Discovery of a Cryptic Intermediate in Late Steps of Mithramycin Biosynthesis.
Angew Chem Int Ed Engl
; 59(2): 826-832, 2020 01 07.
Article
em En
| MEDLINE
| ID: mdl-31702856
ABSTRACT
MtmOIV and MtmW catalyze the final two reactions in the mithramycin (MTM) biosynthetic pathway, the Baeyer-Villiger opening of the fourth ring of premithramycinâ
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 ß 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.
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01-internacional
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MEDLINE
Assunto principal:
Produtos Biológicos
/
Plicamicina
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article