Epoxyquinol B

Several epoxyquinoids interfere with NF-kappaB signaling by targeting IKKbeta or NF-kappaB. We report that epoxyquinol B (EPQB), classified as an epoxyquiniod, inhibits NF-kappaB signaling through inhibition of the TAK1 complex, a factor upstream of IKKbeta and NF-kappaB. cDNA microarray analysis revealed that EPQB decreased TNF-alpha-induced expression of NF-kappaB target genes. EPQB covalently bound to a recombinant TAK1-TAB1 fusion protein in vitro, and inhibited its kinase activity. Furthermore, in vitro/in situ treatment with EPQB resulted in a ladder-like hypershift of TAK1 protein bands. We reported recently that EPQB crosslinks proteins via cysteine residues by opening its two epoxides, and our current results suggest that EPQB inhibits NF-kappaB signaling by crosslinking TAK1 itself or TAK1 through other proteins.

Epoxyquinol B (EPQB) is a fungal metabolite, containing two alpha,beta-epoxy ketones. We previously showed that EPQB inhibited the signal transduction involved in angiogenesis through the binding to cysteine residues of receptor kinases. However, the inhibitory mechanism was undefined. In this report, we found that one EPQB molecule is covalently bound to two L-cysteine molecules through two epoxide residues on EPQB. Furthermore, EPQB crosslinked binding proteins through the cysteine residues. These results suggest that EPQB inhibits receptor kinases by crosslinking with other protein or by intramolecular crosslinking.

The biosynthetic origins of epoxyquinols A (1) and B (2) produced by an unidentified fungus have attracted considerable interest because these compounds could be assembled from a biosynthetic precursor, epoxycyclohexenone aldehyde (3), via an electrocyclization/intermolecular Diels-Alder dimerization cascade reaction. Furthermore, very little is known about the biosynthetic origins of naturally occurring epoxyquinone moieties. We herein describe the incorporation of (13)C at specific positions within the structure of a shunt product, epoxycyclohexenone (4), using stable isotope feeding experiments with sodium [1-(13)C]-acetate and sodium [1,2-(13)C2]-acetate. The results of these experiments strongly suggest that the epoxyquinone skeleton is assembled by a polyketide synthase.