Dinuclear Hydrolases

Averill, Bruce A.

doi:10.1016/b0-08-043748-6/08165-2

Cited by 6 publications

(4 citation statements)

References 227 publications

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“…Zinc Complexes of the Binucleating Ligands. Assemblies of cooperating Zn 2+ ions form the active site of many hydrolytic enzymes . Recent attention has come from multimetallic mechanisms for Zn 2+ -catalyzed alternating copolymerization of epoxides with CO 2 ,3g and multimetallic strategies for detecting biological Zn 2+ .…”

Section: Resultsmentioning

confidence: 99%

Macrocyclic Binucleating β-Diketiminate Ligands and Their Lithium, Aluminum, and Zinc Complexes

et al. 2007

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The incorporation of rigid aromatic linkers into β-diketiminate ligands creates a binucleating scaffold that holds two metals near each other. This paper discloses the synthesis, characterization, and reactivity of mBin 2− , which has a meta-substituted xylylene spacer, and pBin 2− , which has a parasubstituted xylylene spacer. Lithium, aluminum, and zinc complexes of each ligand are isolated, and in some cases are characterized by X-ray crystallography. The lithium complexes are coordinated to solvent-derived THF ligands, while the zinc and aluminum complexes have alkyl ligands. Complexes of the mBin 2− ligand have an anti conformation in which the metals are on opposite sides of the macrocycle, while pBin 2− complexes prefer a syn conformation. The 1 H NMR spectra of the complexes demonstrate that the conformations rapidly interconvert in the lithium complexes, and less rapidly in the zinc and aluminum complexes.

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Section: Resultsmentioning

confidence: 99%

Macrocyclic Binucleating β-Diketiminate Ligands and Their Lithium, Aluminum, and Zinc Complexes

et al. 2007

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“…The zinc ions are separated by approximately 4.0 Å, and there are no protein ligands bridging the two zinc ions (Stec et al 2000;Averill 2003). The Zn 1 ion is five-coordinate with two histidine imidazoles, a bidentate aspartate carboxylate, and water as ligands.…”

Section: Fig 13mentioning

confidence: 99%

“…Several of reviews on dinuclear metallohydrolases have also been published (Wilcox 1996;Ciurli et al 1999;Kimura 2000;Holz 2002;Lowther and Matthews 2002;Averill 2003;Weston 2005;Mitić et al 2006;Schenk et al 2012). However, the two topics have never been combined in one review.…”

Section: Introductionmentioning

confidence: 95%

Use of magnetic circular dichroism to study dinuclear metallohydrolases and the corresponding biomimetics

et al. 2015

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Magnetic circular dichroism (MCD) is a convenient technique for providing structural and mechanistic insight into enzymatic systems in solution. The focus of this review is on aspects of geometric and electronic structure that can be determined by MCD, and how this method can further our understanding of enzymatic mechanisms. Dinuclear Co(II) systems that catalyse hydrolytic reactions were selected to illustrate the approach. These systems all contain active sites with similar structures consisting of two Co(II) ions bridged by one or two carboxylates and a water or hydroxide. In most of these active sites one Co(II) is five-coordinate and one is six-coordinate, with differing binding affinities. It is shown how MCD can be used to determine which binding site--five or six-coordinate--has the greater affinity. Importantly, zero-field-splitting data and magnetic exchange coupling constants may be determined from the temperature and field dependence of MCD data. The relevance of these data to the function of the enzymatic systems is discussed.

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“…The binuclear metalloenzyme purple acid phosphatase (PAP) [1], which may be involved in disorders such as osteoporosis [2–4], Gaucher disease [5], hairy cell leukemia [6], and AIDS [7] is widely distributed in mammalian tissues [8,9]. The expression level of PAP [also referred to as tartrate resistant acid phosphatase (TRAP) or type 5 acid phosphatase (AcP5; EC 3.1.3.2)] is elevated in these disorders, suggesting a relationship between the increased levels of the enzyme and the clinical picture.…”

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confidence: 99%

Substrate positioning by His92 is important in catalysis by purple acid phosphatase

et al. 2005

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The binuclear metalloenzyme purple acid phosphatase (PAP) [1], which may be involved in disorders such as osteoporosis [2][3][4], Gaucher disease [5], hairy cell leukemia [6], and AIDS [7] is widely distributed in mammalian tissues [8,9]. The expression level of PAP [also referred to as tartrate resistant acid phosphatase (TRAP) or type 5 acid phosphatase (AcP5; EC 3.1.3.2)] is elevated in these disorders, suggesting a relationship between the increased levels of the enzyme and the clinical picture. The presumed role of PAP makes it important to develop drugs that can inhibit PAP activity. In order to facilitate this process, the precise catalytic mechanism must be elucidated, including the function of each residue involved in catalysis.Although the available crystal structures of PAPs [10][11][12] provide structural information about the residues potentially involved in catalysis, to date only structures of inactive redox and protonation states of the enzymes have been reported. All structures show an active site composed of two metal ions bridged by a solvent-derived species and a bidentate aspartate residue. In addition, the iron(III) ion is coordinated by a tyrosinate [resulting in a ligand-to-metal charge transfer (LMCT) transition that is responsible for the Proteolysis of single polypeptide mammalian purple acid phosphatases (PAPs) results in the loss of an interaction between the loop residue Asp146 and the active site residues Asn91 and ⁄ or His92. While Asn91 is a ligand to the divalent metal of the mixed-valent di-iron center, the role of His92 in the catalytic mechanism is unknown. Site-directed mutagenesis of His92 was performed to examine the role of this residue in single polypeptide PAP. Conversion of His92 into Ala, which eliminates polar interactions of this residue with the active site, resulted in a 10-fold decrease in catalytic activity at the optimal pH. Conversely, conversion of this residue into Asn, which cannot function as either a proton donor or acceptor, but can provide hydrogen-bonding interactions, resulted in a three-fold increase in activity at the optimal pH. Both mutant enzymes had more acidic pH optima, with pK es,1 values consistent with the involvement of an iron(III) hydroxide unit or a hydroxide in the second coordination sphere in catalysis. These results, together with EPR data, support a role of His92 in positioning either the nucleophile or the substrate, rather than directly in acid or base catalysis. The existence of an extensive hydrogen-bonding network that could fine-tune the position of His92 is consistent with this proposal.Abbreviations kPP, protein phosphatase from phage k; KBPAP, kidney bean PAP; LMCT, ligand-to-metal charge transfer; MOI, multiplicity of infection; PAP, purple acid phosphatase; p-NPP, para-nitrophenylphosphate; PP, protein phosphatase; recHPAP, recombinant human purple acid phosphatase; recRPAP, recombinant rat PAP; TRAP, tartrate resistant acid phosphatase.

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Dinuclear Hydrolases

Cited by 6 publications

References 227 publications

Macrocyclic Binucleating β-Diketiminate Ligands and Their Lithium, Aluminum, and Zinc Complexes

Macrocyclic Binucleating β-Diketiminate Ligands and Their Lithium, Aluminum, and Zinc Complexes

Use of magnetic circular dichroism to study dinuclear metallohydrolases and the corresponding biomimetics

Substrate positioning by His92 is important in catalysis by purple acid phosphatase

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