Mithramycin analogues generated by combinatorial biosynthesis show improved bioactivity

Journal of Natural Products
Irfan BaigJürgen Rohr

Abstract

Plasmid pLNBIV was used to overexpress the biosynthetic pathway of nucleoside-diphosphate (NDP)-activated l-digitoxose in the mithramycin producer Streptomyces argillaceus. This led to a "flooding" of the biosynthetic pathway of the antitumor drug mithramycin (MTM) with NDP-activated deoxysugars, which do not normally occur in the pathway, and consequently to the production of the four new mithramycin derivatives 1- 4 with altered saccharide patterns. Their structures reflect that NDP sugars produced by pLNBIV, namely, l-digitoxose and its biosynthetic intermediates, influenced the glycosyl transfer to positions B, D, and E, while positions A and C remained unaffected. All four new structures have unique, previously not found sugar decoration patterns, which arise from either overcoming the substrate specificity or inhibition of certain glycosyltransferases (GTs) of the MTM pathway with the foreign NDP sugars expressed by pLNBIV. An apoptosis TUNEL (=terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) assay revealed that compounds 1 (demycarosyl-3D-beta- d-digitoxosyl-MTM) and 3 (deoliosyl-3C-beta- d-mycarosyl-MTM) show improved activity (64.8 +/- 2% and 50.3 +/- 2.5% induction of apoptosis, respectively) aga...Continue Reading

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Citations

Oct 1, 2011·Applied Microbiology and Biotechnology·Ah Reum HanYeo Joon Yoon
Sep 24, 2008·Organic Letters·Rajan Pragani, William R Roush
May 13, 2011·The Journal of Biological Chemistry·Nicholas NoinajJürgen Rohr
Nov 16, 2010·Applied and Environmental Microbiology·Micah D ShepherdJürgen Rohr
Jan 31, 2012·International Journal of Nanomedicine·Lorenzo CaprettoClaudio Nastruzzi
Feb 5, 2011·Metabolic Engineering·Jine LiHuarong Tan
Feb 24, 2011·Microbial Biotechnology·Carlos OlanoJosé A Salas
Sep 4, 2015·Chemical Society Reviews·Dong-Mei LiangJian-Jun Qiao
Mar 31, 2019·Biomedical Chromatography : BMC·Joseph M EckenrodeMarkos Leggas
Sep 9, 2011·Natural Product Reports·Richard W GanttJon S Thorson
Dec 2, 2010·Natural Product Reports·Barbara La FerlaFrancesco Nicotra
Jul 21, 2020·Applied Microbiology and Biotechnology·Jan KormanecDagmar Homerova
Nov 5, 2019·Frontiers in Immunology·Seila Lorenzo-HerreroAlejandro López-Soto
Aug 3, 2013·Organic Letters·John Paul IssaClay S Bennett

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