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Biotechnology

Cooperative Involvement of Glycosyltransferases in the Transfer of Amino Sugars during the Biosynthesis of the Macrolactam Sipanmycin by Streptomyces sp. Strain CS149

Mónica G. Malmierca, Ignacio Pérez-Victoria, Jesús Martín, Fernando Reyes, Carmen Méndez, Carlos Olano, José A. Salas
Harold L. Drake, Editor
Mónica G. Malmierca
Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Asturias, SpainInstituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Asturias, SpainInstituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
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Ignacio Pérez-Victoria
Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Granada, Spain
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Jesús Martín
Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Granada, Spain
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Fernando Reyes
Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Granada, Spain
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Carmen Méndez
Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Asturias, SpainInstituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Asturias, SpainInstituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
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Carlos Olano
Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Asturias, SpainInstituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Asturias, SpainInstituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
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José A. Salas
Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Asturias, SpainInstituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Asturias, SpainInstituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
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Harold L. Drake
University of Bayreuth
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DOI: 10.1128/AEM.01462-18
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ABSTRACT

Macrolactams comprise a family of natural compounds with important bioactivities, such as antibiotic, antifungal, and antiproliferative activities. Sipanmycins A and B are two novel members of this family, with two sugar moieties attached to the aglycon. In the related macrolactam vicenistatin, the sugar moiety has been proven to be essential for cytotoxicity. In this work, the gene cluster responsible for the biosynthesis of sipanmycins (sip cluster) in Streptomyces sp. strain CS149 is described and the steps involved in the glycosylation of the final compounds unraveled. Also, the cooperation of two different glycosyltransferases in each glycosylation step is demonstrated. Additionally, the essential role of SipO2 as an auxiliary protein in the incorporation of the second deoxy sugar is addressed. In light of the results obtained by the generation of mutant strains and in silico characterization of the sip cluster, a biosynthetic pathway for sipanmycins and the two deoxy sugars attached is proposed. Finally, the importance of the hydroxyl group at C-10 of the macrolactam ring and the sugar moieties for cytotoxicity and antibiotic activity of sipanmycins is shown.

IMPORTANCE The rapid emergence of infectious diseases and multiresistant pathogens has increased the necessity for new bioactive compounds; thus, novel strategies have to be developed to find them. Actinomycetes isolated in symbiosis with insects have attracted attention in recent years as producers of metabolites with important bioactivities. Sipanmycins are glycosylated macrolactams produced by Streptomyces sp. CS149, isolated from leaf-cutting ants, and show potent cytotoxic activity. Here, we characterize the sip cluster and propose a biosynthetic pathway for sipanmycins. As far as we know, it is the first time that the cooperation between two different glycosyltransferases is demonstrated to be strictly necessary for the incorporation of the same sugar. Also, a third protein with homology to P450 monooxygenases, SipO2, is shown to be essential in the second glycosylation step, forming a complex with the glycosyltransferase pair SipS9-SipS14.

FOOTNOTES

    • Received 14 June 2018.
    • Accepted 11 July 2018.
    • Accepted manuscript posted online 13 July 2018.
  • Address correspondence to José A. Salas, jasalas{at}uniovi.es.
  • Citation Malmierca MG, Pérez-Victoria I, Martín J, Reyes F, Méndez C, Olano C, Salas JA. 2018. Cooperative involvement of glycosyltransferases in the transfer of amino sugars during the biosynthesis of the macrolactam sipanmycin by Streptomyces sp. strain CS149. Appl Environ Microbiol 84:e01462-18. https://doi.org/10.1128/AEM.01462-18.

  • Copyright © 2018 American Society for Microbiology.

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Cooperative Involvement of Glycosyltransferases in the Transfer of Amino Sugars during the Biosynthesis of the Macrolactam Sipanmycin by Streptomyces sp. Strain CS149
Mónica G. Malmierca, Ignacio Pérez-Victoria, Jesús Martín, Fernando Reyes, Carmen Méndez, Carlos Olano, José A. Salas
Appl. Environ. Microbiol. Aug 2018, 84 (18) e01462-18; DOI: 10.1128/AEM.01462-18

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Cooperative Involvement of Glycosyltransferases in the Transfer of Amino Sugars during the Biosynthesis of the Macrolactam Sipanmycin by Streptomyces sp. Strain CS149
Mónica G. Malmierca, Ignacio Pérez-Victoria, Jesús Martín, Fernando Reyes, Carmen Méndez, Carlos Olano, José A. Salas
Appl. Environ. Microbiol. Aug 2018, 84 (18) e01462-18; DOI: 10.1128/AEM.01462-18
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KEYWORDS

Streptomyces
actinomycetes
antibiotics
biosynthesis gene cluster
glycosylation
glycosyltransferases
sugars

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