Nickel in Acireductone Dioxygenase

Pochapsky, Thomas C.; Ju, Tingting; Dang, Marina; Beaulieu, Rachel; Pagani, G; OuYang, Bo

doi:10.1002/9780470028131.ch12

Cited by 23 publications

(65 citation statements)

References 45 publications

(107 reference statements)

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“…The initial structure of ARD was obtained from the Protein Data Base (PDB) (code: 2HJI [13] to the equatorial plane of the Co complex, in accord with experimental and theoretical predictions for other metal forms of ARD [14][15][16] (Figure 2A). Previous QM/DMD simulations on the Fe-ARD 0 and Ni-ARD systems elucidated the need for adequate sampling of the backbone and substrate since the two residues, R104 and R154, were found to form vital hydrogen bonds with the substrate and active site [2], to stabilize the doubled deprotonated substrate and the six-membered ring orientation of the substrate to the metal.…”

Section: Theoretical Methodsmentioning

confidence: 93%

Co2+ acireductone dioxygenase: Fe2+ mechanism, Ni2+ mechanism, or something else?

Valdez

Gallup

Alexandrova

2014

Chemical Physics Letters

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a b s t r a c tAcireductone dioxygenase (ARD) oxidizes 1,2-dihydroxy-3-keto-5-(methylthio)pentene to either formate and an a-keto acid, or formate, methylthiopropionate and CO, depending on the nature of the catalytic metal, Fe 2+ or Ni 2+. We recently showed that, contrary to established hypotheses, the mechanistic preference is driven solely by the RedOx behavior of the metal. Here, we address the functionality of Co 2+ -ARD. Using mixed quantum-classical dynamics simulations and density functional theory calculations, we show that both Fe 2+ -like and Ni 2+ -like routes are accessible to Co 2+ -ARD, but the mechanism involves a bifurcating transition state, and so the exact product distribution would be determined by the reaction dynamics.

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Section: Theoretical Methodsmentioning

confidence: 93%

Co2+ acireductone dioxygenase: Fe2+ mechanism, Ni2+ mechanism, or something else?

Valdez

Gallup

Alexandrova

2014

Chemical Physics Letters

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“…3 While the guanidine functionality is usually too basic to serve as a general base in enzymatic reactions (pK a ~ 12.5), the side chain of Arg147, also strongly conserved, is parallel to the side-chain of Arg 96, and so may modulate the of pK a of Arg96 sufficiently so that the residue can act as a general base at physiological pH. 17 This parallel arrangement is also seen in the KoARD active site (Arg104 and Arg154, in the KoARD sequence). Other conserved residues in the active sites of ARD orthologs include Phe135, Phe105, Phe84 and Ala145.…”

Section: Proposed Enzymatic Mechanisms For Ardmentioning

confidence: 99%

The Metal Drives the Chemistry: Dual Functions of Acireductone Dioxygenase

2017

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Acireductone dioxygenase (ARD) from the methionine salvage pathway (MSP) is a unique enzyme that exhibits dual chemistry determined solely by the identity of the divalent transition metal ion (Fe2+ or Ni2+) in the active site. The Fe2+ containing isozyme catalyzes the on-pathway reaction using substrates 1,2 dihydroxy-3-keto-5-methylthiopent-1-ene (acireductone) and dioxygen to generate formate and the ketoacid precursor of methionine, 2-keto-4-methylthiobutyrate, whereas the Ni2+ containing isozyme catalyzes an off-pathway shunt with the same substrates, generating methylthiopropionate, carbon monoxide and formate. The dual chemistry of ARD was originally discovered in the bacterium Klebsiella oxytoca, but it has recently been shown that mammalian ARD enzymes (mouse and human) are also capable of catalyzing metal-dependent dual chemistry in vitro. This is particularly interesting since carbon monoxide, one of the products of off-pathway reaction, has been identified as an anti-apoptotic molecule in mammals. In addition, several biochemical and genetic studies have indicated an inhibitory role of human ARD in cancer. This comprehensive review describes the biochemical and structural characterization of the ARD family, the proposed experimental and theoretical approaches to establishing mechanisms for the dual chemistry, insights into the mechanism based on comparison with structurally and functionally similar enzymes and the applications of this research to the field of artificial metalloenzymes and synthetic biology.

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“…Thus, two classes of Glo I have emerged based on metal activation: class I, which can be activated by Zn(II), and class II, which cannot be activated by Zn(II) and is maximally activated by Ni(II) ions. 16b …”

Section: Glyoxalase Imentioning

confidence: 99%

“…The Fe(II)-dependent enzyme, Fe-ARD (EC 1.13.11.54; E2′ or ARD′), catalyzes a key step in the methionine salvage pathway (Figure 15), 16c that is, the conversion of acireductone to 4-(methylthio)-2-oxobutanoate, the α -keto acid precursor of methionine, and formate. The Ni(II)-dependent enzyme, Ni-ARD (EC 1.13.11.53; E2 or ARD), catalyzes the conversion of acireductone to 3-(methylthio)propionate, formate, and carbon monoxide.…”

Section: Acireductone Dioxygenasementioning

confidence: 99%