, and eukaryotic ribosomes complexed with P-site-bound tRNA, on irradiating with low energy ultraviolet light (at 365 nm). The crosslink was localized exclusively to the universally conserved nucleotide A2602 within the peptidyl transferase loop region of 23S-like rRNA by using a combination of a primer extension approach, RNase H fragment analysis, and crosslinking with radioactive [ 125 I]phenol-alanine-sparsomycin. Crosslinking of several sparsomycin derivatives, modified near the sulfoxy group, implicated the modified uracil residue in the rRNA crosslink. The yield of the antibiotic crosslink was weak in the presence of deacylated tRNA and strong in the presence of an N-blocked P-site-bound tRNA, which, as was shown earlier, increases the accessibility of A2602 on the ribosome. We infer that both A2602 and its induced conformational switch are critically important both for the peptidyl transfer reaction and for antibiotic inhibition. This supposition is reinforced by the observation that other antibiotics that can prevent peptide bond formation in vitro inhibit, to different degrees, formation of the crosslink. Sparsomycin (Fig.

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“…Sparsomycin has been derivatized extensively to improve its clinical properties (1). Whereas all attempts to alter the modified uracil base, except for removal of the methyl group (Fig.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Sparsomycin (mentioning

confidence: 99%

See 1 more Smart Citation

Direct crosslinking of the antitumor antibiotic sparsomycin, and its derivatives, to A2602 in the peptidyl transferase center of 23S-like rRNA within ribosome-tRNA complexes

Porse

Kirillov²,

Awayez³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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“…Cell extracts were separated in the SDS-polyacrylamide gel and immunoblotted by using the rabbit polyclonal antibodies raised against p24. (Ottenheijm et al, 1986;Porse et al, 1999). Sparsomycin has the ability to enhance the -1 frameshift in mammalian cells as well as S. cervisiae (Dinman et al, 1997).…”

Section: The Structure Of Sparsomycin a Metabolite From Streptomycesmentioning

confidence: 99%

Rapid Propagation of Low-Fitness Drug-Resistant Mutants of Human Immunodeficiency Virus Type 1 by a Streptococcal Metabolite Sparsomycin

Miyauchi

Komano

Myint

et al. 2006

Antivir Chem Chemother

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Here we report that sparsomycin, a streptococcal metabolite, enhances the replication of HIV-1 in multiple human T cell lines at a concentration of 400 nM. In addition to wild-type HIV-1, sparsomycin also accelerated the replication of lowfitness, drug-resistant mutants carrying either D30N or L90M within HIV-1 protease, which are frequently found mutations in HIV-1-infected patients on highly active antiretroviral therapy (HAART). Of particular interest was that replication enhancement appeared profound when HIV-1 such as the L90M-carrying mutant displayed relatively slower replication kinetics. The presence of sparsomycin did not immediately select the fast-replicating HIV-1 mutants in culture. In addition, sparsomycin did not alter the 50% inhibitory concentration (IC 50 ) of antiretroviral drugs directed against HIV-1 including nucleoside reverse transcriptase inhibitors (lamivudine and stavudine), non-nucleoside reverse transcriptase inhibitor (nevirapine) and protease inhibitors (nelfinavir, amprenavir and indinavir). The IC 50 s of both zidovudine and lopinavir against multidrug resistant HIV-1 in the presence of sparsomycin were similar to those in the absence of sparsomycin. The frameshift reporter assay and Western blot analysis revealed that the replication-boosting effect was partly due to the sparsomycin's ability to increase the -1 frameshift efficiency required to produce the Gag-Pol transcript. In conclusion, the use of sparsomycin should be able to facilitate the drug resistance profiling of the clinical isolates and the study on the lowfitness viruses.

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“…[7][8][9][10] These potentially important biological activities have made 3 an attractive target for a potential antineoplastic compound. 11) Since thê rst synthetic study of sparsomycin in 1976, 12) synthetic studies of sparsomycin, [13][14][15] total synthesis, [16][17][18] biosynthesis, 19,20) and structure-activity relationship studies [21][22][23][24][25][26][27] have been widely reported. There have been many reports on the antitumor, antibacterial, antifungal, and antiviral properties; however, normalization of the phenotype of oncogene-transformed cells by 3 and its analogues has not previously been reported.…”

mentioning

confidence: 99%

Synthesis and Activity of Pyrimidinylpropenamide Antibiotics: The Alkyl Analogues of Sparsomycin

Nakajima

Enomoto

Watanabe

et al. 2003

Bioscience, Biotechnology, and Biochemistry

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6 Chemical and Biological Aspects of Sparsomycin, an Antibiotic, from Streptomyces

Cited by 27 publications

References 76 publications

Direct crosslinking of the antitumor antibiotic sparsomycin, and its derivatives, to A2602 in the peptidyl transferase center of 23S-like rRNA within ribosome-tRNA complexes

Direct crosslinking of the antitumor antibiotic sparsomycin, and its derivatives, to A2602 in the peptidyl transferase center of 23S-like rRNA within ribosome-tRNA complexes

Rapid Propagation of Low-Fitness Drug-Resistant Mutants of Human Immunodeficiency Virus Type 1 by a Streptococcal Metabolite Sparsomycin

Synthesis and Activity of Pyrimidinylpropenamide Antibiotics: The Alkyl Analogues of Sparsomycin

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