The mtmVUC genes of the mithramycin gene cluster in Streptomyces argillaceus are involved in the biosynthesis of the sug
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O R I GI N A L P A P E R
A. GonzaÂlez á L. L. Remsing á F. Lombo M. J. FernaÂndez á L. Prado á A. F. BranÄa á E. KuÈnzel J. Rohr á C. MeÂndez á J. A. Salas
The mtmVUC genes of the mithramycin gene cluster in Streptomyces argillaceus are involved in the biosynthesis of the sugar moieties Received: 5 May 2000 / Accepted: 7 September 2000 / Published online: 10 November 2000 Ó Springer-Verlag 2000
Abstract Mithramycin is a glycosylated aromatic polyketide produced by Streptomyces argillaceus, and is used as an antitumor drug. Three genes (mtmV, mtmU and mtmC) from the mithramycin gene cluster have been cloned, and characterized by DNA sequencing and by analysis of the products that accumulate in nonproducing mutants, which were generated by insertional inactivation of these genes. The mtmV gene codes for a 2,3-dehydratase that catalyzes early and common steps in the biosynthesis of the three sugars found in mithramycin (D-olivose, D-oliose and D-mycarose); its inactivation caused the accumulation of the nonglycosylated intermediate premithramycinone. The mtmU gene codes for a 4-ketoreductase involved in D-oliose biosynthesis, and its inactivation resulted in the accumulation of premithramycinone and premithramycin A1, the ®rst glycosylated intermediate which contains a D-olivose unit. The third gene, mtmC, is involved in D-mycarose biosynthesis and codes for a C-methyltransferase. Two mutants with lesions in the mtmC gene accumulated mithramycin intermediates lacking the D-mycarose moiety but containing D-olivose units attached to C-12a in which the 4-keto group is unreduced. This suggests that mtmC could code for a second enzyme activity, probably a D-olivose 4-ketoreductase, and that the glycosyltransferase responsible for the incorporation of D-olivose (MtmGIV) shows some degree of ¯exibility with respect to its sugar co-substrate, since the 4-ketoCommunicated by W. Goebel A. GonzaÂlez á F. Lombo á M. J. FernaÂndez á L. Prado A. F. BranÄa á C. MeÂndez á J A. Salas (&) Departamento de Biologõ a Funcional e Instituto Universitario de Oncologõ a del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, 33006 Oviedo, Spain Tel.: +34-985-103652 L. L. Remsing á E. KuÈnzel á J. Rohr Medical University of South Carolina, Department of Pharmaceutical Sciences, 171 Ashley Avenue, Charleston, SC 29425-2303, USA
analog is also transferred. A pathway is proposed for the biosynthesis of the three sugar moieties in mithramycin. Key words Antitumor drug á Polyketides á Deoxyhexoses á Glycosylation á Methylation
Introduction The aureolic acid family of drugs comprises a series of compounds that show antibiotic activity against grampositive bacteria. The aureolic acid drugs also show remarkable cytotoxicity against a variety of tumor cell culture lines, including brain tumors and experimental animal tumors. One of the components of the family, mithramycin (also referred to as aureolic acid, plicamycin, mithracin, LA7017, and A2371; Fig. 1), has found clinical use in the treatment of certain tumours, such as disseminated
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