Transfer of iron from uteroferrin (purple acid phosphatase) to transferrin related to acid phosphatase activity.

Nuttleman, Peter R.; Roberts, R. Michael

doi:10.1016/s0021-9258(19)38330-9

Cited by 48 publications

(16 citation statements)

References 23 publications

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“…In this complex, the metal−metal distance is substantially longer than that in E b -S (3.13 Å vs 4.74 Å; Figure 9) [RI (11,12) in Figure 4c and RI (10,11) in Figure 4e]. Additionally, a terminal water that is not observed in E b -S coordinates to the metal in the α site in E b -S -H , and the first coordination shell Asp8 changes its coordination mode from mono-to μ-1,3 bidentate, effectively occupying the bridging position previously held by the μ-hydroxyl group [compare RI (1,11) in Figure 4e and RI (1,12) in Figure 4c]. This significant rearrangement of Asp8 was possibly due to the absence of a steric clash with that bridging hydroxyl group.…”

Section: Resultsmentioning

confidence: 99%

“…Binuclear metallophosphatases are ubiquitous in bacteria, yeast, plants, and mammalian organisms. − These enzymes have been implicated in a wide range of critical chemical/biochemical processes such as iron transport, generation of reactive oxygen species, , DNA replication, and bone turnover . They catalyze the hydrolytic cleavage of phosphoester bonds of a variety of biological substrates. − There are three types of phosphoester bonds (mono-, di-, and triesters) that are cleaved by specialized enzymes known as phosphomono-, phosphodi-, and phosphotriesterases, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…Binuclear metallophosphatases are ubiquitous in bacteria, yeast, plants, and mammalian organisms. 1−4 These enzymes have been implicated in a wide range of critical chemical/ biochemical processes such as iron transport, 1 generation of reactive oxygen species, 2,3 DNA replication, and bone turnover. 4 They catalyze the hydrolytic cleavage of phosphoester bonds of a variety of biological substrates.…”

Section: Introductionmentioning

confidence: 99%

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Formation of Catalytically Active Binuclear Center of Glycerophosphodiesterase: A Molecular Dynamics Study

2018

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Glycerophosphodiesterase (GpdQ) is a binuclear metallophosphatase that catalyzes the hydrolytic cleavage of mono-, di-, and triphosphoester bonds of a wide range of critical molecules. Upon substrate binding, this enzyme undergoes a complex transformation from an inactive mononuclear form (E, where the metal resides in the α site) to an active binuclear center (E-S, with metals bound to both the α and β sites) through a mononuclear, substrate-bound intermediate state (E-S). In this study, all-atom molecular dynamics simulations have been employed to investigate structures and dynamical transformations in this process using eight different variants, i.e., five wild-type and three mutant forms of the enzyme. Additionally, the effects of an actual substrate, bis-( para-nitrophenyl) phosphate (b pNPP), a metal-bridging nucleophilic hydroxyl, and specific first and second coordination shell residues have been investigated. The initial binding of the substrate to E enhances the metal binding affinity of the α site and prepares the β site for coordination of the second metal ion. These results are in agreement with stopped-flow fluorescence and calorimetry data. In E-S, the computed increase in the substrate and metal (both α and β) binding energies is also in line with the experimental data. However, removal of the substrate from this complex is found to cause substantial reduction in binding energies of both α and β metals. The role of the substrate in the creation and stabilization of the active site predicted in this study is supported by the kinetic measurements using both stopped-flow and nuclear magnetic resonance techniques. Importantly, residue Asn80, a ligand of the metal in the β site, exhibits coordination flexibility by acting as a gate in the formation of E-S, in good agreement with mutagenesis and spectroscopic data.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Formation of Catalytically Active Binuclear Center of Glycerophosphodiesterase: A Molecular Dynamics Study

2018

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“…Glycerophosphodiesterase (GpdQ) from Enterobacter aerogenes , is a member of the family of binuclear metallohydrolases that are commonly found in bacteria, yeast, plants, and mammals. Enzymes from this family include aminopeptidases, lactamases, nucleases, protein phosphatases, purple acid phosphatases (PAPs), and ureases, and they have been implicated in several critical biological processes such as DNA replication, bone turnover, iron transport, and the generation of reactive oxygen species (ROS). − Among the metallohydrolases, phosphatases form a subgroup that catalyzes the hydrolysis of a range of phosphoester bonds. − In general, there are three types of phosphoester bonds (i.e., mono-, di-, and triesters) that are hydrolyzed by specialized enzymes known as phosphomono-, phosphodi-, and phosphotriesterases, respectively. GpdQ exhibits extensive substrate promiscuity, while diesters such as glycerol-3-phosphoethanolamine (GPE) are its preferred and biologically most relevant substrates. , This enzyme also hydrolyzes a range of non-natural phosphomono-, phosphodi-, and phosphotriester substrates such as 4-nitrophenyl phosphate (NPP), bis(4-nitrophenyl) phosphate (BNPP), and diethyl 4-nitrophenylphosphate (paraoxon) over a large pH range (Figure a). ,,− Since the substrates of this enzyme include several organophosphate pesticides and nerve agents such as paraoxon, demeton, sarin, soman, and VX, it has considerable potential in agricultural remediation and as an antiwarfare agent. − …”

Section: Introductionmentioning

confidence: 99%

Effect of Chemically Distinct Substrates on the Mechanism and Reactivity of a Highly Promiscuous Metallohydrolase

Sharma

Jayasinghe‐Arachchige

et al. 2020

ACS Catal.

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In this DFT study, the substrate promiscuity of the binuclear [Fe(II)-Zn(II)] core containing glycerophosphodiesterase (GpdQ) from Enterobacter aerogenes has been investigated through the hydrolysis of three chemically diverse groups of substrates: i.e., phosphomono-, phosphodi-, and phosphotriesters. The hydrolysis of these substrates is studied by comparing stepwise, concerted, and substrate-assisted mechanisms. Both the stepwise and concerted mechanisms occur with similar barriers, while the energetics for the substrate-assisted mechanism are significantly less favorable. Irrespective of the mechanism, active site residue His217 plays a critical role, in agreement with structural, kinetics, and spectroscopic data, but the transition state of the reaction depends on the identity of the substrate (dissociative for the triester paraoxon, associative for the monoester 4-nitrophenyl phosphate (NPP), and in-between for the diesters glycerol-3-phosphoethanolamine (GPE) and bis(4-nitrophenyl)phosphate (BNPP)). In good agreement with available kinetic and spectrophotometric data, the calculations highlight the preference of GpdQ for diester substrates, followed by tri- and monoesters. For substrates with two different types of scissile bonds (paraoxon and GPE) a clear preference for the bond with the stronger electron withdrawing leaving group was observed. The extensive agreement between experimental data and DFT calculations enhances the understanding of the mechanism of GpdQ-catalyzed hydrolysis and paves the way for the rational design of optimized catalysts for the hydrolysis of different types of phosphoesters.

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“…[2] Obwohl die physiologische Funktion dieser Enzyme nicht genau bekannt ist, vermutet man eine Rolle als intrazelluläre Monophosphatasen [43,45] und auch eine Beteiligung im Eisenmetabolismus von Säugetieren. [46] Die aktive, reduzierte Fe(II)/Fe(III)-Form der Säugetier-PAP konnte bisher aufgrund der Labilität des Fe 2+ nicht röntgenographisch charakterisiert werden, jedoch die PAP der Weißen Bohne (kbPAP). [47,48] Diese enthält ein Fe(III) und ein Zn(II) in ihrem dimetallischen aktiven Zentrum.…”

Section: Violette Saure Phosphatasen (Pap)unclassified

Zweikernige Zinkkomplexe als Modellverbindungen für Hydrolasen

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Transfer of iron from uteroferrin (purple acid phosphatase) to transferrin related to acid phosphatase activity.

Cited by 48 publications

References 23 publications

Formation of Catalytically Active Binuclear Center of Glycerophosphodiesterase: A Molecular Dynamics Study

Formation of Catalytically Active Binuclear Center of Glycerophosphodiesterase: A Molecular Dynamics Study

Effect of Chemically Distinct Substrates on the Mechanism and Reactivity of a Highly Promiscuous Metallohydrolase

Zweikernige Zinkkomplexe als Modellverbindungen für Hydrolasen

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