Structure and function of atypically coordinated enzymatic mononuclear non-heme-Fe(II) centers

Buongiorno, Daniela; Straganz, Grit Daniela

doi:10.1016/j.ccr.2012.04.028

Cited by 103 publications

(81 citation statements)

References 173 publications

(188 reference statements)

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“…In rubredoxin, Fe(III) is coordinated to four cysteinyl sulfurs occurring on two Cys-X 2 -Cys segments or one Cys-X 2 -Cys and one Cys-Cys40. By contrast, in order to coordinate the Fe(II) center, “cupin superfamily” proteins have a conserved motif, in which no cysteine is contained as a ligand: His-X 2 -[His/Asp]-X 4 -Glu-X n -His41. These specific motifs are not found in the sequences of AcnX enzymes (Fig.…”

Section: Resultsmentioning

confidence: 99%

Functional characterization of aconitase X as a cis-3-hydroxy-L-proline dehydratase

Watanabe

Tajima

Fujii

et al. 2016

Sci Rep

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In the aconitase superfamily, which includes the archetypical aconitase, homoaconitase, and isopropylmalate isomerase, only aconitase X is not functionally annotated. The corresponding gene (LhpI) was often located within the bacterial gene cluster involved in L-hydroxyproline metabolism. Screening of a library of (hydroxy)proline analogues revealed that this protein catalyzes the dehydration of cis-3-hydroxy-L-proline to Δ1-pyrroline-2-carboxylate. Furthermore, electron paramagnetic resonance and site-directed mutagenic analyses suggests the presence of a mononuclear Fe(III) center, which may be coordinated with one glutamate and two cysteine residues. These properties were significantly different from those of other aconitase members, which catalyze the isomerization of α- to β-hydroxy acids, and have a [4Fe-4S] cluster-binding site composed of three cysteine residues. Bacteria with the LhpI gene could degrade cis-3-hydroxy-L-proline as the sole carbon source, and LhpI transcription was up-regulated not only by cis-3-hydroxy-L-proline, but also by several isomeric 3- and 4-hydroxyprolines.

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Section: Resultsmentioning

confidence: 99%

Functional characterization of aconitase X as a cis-3-hydroxy-L-proline dehydratase

Watanabe

Tajima

Fujii

et al. 2016

Sci Rep

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“…However, among this group of enzymes, CCDs appear to employ the most extensive use of a negatively charged second ligand sphere for maintenance of the iron center structure and function. The strict conservation of Glu, or in rare cases Asp, at the second sphere positions in this ancient family indicates a profound selective pressure maintaining the anionicity that envelops the 4-His-Fe(II) center (41,58). The neutral 4-His inner sphere of CCDs contrasts with metal-binding ligand sets of most other non-heme iron proteins, which usually contain at least one negatively charged residue (59).…”

Section: Structure-activity Relationships Of Apocarotenoid Oxygenasementioning

confidence: 96%

“…In addition, three conserved Glu residues indirectly contribute to iron coordination through hydrogen bonding interactions with three of the direct His ligands. This 4-His ϩ 3-Glu dual-sphere metal-binding motif distinguishes CCDs from other non-heme mononuclear iron centers (41). Involvement of the Glu sphere is indispensable for CCD catalytic function as shown by previous studies (28,36,42).…”

mentioning

confidence: 94%

Key Residues for Catalytic Function and Metal Coordination in a Carotenoid Cleavage Dioxygenase

Sui

Zhang

Golczak

et al. 2016

Journal of Biological Chemistry

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Carotenoid cleavage dioxygenases (CCDs) are non-heme iron-containing enzymes found in all domains of life that generate biologically important apocarotenoids. Prior studies have revealed a critical role for a conserved 4-His motif in forming the CCD iron center. By contrast, the roles of other active site residues in catalytic function, including maintenance of the stringent regio-and stereo-selective cleavage activity, typically exhibited by these enzymes have not been thoroughly investigated. Here, we examined the functional and structural importance of active site residues in an apocarotenoid-cleaving oxygenase (ACO) from Synechocystis. Most active site substitutions variably lowered maximal catalytic activity without markedly affecting the K m value for the all-trans-8-apocarotenol substrate. Native C15-C15 cleavage activity was retained in all ACO variants examined suggesting that multiple active site residues contribute to the enzyme's regioselectivity. Crystallographic analysis of a nearly inactive W149A-substituted ACO revealed marked disruption of the active site structure, including loss of iron coordination by His-238 apparently from an altered conformation of the conserved second sphere Glu-150 residue. Gln-and Asp-150-substituted versions of ACO further confirmed the structural/functional requirement for a Glu side chain at this position, which is homologous to Glu-148 in RPE65, a site in which substitution to Asp has been associated with loss of enzymatic function in Leber congenital amaurosis. The novel links shown here between ACO active site structure and catalytic activity could be broadly applicable to other CCD members and provide insights into the molecular pathogenesis of vision loss associated with an RPE65 point mutation.

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“…27 The catalytic implications of this alteration in the first-sphere coordination sphere (3His vs. 2H1C triad) have been widely discussed, but no consensus explanation has emerged. 28 …”

Section: Introductionmentioning

confidence: 99%

Synthesis, X-ray Structures, Electronic Properties, and O₂/NO Reactivities of Thiol Dioxygenase Active-Site Models

et al. 2016

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Mononuclear nonheme iron complexes that serve as structural and functional mimics of the thiol dioxygenases (TDOs), cysteine dioxygenase (CDO) and cysteamine dioxygenase (ADO), have been prepared and characterized with crystallographic, spectroscopic, kinetic, and computational methods. The high-spin Fe(II) complexes feature the facially-coordinating tris(4,5-diphenyl-1-methylimidazol-2-yl)phosphine (Ph2TIP) ligand that replicates the three histidine (3His) triad of the TDO active sites. Further coordination with bidentate L-cysteine ethyl ester (CysOEt) or cysteamine (CysAm) anions yielded five-coordinate (5C) complexes that resemble the substrate-bound forms of CDO and ADO, respectively. Detailed electronic-structure descriptions of the [Fe(Ph2TIP)(LS,N)]BPh4 complexes, where LS,N = CysOEt (1) or CysAm (2), were generated through a combination of spectroscopic techniques [electronic absorption, magnetic circular dichroism (MCD)] and density functional theory (DFT). Complexes 1 and 2 decompose in the presence of O2 to yield the corresponding sulfinic acid (RSO2H) products, thereby emulating the reactivity of the TDO enzymes and related complexes. Rate constants and activation parameters for the dioxygenation reactions were measured and interpreted with the aid of DFT calculations for O2-bound intermediates. Treatment of the TDO models with nitric oxide (NO) – a well-established surrogate of O2 – led to a mixture of high-spin and low-spin {FeNO}7 species at low temperature (−70 °C), as indicated by electron paramagnetic resonance (EPR) spectroscopy. At room temperature, these Fe/NO adducts convert to a common species with EPR and infrared (IR) features typical of cationic dinitrosyl iron complexes (DNICs). To complement these results, parallel spectroscopic, computational, and O2/NO reactivity studies were carried out using previously-reported TDO models that feature an anionic hydrotris(3-phenyl-5-methyl-pyrazolyl)borate (Ph,MeTp−) ligand. Though the O2 reactivities of the Ph2TIP- and Ph,MeTp-based complexes are quite similar, the supporting ligand perturbs the energies of Fe 3d-based molecular orbitals and modulates Fe-S bond covalency, suggesting possible rationales for the presence of neutral 3His coordination in CDO and ADO.

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Structure and function of atypically coordinated enzymatic mononuclear non-heme-Fe(II) centers

Cited by 103 publications

References 173 publications

Functional characterization of aconitase X as a cis-3-hydroxy-L-proline dehydratase

Functional characterization of aconitase X as a cis-3-hydroxy-L-proline dehydratase

Key Residues for Catalytic Function and Metal Coordination in a Carotenoid Cleavage Dioxygenase

Synthesis, X-ray Structures, Electronic Properties, and O₂/NO Reactivities of Thiol Dioxygenase Active-Site Models

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Structure and function of atypically coordinated enzymatic mononuclear non-heme-Fe(II) centers

Cited by 103 publications

References 173 publications

Functional characterization of aconitase X as a cis-3-hydroxy-L-proline dehydratase

Functional characterization of aconitase X as a cis-3-hydroxy-L-proline dehydratase

Key Residues for Catalytic Function and Metal Coordination in a Carotenoid Cleavage Dioxygenase

Synthesis, X-ray Structures, Electronic Properties, and O2/NO Reactivities of Thiol Dioxygenase Active-Site Models

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Product

Resources

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Synthesis, X-ray Structures, Electronic Properties, and O₂/NO Reactivities of Thiol Dioxygenase Active-Site Models