Quercetin 2,4‐Dioxygenase Activates Dioxygen in a Side‐On O₂–Ni Complex

Abstract

Quercetin 2,4-dioxygenase (quercetinase) from Streptomyces uses nickel as the active-site cofactor to catalyze oxidative cleavage of the flavonol quercetin. How this unusual active-site metal supports catalysis and O2 activation is under debate. We present crystal structures of Ni-quercetinase in three different states, thus providing direct insight into how quercetin and O2 are activated at the Ni(2+) ion. The Ni(2+) ion is coordinated by three histidine residues and a glutamate residue (E(76)) in all three states. Upon binding, quercetin replaces one water ligand at Ni and is stabilized by a short hydrogen bond through E(76) , the carboxylate group of which rotates by 90°. This conformational change weakens the interaction between Ni and the remaining water ligand, thereby preparing a coordination site at Ni to bind O2. O2 binds side-on to the Ni(2+) ion and is perpendicular to the C2-C3 and C3-C4 bonds of quercetin, which are cleaved in the following reaction steps.

The Metal Drives the Chemistry: Dual Functions of Acireductone Dioxygenase

“…However, only the QueD from Streptomyces appears to use Ni 2+ as a co-factor. 65–66 OxDC and OxOx are both bicupins, containing one Mn 2+ per cupin subunit. As with ARD, the metal is present in an octahedral geometry with the two open sites occupied by non-protein ligands.…”

Spectroscopically Characterized Synthetic Mononuclear Nickel–Oxygen Species

“…[27,28] This is also ap lausible formulation for the nickel-dioxygen speciesw hich was recently crystallographically characterizedi nn ickel-dependent quercetin 2,4-dioxygenase ( Figure 1). [7] In 2004 Riordana nd co-workersr eported the formation of as ide-on superoxonickel(II) species by reactiono ft he nickel(I) complex [Ni I (PhTt Ad )(CO)] with O 2 . [29] Compound [Ni II (O 2 )(PhTt Ad )] ( Figure 5, Ta ble 1) was ap recursor of ab is(moxo)dinickel(III) species previously characterizedb yt he same Chem.…”

“…For example, nickel superoxide dismutase catalyzes the disproportionation of superoxide in a process in which a superoxonickel(II) and superoxonickel(III) species play a key role . Similarly, a nickel–dioxyen adduct has been crystallographically detected in the active site of quercetin 2,4‐dioxygenase, during the oxidative cleavage of the flavonol quercetin . Acireductone dioxygenase also employs nickel to catalyze the conversion of acireductone to 3‐(methylthio)propionate, formate, and carbon monoxide .…”

“…[6] Similarly,anickel-dioxyen adduct has been crystallographically detected in the actives ite of quercetin 2,4-dioxygenase, during the oxidative cleavage of the flavonol quercetin. [7] Acireductone dioxygenase also employs nickel to catalyze the conversion of acireductone to 3-(methylthio)propionate, formate,a nd carbon monoxide. [8] However,i nt his enzymet he metal activates the substrate towards reaction with O 2 by acting as aLewis acid andnoevidencefor metal-centered redox chemistry involving nickel-O 2 speciese xists.…”

Bioinspired Trispyrazolylborato Nickel(II) Flavonolate Complexes and Their Reactivity Toward Dioxygen

“…Nickel(II), for instance, is not among the metal ions that are known to be efficient in O 2 activation and still it can be used as well as copper. The Ni‐QueD was the subject of a recent investigation by Fetzner, Dobbek , and co‐workers and a X‐ray crystal structure analysis performed for a substrate complex after treatment with O 2 could be identified as a nickel‐O 2 species, whose electronic structure is still not clear, though . Conceivable would be a nickel(II) superoxide, the formation of which would require an electron transfer from the redox‐active substrate.…”