title: The chromomycin CmmA acetyltransferase: a membrane-bound enzyme as a tool for increasing structural diversity of the antitumour mithramycin.
abstract: Mithramycin and chromomycin A(3) are two structurally related antitumour compounds, which differ in the glycosylation profiles and functional group substitutions of the sugars. Chromomycin contains two acetyl groups, which are incorporated during the biosynthesis by the acetyltransferase CmmA in Streptomyces griseus ssp. griseus. A bioconversion strategy using an engineered S. griseus strain generated seven novel acetylated mithramycins. The newly formed compounds were purified and characterized by MS and NMR. These new compounds differ from their parental compounds in the presence of one, two or three acetyl groups, attached at 3E, 4E and/or 4D positions. All new mithramycin analogues showed antitumour activity at micromolar of lower concentrations. Some of the compounds showed improved activities against glioblastoma or pancreas tumour cells. The CmmA acetyltransferase was located in the cell membrane and was shown to accept several acyl-CoA substrates. All these results highlight the potential of CmmA as a tool to create structural diversity in these antitumour compounds.
authors.affiliation: Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, Oviedo, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: García
authors.forename: Javier
authors.initials: J
authors.lastname: González-Sabín
authors.forename: Nuria
authors.initials: N
authors.lastname: Menéndez
authors.forename: Alfredo F
authors.initials: AF
authors.lastname: Braña
authors.forename: Luz Elena
authors.initials: LE
authors.lastname: Núñez
authors.forename: Francisco
authors.initials: F
authors.lastname: Morís
authors.forename: José A
authors.initials: JA
authors.lastname: Salas
authors.forename: Carmen
authors.initials: C
authors.lastname: Méndez
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001711:Biotransformation; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D002865:Chromomycins / Q000378:metabolism; D006801:Humans; D008926:Plicamycin / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D013305:Streptomyces griseus / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D002865:Chromomycins; D000123:Acetyltransferases; D008926:Plicamycin