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. 2012 Nov 7;134(44):18181-4.
doi: 10.1021/ja3081154. Epub 2012 Oct 29.

Baeyer-Villiger C-C bond cleavage reaction in gilvocarcin and jadomycin biosynthesis

Nidhi Tibrewal  1 , Pallab Pahari, Guojun Wang, Madan K Kharel, Caleb Morris, Theresa Downey, Yanpeng Hou, Tim S Bugni, Jürgen Rohr
Affiliations

Baeyer-Villiger C-C bond cleavage reaction in gilvocarcin and jadomycin biosynthesis

Nidhi Tibrewal et al. J Am Chem Soc. .

Abstract

GilOII has been unambiguously identified as the key enzyme performing the crucial C-C bond cleavage reaction responsible for the unique rearrangement of a benz[a]anthracene skeleton to the benzo[d]naphthopyranone backbone typical of the gilvocarcin-type natural anticancer antibiotics. Further investigations of this enzyme led to the isolation of a hydroxyoxepinone intermediate, leading to important conclusions regarding the cleavage mechanism.

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Figures

Figure 1
Figure 1
HPLC traces of the enzymatic reactions: A) standard dehydrorabelomycin (11), B) 11 + GilOII + GilMT + GilM + GilR producing defucogilvocarcin M (1), C) 11 + GilOII + GilM + GilMT producing defucopregilvocarcin M (6), D) 11 + GilMT.
Figure 2
Figure 2
HPLC traces of the enzymatic reactions: A) dehydrorabelomycin (11) + GilOII + NADPH + FAD + Fre, B) 11 + GilOII C) 11 + GilOII + NADPH + Fre (traces of 18 were formed due to traces of FAD co-purified with Fre), D) 11 + JadG + GilMT + GilM + GilR producing defucogilvocarcin M (1), E) 11 + JadG + NADPH + FAD + Fre.
Figure 3
Figure 3
Top: In vitro reactions of 18 with different combinations of downstream enzymes; GilOII, GilM, GilMT and GilR. Bottom: HPLC traces of the enzymatic reactions: A) 18 + GilMT + GilM + GilR + Fre + FAD + NADPH; B) 18 + GilOII; C) 18 + GilOII + GilMT + GilM + GilR + Fre + FAD + NADPH.
Scheme 1
Scheme 1
Representative members of the gilvocarcin and jadomycin groups of natural products.
Scheme 2
Scheme 2
Sequence of events en route to defucogilvocarcin M.
Scheme 3
Scheme 3
Enzymatic reaction of dehydrorabelomycin (11) with GilMT and GilOII; Fre: E. coli flavin reductase.
Scheme 4
Scheme 4
Mechanistic alternatives for the key C-C bond cleavage reaction
See this image and copyright information in PMC

References

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