6OVX

Crystal structure of mithramycin 3-side chain keto-reductase MtmW in complex with NAD+, P422 form

Summary for 6OVX

• Entry DOI: 10.2210/pdb6ovx/pdb
• Descriptor: Putative side chain reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, GLYCEROL, ... (4 entities in total)
• Functional Keywords: natural product, biosynthesis, aureolic acid, reductase, oxidoreductase
• Biological source: Streptomyces argillaceus
• Total number of polymer chains: 2
• Total formula weight: 74345.70

Authors

Hou, C.,Yu, X.,Rohr, J.,Tsodikov, O.V. (deposition date: 2019-05-08, release date: 2019-11-27, Last modification date: 2023-10-11)

Primary citation

Wheeler, R.,Yu, X.,Hou, C.,Mitra, P.,Chen, J.M.,Herkules, F.,Ivanov, D.N.,Tsodikov, O.V.,Rohr, J.
Discovery of a Cryptic Intermediate in Late Steps of Mithramycin Biosynthesis.
Angew.Chem.Int.Ed.Engl., 59:826-832, 2020

PubMed 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 Mg 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.

PubMed: 31702856
DOI: 10.1002/anie.201910241

Experimental method

X-RAY DIFFRACTION (2.1 Å)