Crystal structure of acireductone dioxygenase (ARD) from <i>Mus musculus</i> at 2.06 Å resolution

Xu, Qingping; Schwarzenbacher, Robert; Krishna, Sanjeev; McMullan, Daniel; Agarwalla, Sanjay; Quijano, Kevin; Abdubek, Polat; Ambing, Eileen; Axelrod, Herbert L.; Biorac, Tanya; Cánaves, Jaume M.; Chiu, Hsiu‐Ju; Elsliger, Marc‐André; Grittini, Carina; Grzechnik, Slawomir K.; DiDonato, Michael; Hale, Joanna; Hampton, Eric; Han, Gye Won; Haugen, Justin; Hornsby, Michael; Jaroszewski, Lukasz; Klock, Heath E.; Knuth, Mark W.; Koesema, Eric; Kreusch, Andreas; Kühn, Peter; Miller, Mitchell D.; Moy, Kin; Nigoghossian, Edward; Paulsen, Jessica; Reyes, Ron; Rife, Chris; Spraggon, Glen; Stevens, Raymond C.; Bedem, Henry van den; Velasquez, Jeff; White, Aprilfawn; Wolf, Guenter; Hodgson, Keith O.; Wooley, John; Deacon, Ashley M.; Godzik, Adam; Lesley, Scott A.; Wilson, Ian A.

doi:10.1002/prot.20947

Cited by 28 publications

(43 citation statements)

References 26 publications

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“…These features are generally attributed to the presence of histidine imidazole ligands; thus, inspection of the spectra indicates either the displacement of a histidine ligand or that a large increase in static disorder leading to an increase of σ 2 occurs upon substrate binding. The crystallographic structure of MmARD shows the metal (presumed but not proven to be Ni +2 ) bound by a 3-His 1-Glu ligation scheme, identical in geometry and sequentially homologous to that proposed in the NMR-derived structures of both NiARD and FeARD' (13,17). …”

Section: Exafs Analysismentioning

confidence: 61%

“…Comparable fits were obtained with either O or N-donors, and when the ΔE 0 was constrained to a single value for fitting both first and second + third shell scattering atoms or was allowed to vary by atom type (N vs. O) and shell. The best fit of the data obtained using one value of E 0 for N-donors The crystallographic structure of MmARD shows the metal (presumed but not proven to be Ni +2 ) bound by a 3-His 1-Glu ligation scheme, identical in geometry and sequentially homologous to that proposed in the NMR-derived structures of both NiARD and FeARD' (13,17). observed in this structure indicates a high degree of static disorder in the M-L distances and accounts in part for the larger than typical values of σ 2 in the EXAFS models, which were constrained to a maximum of two shells in the first coordination sphere in order to minimize the number of free running parameters in the fits and still accommodate both N-and Oscattering atoms.…”

Section: Exafs Analysismentioning

confidence: 77%

“…The recently-published crystal structure of MmARD supports the assignment of these residues as the protein-based ligands (17). However, the identity of the metal in the MmARD structure is unknown, and considering the importance of the identity of the metal in determining both structure and function of ARD, the possibility of alternate metal binding modes involving ligand switching between FeARD' and NiARD could not be ignored.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of Metal Binding in the Active Sites of Acireductone Dioxygenase Isoforms from Klebsiella ATCC 8724

Chai

Dang

et al. 2008

Biochemistry

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The two acireductone dioxygenase (ARD) isozymes from the methionine salvage pathway of Klebsiella ATCC 8724 present an unusual case in which two enzymes with different structures and distinct activities towards their common substrates (1,2-dihydroxy-3-oxo-5-(methylthio)pent-1-ene and dioxygen) are derived from the same polypeptide chain. Structural and functional differences between the two isozymes are determined by the type of M +2 metal ion bound in the active site. The Ni +2 -bound NiARD catalyzes an off-pathway shunt from the methionine salvage pathway leading to the production of formate, methylthiopropionate and carbon monoxide, while the Fe +2 -bound FeARD' catalyzes the on-pathway formation of methionine precursor 2-keto-4-methylthiobutyrate and formate. Four potential protein-based metal ligands were identified by sequence homology and structural considerations. Based on the results of site-directed mutagenesis experiments, X-ray absorption spectroscopy (XAS) and isothermal calorimetry measurements, it is concluded that the same four residues, His 96, His 98, Glu 102 and His 140, provide the protein-based ligands for the metal in both the Ni-and Fe-containing forms of the enzyme, and subtle differences in the local backbone conformations trigger the observed structural and functional differences between the FeARD' and NiARD isozymes. Furthermore, both forms of the enzyme bind their respective metals with pseudo-octahedral geometry, and both may lose a His ligand upon binding of substrate under anaerobic conditions. However, mutations at two conserved non-ligand acidic residues, Glu 95 and Glu 100, result in low metal contents for the mutant proteins as isolated, suggesting that some of the conserved charged residues may aid in transfer of metal from in vivo sources or prevent the loss of metal to stronger chelators. The Glu 100 mutant reconstitutes readily but has low activity. Mutation of Asp 101 results in an active enzyme that incorporates metal in vivo but shows evidence of mixed forms.* To whom correspondence should be addressed: pochapsk@brandeis.edu, phone 781−736−2559, fax 781−736−2516. e Current address: Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, 70 Ship Street, GE3, Providence, RI, 02912 f Current address: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Dr., Room 1007, Indianapolis IN 46202 g This work was supported in part by USPHS grant (R01-GM067786 TCP). Acknowledgment is made to the donors of The American Chemical Society Petroleum Research Fund for partial support (MJM). Trainee funding (SCC) was provided by the NIH-Chemistry Biology Interface Program, T32-GM08515. XAS data collection at the National Synchrotron Light Source at Brookhaven National Laboratory was supported by the U.S. Department of Energy, Division of Materials Sciences and Division of Chemical Sciences. Beamline X9B at NSLS is supported in part by the NIH.Supporting information available Fits for resting state and ES...

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Section: Exafs Analysismentioning

confidence: 61%

Section: Exafs Analysismentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

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Characterization of Metal Binding in the Active Sites of Acireductone Dioxygenase Isoforms from Klebsiella ATCC 8724

Chai

Dang

et al. 2008

Biochemistry

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“…In the original structure (1M4O), this modeling was based on a phylogenetically distant member of the cupin family, jack bean canavalin (13). Recently, a crystallographic structure of a mouse homologue of ARD was deposited in the RCSB PDB by researchers from the Joint Center for Structural Genomics (PDB entry 1VR3) (14). In our refinement of the ARD structure, we replaced the canavalin coordinates used in the original modeling of the active site with those from the corresponding residues in the 1VR3 structure.…”

Section: Introductionmentioning

confidence: 99%

One Protein, Two Enzymes Revisited: A Structural Entropy Switch Interconverts the Two Isoforms of Acireductone Dioxygenase

Goldsmith

Chai

et al. 2006

Journal of Molecular Biology

130

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SummaryAcireductone dioxygenase (ARD) catalyzes different reactions between O 2 and 1,2-dihydroxy-3-oxo-5-(methylthio)pent-1-ene (acireductone) depending upon the metal bound in the active site. Ni +2 -ARD cleaves acireductone to formate, CO and methylthiopropionate. If Fe +2 is bound (ARD ′), the same substrates yield methylthioketobutyrate and formate. The two forms differ in structure, and are chromatographically separable. Paramagnetism of Fe +2 renders the active site of ARD′ inaccessible to standard NMR methods. The structure of ARD′ has been determined using Fe +2 binding parameters determined by X-ray absorption spectroscopy and NMR restraints from H98S ARD, a metal-free diamagnetic protein that is isostructural with ARD′. ARD′ retains the β-sandwich fold of ARD, but a structural entropy switch increases order at one end of a two-helix system that bisects the β-sandwich and decreases order at the other upon interconversion of ARD and ARD′, causing loss of the C-terminal helix in ARD′ and rearrangements of residues involved in substrate orientation in the active site.

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“…These enzymes differ in the metal ion present (Ni II or Fe II ) at the active site (Dai et al, 1999). The structure of the nickel-containing version have revealed that the Ni-ARD possesses Ni II coordinated to three histidine nitrogens, one carboxylate oxygen, and two water molecules Xu et al, 2006), however, a variant enzyme bearing replacement of Glu69 by glutamine displayed similar properties to those of the wild-type enzyme (Straganz et al, 2006) suggesting that the conserved glutamate residue is not important for enzyme function. Depending on the metal bound at the active site, ARD catalyzes two different reactions.…”

Section: Acireductone Dioxygenase (Pdb: 1vr3)mentioning

confidence: 99%

Modeling the Metal Binding Site in Cupin Proteins

Chavez¹,

Banerjee²,

Sljivic³

2011

On Biomimetics

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Crystal structure of acireductone dioxygenase (ARD) from Mus musculus at 2.06 Å resolution

Cited by 28 publications

References 26 publications

Characterization of Metal Binding in the Active Sites of Acireductone Dioxygenase Isoforms from Klebsiella ATCC 8724

Characterization of Metal Binding in the Active Sites of Acireductone Dioxygenase Isoforms from Klebsiella ATCC 8724

One Protein, Two Enzymes Revisited: A Structural Entropy Switch Interconverts the Two Isoforms of Acireductone Dioxygenase

Modeling the Metal Binding Site in Cupin Proteins

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