Discovery of a Cryptic Intermediate in Late Steps of Mithramycin Biosynthesis

Angew Chem Int Ed Engl. 2020 Jan 7;59(2):826-832. doi: 10.1002/anie.201910241. Epub 2019 Nov 27.


MtmOIV and MtmW catalyze the final two reactions in the mithramycin (MTM) biosynthetic pathway, the Baeyer-Villiger opening of the fourth ring of premithramycin B (PMB), creating the C3 pentyl side chain, strictly followed by reduction of the distal keto group on the new side chain. Unexpectedly this results in a C2 stereoisomer of mithramycin, iso-mithramycin (iso-MTM). Iso-MTM undergoes a non-enzymatic isomerization to MTM catalyzed by Mg2+ ions. Crystal structures of MtmW and its complexes with co-substrate NADPH and PEG, suggest a catalytic mechanism of MtmW. The structures also show that a tetrameric assembly of this enzyme strikingly resembles the ring-shaped β subunit of a vertebrate ion channel. We show that MtmW and MtmOIV form a complex in the presence of PMB and NADPH, presumably to hand over the unstable MtmOIV product to MtmW, yielding iso-MTM, as a potential self-resistance mechanism against MTM toxicity.

Keywords: biocatalysis; biosynthesis; isomerization; natural products; protein structures.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Biological Products / metabolism*
  • Catalysis
  • Plicamycin / biosynthesis*


  • Biological Products
  • Plicamycin