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Set of Fe(II)-3-Hydroxyflavonolate Enzyme-Substrate Model Complexes of Atypically Coordinated Mononuclear Non-Heme Fe(II)-Dependent Quercetin 2,4-Dioxygenase.

ABSTRACT: With the aim of revealing the catalytic role of atypically coordinated (3His-1Glu) active site mononuclear non-heme Fe(II)-dependent quercetin 2,4-dioxygenase (Fe-2,4-QD) and the electronic effects of the model ligands on the reactivity toward dioxygen, a set of p/m-R-substituted carboxylate-containing ligand-supported Fe(II)-3-hydroxyflavonolate complexes, [Fe^IIL^R(fla)] (L^RH: 2-{[bis(pyridin-2-ylmethyl)amino]methyl}-p/m-R-benzoic acid; R: p-OMe (1), p-Me (2), m-Br (4), and m-NO₂ (5); fla: 3-hydroxyflavonolate), were synthesized and characterized as structural and functional models for the ES (enzyme-substrate) complexes of Fe-2,4-QD. [Fe^IIL^R(fla)] show relatively high enzyme-type reactivity (dioxygenative ring opening of the coordinated substrate fla, single-turnover reaction) at low temperatures (30-65 °C). The reaction shows a linear Hammett plot (? = -1.21), and electron donating groups enhance the reaction rates. The notable difference on the reactivity can be rationalized from the electronic nature of the substituent in the ligands, which could tune the reactivity via tuning Lewis acidity of the Fe(II) ion, electron density, and the redox potential of fla. The properties and the reactivity show approximately linear correlations between ?_max or E _1/2 of fla and the reaction rate constant k. This work sheds light not only on understanding of electronic effects of the ligands and the property-reactivity relationship but also on the role of the catalytic reaction by Fe-2,4-QD.

SUBMITTER: Sun YJ

PROVIDER: S-EPMC6644611 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Set of Fe(II)-3-Hydroxyflavonolate Enzyme-Substrate Model Complexes of Atypically Coordinated Mononuclear Non-Heme Fe(II)-Dependent Quercetin 2,4-Dioxygenase.

Sun Ying-Ji YJ Huang Qian-Qian QQ Zhang Jian-Jun JJ

ACS omega 20170918 9

With the aim of revealing the catalytic role of atypically coordinated (3His-1Glu) active site mononuclear non-heme Fe(II)-dependent quercetin 2,4-dioxygenase (Fe-2,4-QD) and the electronic effects of the model ligands on the reactivity toward dioxygen, a set of p/m-R-substituted carboxylate-containing ligand-supported Fe(II)-3-hydroxyflavonolate complexes, [FeIILR(fla)] (LRH: 2-{[bis(pyridin-2-ylmethyl)amino]methyl}-p/m-R-benzoic acid; R: p- ...[more]

PMID: 31457842

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Project description:Three new nickel(ii)-flavonolate complexes of the type [Ni(L)(fla)](ClO4) 1-3, where L is the tripodal 4N ligand tris(pyrid-2-ylmethyl)amine (tpa, L1) or (pyrid-2-ylmethyl)bis(6-methylpyrid-2-ylmethyl)amine (6-Me2-tpa, L2) or tris(N-Et-benzimidazol-2-ylmethyl)amine (Et-ntb, L3), have been isolated as functional models for Ni(ii)-containing quercetin 2,4-dioxygenase. Single crystal X-ray structures of 1 and 3 reveal that Ni(ii) is involved in π-back bonding with flavonolate (fla-), as evident from enhancement in C[double bond, length as m-dash]O bond length upon coordination [H(fla), 1.232(3); 1, 1.245(7); 3, 1.262(8) Å]. More asymmetric chelation of fla- in 3 than in 1 [Δd = (Ni-Ocarbonyl - Ni-Oenolate): 1, 0.126; 3, 0.182 Å] corresponds to lower π-delocalization in 3 with electron-releasing N-Et substituent. The optimized structures of 1-3 and their geometrical isomers have been computed by DFT methods. The HOMO and LUMO, both localized on Ni(ii)-bound fla-, are highly conjugated bonding π- and antibonding π*-orbitals respectively. They are located higher in energy than the Ni(ii)-based MOs (HOMO-1, dx2-y2; HOMO-2/6, dz2), revealing that the Ni(ii)-bound fla- rather than Ni(ii) would undergo oxidation upon exposure to dioxygen. The results of computational studies, in combination with spectral and electrochemical studies, support the involvement of redox-inactive Ni(ii) in π-back bonding with fla-, tuning the π-delocalization in fla- and hence its activation. Upon exposure to dioxygen, all the flavonolate adducts in DMF solution decompose to produce CO and depside, which then is hydrolyzed to give the corresponding acids at 70 °C. The highest rate of dioxygenase reactivity of 3 (kO2: 3 (29.10 ± 0.16) > 1 (16.67 ± 0.70) > 2 (1.81 ± 0.04 × 10-1 M-1 s-1)), determined by monitoring the disappearance of the LMCT band in the range 440-450 nm, is ascribed to the electron-releasing N-Et substituent on bzim ring, which decreases the π-delocalization in fla- and enhances its activation.

Project description:We present here a computational study of reactions at a model complex of the SyrB2 enzyme active site. SyrB2, which chlorinates L-threonine in the syringomycin biosynthetic pathway, belongs to a recently discovered class of alpha-ketoglutarate (alphaKG), non-heme Fe(II)-dependent halogenases that share many structural and chemical similarities with hydroxylases. Namely, halogenases and hydroxylases alike decarboxylate the alphaKG co-substrate, facilitating formation of a high-energy ferryl-oxo intermediate that abstracts a hydrogen from the reactant complex. The reaction mechanisms differ at this point, and mutation of active site residues (Asp for the hydroxylase to Ala or Ala to Asp/Glu for halogenase) fails to reproduce hydroxylating activity in SyrB2 or halogenating activity in similar hydroxylases. Using a density functional theory approach with a recently implemented Hubbard U correction for accurate treatment of transition-metal chemistry, we explore probable reaction pathways and mechanisms via a model complex consisting of only the iron center and its direct ligands. We show that the first step, alphaKG decarboxylation, is barrierless and exothermic, but the subsequent hydrogen abstraction step has an energetic barrier consistent with that accessible under biological conditions. In the model complex we use, radical chlorination is barrierless and exothermic, whereas the analogous hydroxylation is found to have a small energetic barrier. The hydrogen abstraction and radical chlorination steps are strongly coupled: the barrier for the hydrogen abstraction step is reduced when carried out concomitantly with the exothermic chlorination step. Our work suggests that the lack of chlorination in mutant hydroxylases is most likely due to poor binding of chlorine in the active site, whereas mutant halogenases do not hydroxylate for energetic reasons. Although secondary shell residues undoubtedly modulate the overall reactivity and binding of relevant substrates, we show that a small model compound consisting exclusively of the direct ligands to the metal can help explain reactivity heretofore not yet understood in the halogenase SyrB2.

Dataset Information

Set of Fe(II)-3-Hydroxyflavonolate Enzyme-Substrate Model Complexes of Atypically Coordinated Mononuclear Non-Heme Fe(II)-Dependent Quercetin 2,4-Dioxygenase.

Publications

Set of Fe(II)-3-Hydroxyflavonolate Enzyme-Substrate Model Complexes of Atypically Coordinated Mononuclear Non-Heme Fe(II)-Dependent Quercetin 2,4-Dioxygenase.

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