Identification of the Biosynthetic Gene Cluster of New Piperazic Acid-Containing Lipopeptides with Cytotoxic Activity in the Genome of Marine Streptomyces PHM034
Ana Ceniceros,
Librada Cañedo,
Carmen Méndez,
Carlos Olano,
Carmen Schleissner,
Carmen Cuevas,
Fernando de la Calle,
José A. Salas
Affiliations
Ana Ceniceros
Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain
Librada Cañedo
Drug Discovery Area, PharmaMar S.A. Avda. de los Reyes 1, Colmenar Viejo, 28770 Madrid, Spain
Carmen Méndez
Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain
Carlos Olano
Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain
Carmen Schleissner
Unolab Manufacturing, Avenida de las Flores 6, Humanes de Madrid, 28970 Madrid, Spain
Carmen Cuevas
Drug Discovery Area, PharmaMar S.A. Avda. de los Reyes 1, Colmenar Viejo, 28770 Madrid, Spain
Fernando de la Calle
Drug Discovery Area, PharmaMar S.A. Avda. de los Reyes 1, Colmenar Viejo, 28770 Madrid, Spain
José A. Salas
Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain
Three novel lipopeptides, PM130391 (1), PM130392 (2), and PM140293 (3) were obtained from cultures of Streptomyces tuirus PHM034 isolated from a marine sediment. Structural elucidation of the three compounds showed they belong to the nonribosomal peptides family, and they all contain an acylated alanine, three piperazic acids, a methylated glycine, and an N-hydroxylated alanine. The difference between the three compounds resides in the acyl chain bound to the alanine residue. All three compounds showed cytotoxic activity against human cancer cell lines. Genome sequence and bioinformatics analysis allowed the identification of the gene cluster responsible for the biosynthesis. Inactivation of a nonribosomal peptide synthase of this cluster abolished the biosynthesis of the three compounds, thus demonstrating the involvement of this cluster in the biosynthesis of these lipopeptides.
