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- Title
Discovery of a Cryptic Intermediate in Late Steps of Mithramycin Biosynthesis.
- Authors
Wheeler, Ryan; Yu, Xia; Hou, Caixia; Mitra, Prithiba; Chen, Jhong‐Min; Herkules, Frank; Ivanov, Dmitri N.; Tsodikov, Oleg V.; Rohr, Jürgen
- 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.
- Subjects
NICOTINAMIDE adenine dinucleotide phosphate; CRYSTAL structure; BIOSYNTHESIS; ISOMERIZATION; ION channels
- Publication
Angewandte Chemie, 2020, Vol 132, Issue 2, p836
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201910241