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Discovery of a Cryptic Intermediate in Late Steps of Mithramycin Biosynthesis.
- Source :
-
Angewandte Chemie . Jan2020, Vol. 132 Issue 2, p836-842. 7p. - Publication Year :
- 2020
-
Abstract
- 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00448249
- Volume :
- 132
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- Angewandte Chemie
- Publication Type :
- Academic Journal
- Accession number :
- 141002535
- Full Text :
- https://doi.org/10.1002/ange.201910241