Burning Off a Carbon

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Science  08 May 2009:
Vol. 324, Issue 5928, pp. 693-695
DOI: 10.1126/science.324_693d
CREDIT: BEAM ET AL., BIOCHEMISTRY 48, 10.1021/BI8023509 (2009)

Streptomycetes are bacterial drug designers, synthesizing a cornucopia of natural products that have found their way onto pharmacists' shelves worldwide. The precursor to one such compound, mithramycin, contains di- and trisaccharide chains (green and yellow) linked to a tetracyclic polyketide. In a subsequent down-sizing reaction, dioxygen is activated by attaching it to FADH (black) at C4a (red), and the resulting peroxyflavin attacks the ketone at C1 (red) of premithramycin B (blue) in a Baeyer-Villiger oxidation. The consequences are that one of the rings can then be opened by hydrolysis of the lactone, and one of the carbon atoms can be removed via decarboxylation. Beam et al. describe the crystal structure of the Baeyer-Villiger monooxygenase MtmOIV (gray) and the binding of FAD and premithramycin in the active site. Of particular interest are the residues that allow the enzyme to accommodate the saccharide chains, as these are prime targets for modifications aimed at enhancing the activity of mithramycin as a DNA cross-linking agent and at decreasing its toxicity.

Biochemistry48, 10.1021/bi8023509 (2009).

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