Characterization of two glycosyltransferases involved in early glycosylation steps during biosynthesis of the antitumor polyketide mithramycin by Streptomyces argillaceus

G. Blanco; E. Fernández; M. J. Fernández; A. F. Braña; U. Weissbach; E. Künzel; J. Rohr; C. Méndez; J. A. Salas

doi:10.1007/PL00008667

Characterization of two glycosyltransferases involved in early glycosylation steps during biosynthesis of the antitumor polyketide mithramycin by Streptomyces argillaceus

G. Blanco, E. Fernández, M. J. Fernández, A. F. Braña, U. Weissbach, E. Künzel, J. Rohr, C. Méndez, J. A. Salas

Pharmaceutical Sciences

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55 Scopus citations

Abstract

A 2580-bp region of the chromosome of Streptomyces argillaceus, the producer of the antitumor polyketide mithramycin, was sequenced. Analysis of the nucleotide sequence revealed the presence of two genes (mtmGIII and mtmGIV) encoding proteins that showed a high degree of similarity to glycosyltransferases involved in the biosynthesis of various antibiotics and antitumor drugs. Independent insertional inactivation of both genes produced mutants that did not synthesize mithramycin but accumulated several mithramycin intermediates. Both mutants accumulated premithramycinone, a non-glycosylated intermediate in mithramycin biosynthesis. The mutant affected in the mtmGIII gene also accumulated premithramycin A1, which contains premithramycinone as the aglycon unit: and a D-olivose attached at C-12a-O. These experiments demonstrate that the glycosyltransferases MtmGIV and MtmGIII catalyze the first two glycosylation steps in mithramycin biosynthesis. A model is proposed for the glycosylation steps in mithramycin biosynthesis.

Original language	English
Pages (from-to)	991-1000
Number of pages	10
Journal	Molecular and General Genetics
Volume	262
Issue number	6
DOIs	https://doi.org/10.1007/PL00008667
State	Published - 2000

Bibliographical note

Funding Information:
Acknowledgments This work was supported by grants of the European Community to J.R. and J.A.S. (BIO4-CT96–0068) and from the Spanish Ministery of Education and Science to J.A.S. through the ``Plan Nacional en Biotecnologia'' (BIO97–0771), and the Medical University of South Carolina to J.R.

Keywords

Antitumor
Aureolic acid
Polyketides
Streptomycetes

ASJC Scopus subject areas

Genetics

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10.1007/PL00008667

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Blanco, G., Fernández, E., Fernández, M. J., Braña, A. F., Weissbach, U., Künzel, E., Rohr, J., Méndez, C., & Salas, J. A. (2000). Characterization of two glycosyltransferases involved in early glycosylation steps during biosynthesis of the antitumor polyketide mithramycin by Streptomyces argillaceus. Molecular and General Genetics, 262(6), 991-1000. https://doi.org/10.1007/PL00008667

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title = "Characterization of two glycosyltransferases involved in early glycosylation steps during biosynthesis of the antitumor polyketide mithramycin by Streptomyces argillaceus",

abstract = "A 2580-bp region of the chromosome of Streptomyces argillaceus, the producer of the antitumor polyketide mithramycin, was sequenced. Analysis of the nucleotide sequence revealed the presence of two genes (mtmGIII and mtmGIV) encoding proteins that showed a high degree of similarity to glycosyltransferases involved in the biosynthesis of various antibiotics and antitumor drugs. Independent insertional inactivation of both genes produced mutants that did not synthesize mithramycin but accumulated several mithramycin intermediates. Both mutants accumulated premithramycinone, a non-glycosylated intermediate in mithramycin biosynthesis. The mutant affected in the mtmGIII gene also accumulated premithramycin A1, which contains premithramycinone as the aglycon unit: and a D-olivose attached at C-12a-O. These experiments demonstrate that the glycosyltransferases MtmGIV and MtmGIII catalyze the first two glycosylation steps in mithramycin biosynthesis. A model is proposed for the glycosylation steps in mithramycin biosynthesis.",

keywords = "Antitumor, Aureolic acid, Polyketides, Streptomycetes",

author = "G. Blanco and E. Fern{\'a}ndez and Fern{\'a}ndez, {M. J.} and Bra{\~n}a, {A. F.} and U. Weissbach and E. K{\"u}nzel and J. Rohr and C. M{\'e}ndez and Salas, {J. A.}",

note = "Funding Information: Acknowledgments This work was supported by grants of the European Community to J.R. and J.A.S. (BIO4-CT96–0068) and from the Spanish Ministery of Education and Science to J.A.S. through the ``Plan Nacional en Biotecnologia'' (BIO97–0771), and the Medical University of South Carolina to J.R.",

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doi = "10.1007/PL00008667",

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Blanco, G, Fernández, E, Fernández, MJ, Braña, AF, Weissbach, U, Künzel, E, Rohr, J, Méndez, C & Salas, JA 2000, 'Characterization of two glycosyltransferases involved in early glycosylation steps during biosynthesis of the antitumor polyketide mithramycin by Streptomyces argillaceus', Molecular and General Genetics, vol. 262, no. 6, pp. 991-1000. https://doi.org/10.1007/PL00008667

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AU - Blanco, G.

AU - Fernández, E.

AU - Fernández, M. J.

AU - Braña, A. F.

AU - Weissbach, U.

AU - Künzel, E.

AU - Rohr, J.

AU - Méndez, C.

AU - Salas, J. A.

N1 - Funding Information: Acknowledgments This work was supported by grants of the European Community to J.R. and J.A.S. (BIO4-CT96–0068) and from the Spanish Ministery of Education and Science to J.A.S. through the ``Plan Nacional en Biotecnologia'' (BIO97–0771), and the Medical University of South Carolina to J.R.

PY - 2000

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N2 - A 2580-bp region of the chromosome of Streptomyces argillaceus, the producer of the antitumor polyketide mithramycin, was sequenced. Analysis of the nucleotide sequence revealed the presence of two genes (mtmGIII and mtmGIV) encoding proteins that showed a high degree of similarity to glycosyltransferases involved in the biosynthesis of various antibiotics and antitumor drugs. Independent insertional inactivation of both genes produced mutants that did not synthesize mithramycin but accumulated several mithramycin intermediates. Both mutants accumulated premithramycinone, a non-glycosylated intermediate in mithramycin biosynthesis. The mutant affected in the mtmGIII gene also accumulated premithramycin A1, which contains premithramycinone as the aglycon unit: and a D-olivose attached at C-12a-O. These experiments demonstrate that the glycosyltransferases MtmGIV and MtmGIII catalyze the first two glycosylation steps in mithramycin biosynthesis. A model is proposed for the glycosylation steps in mithramycin biosynthesis.

AB - A 2580-bp region of the chromosome of Streptomyces argillaceus, the producer of the antitumor polyketide mithramycin, was sequenced. Analysis of the nucleotide sequence revealed the presence of two genes (mtmGIII and mtmGIV) encoding proteins that showed a high degree of similarity to glycosyltransferases involved in the biosynthesis of various antibiotics and antitumor drugs. Independent insertional inactivation of both genes produced mutants that did not synthesize mithramycin but accumulated several mithramycin intermediates. Both mutants accumulated premithramycinone, a non-glycosylated intermediate in mithramycin biosynthesis. The mutant affected in the mtmGIII gene also accumulated premithramycin A1, which contains premithramycinone as the aglycon unit: and a D-olivose attached at C-12a-O. These experiments demonstrate that the glycosyltransferases MtmGIV and MtmGIII catalyze the first two glycosylation steps in mithramycin biosynthesis. A model is proposed for the glycosylation steps in mithramycin biosynthesis.

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KW - Aureolic acid

KW - Polyketides

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Characterization of two glycosyltransferases involved in early glycosylation steps during biosynthesis of the antitumor polyketide mithramycin by Streptomyces argillaceus

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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