Structural studies of human alkaline phosphatase in complex with strontium: Implication for its secondary effect in bones

Llinas, P.; Masella, Michel; Stigbrand, Torgny; Ménèz, Andre; Stura, E.A.; Du, M.H. Le

doi:10.1110/ps.062123806

Cited by 27 publications

(20 citation statements)

References 65 publications

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“…performed structural studies of human alkaline phosphatase using the TCPEp (topological and classical polarization effects for proteins) force field [321]. The enzyme possesses 4 metal binding sites, two for Zn 2+ , one for Mg 2+ and one Ca 2+ .…”

Section: Application Of Polarizable Force Fieldsmentioning

confidence: 99%

Molecular modeling and dynamics studies with explicit inclusion of electronic polarizability: theory and applications

2009

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A current emphasis in empirical force fields is on the development of potential functions that explicitly treat electronic polarizability. In the present article, the commonly used methodologies for modelling electronic polarization are presented along with an overview of selected application studies. Models presented include induced point-dipoles, classical Drude oscillators, and fluctuating charge methods. The theoretical background of each method is followed by an introduction to extended Langrangian integrators required for computationally tractable molecular dynamics simulations using polarizable force fields. The remainder of the review focuses on application studies using these methods. Emphasis is placed on water models, for which numerous examples exist, with a more thorough discussion presented on the recently published models associated with the Drudebased CHARMM and the AMOEBA force fields. The utility of polarizable models for the study of ion solvation is then presented followed by an overview of studies of small molecules (e.g. CCl 4 , alkanes, etc) and macromolecule (proteins, nucleic acids and lipid bilayers) application studies. The review is written with the goal of providing a general overview of the current status of the field and to facilitate future application and developments.

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Section: Application Of Polarizable Force Fieldsmentioning

confidence: 99%

Molecular modeling and dynamics studies with explicit inclusion of electronic polarizability: theory and applications

2009

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“…Several X-ray crystallographic structures of ALP are known including ALP from Escherichia coli [protein data bank (pdb) codes 3dyc and 2g9y] [24,25], Antarctic bacterium TAB5 (pdb code 2iuc) [26], and human PLAP (pdb codes 1ew2, 1zeb, 1zed, 1zef, and 2glq) [27][28][29]. Mammalian ALPs differ from those of E. coli by their allosteric mechanisms and inhibition by L-amino acids such as L-Phe, L-Trp, L-homoarginine, L-Leu, and levamisole via an uncompetitive mechanism [30][31][32].…”

Section: Structurementioning

confidence: 99%

“…PLAP comprises 484 amino acids and consists of a central β-sheet surrounded by α-helices, as shown in Figure 4.2a [27][28][29]. Notably, the catalytic site consisting of Ser92 requires two Zn 2+ and one Mg 2+ [16,28].…”

Section: Structurementioning

confidence: 99%

“…Importantly, it is these three regions that confer specificity for macromolecular substrate to the different forms of human ALP. Cation metal binding sites M1 and M2 coordinate to Zn 2+ , M3 prefers to coordinate to Mg 2+ , and M4 coordinates to Ca 2+ [16,[27][28][29]. Cation metal binding sites M1 and M2 coordinate to Zn 2+ , M3 prefers to coordinate to Mg 2+ , and M4 coordinates to Ca 2+ [16,[27][28][29].…”

Section: Structurementioning

confidence: 99%

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4. Alkaline phosphatase

Schmidt¹

2014

Diagnostic Enzymology

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A 35-year-old male presents to his primary care physician with complaints of fatigue, pruritus, abdominal pain, fevers, weight loss, and intermittent jaundice. Over the past 6 months he has lost 10 kg and his pruritus has been getting increasingly worse. He denies shortness of breath and his appetite has not changed. He has had some diarrhea that is occasionally associated with blood. He has not had any changes in his vision or hearing. He has never smoked and only drinks 2-3 beers on the weekends. He has never used illicit drugs and is married with one child. His father, paternal grandmother, and sister all have ulcerative colitis.Physical examination shows a thin male with scleral icterus and pale mucus membranes. His vital signs are normal, but he has a systolic ejection murmur. He has hepatomegaly with the edge of the liver being 5 cm below the costal margin. Upon examining his skin, excoriations are seen on his arms, legs, chest, and back.Laboratory tests performed on blood collected at his office visit show: hemoglobin 91 g/L, hematocrit 27%, white blood cell count 9.8 ×

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“…Alkaline phosphatases are dimeric metalloenzymes that catalyze the dephosphorylation of phosphate monoesters to inorganic phosphate and an alcohol [1,2]. The active sites of APases are generally highly conserved among species, e.g., Escherichia coli [2], shrimp [3], and human placenta [4].…”

Section: Introductionmentioning

confidence: 99%

Alkaline phosphatase inhibition by vanadyl-β-diketone complexes: electron density effects

Ziegler

Florián

Ballícora

et al. 2008

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of systematically modified vanadyl-b-diketone complexes, VO(b-diketone) 2 , bearing substituent groups with different electron inductive properties were synthesized and evaluated as inhibitors against calf-intestine alkaline phosphatase (APase). A combination of biochemical and quantum mechanical techniques were employed to identify structure-activity relationships relevant for rational design of phosphatase inhibitors. Kinetic parameters and activation free energy, enthalpy, and entropy for calf-intestine APase-catalyzed dephosphorylation of para-nitrophenylphosphate were also determined along with the inhibition constants (K i ) for the VO(b-diketone) 2 complexes. Increased positive charge on the vanadyl group increases the inhibition potency of the complex while the absence of an available coordination site on the complex decreases its inhibition potency. These findings correlate well with the results of ab initio electron density calculations for the complexes.

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Structural studies of human alkaline phosphatase in complex with strontium: Implication for its secondary effect in bones

Cited by 27 publications

References 65 publications

Molecular modeling and dynamics studies with explicit inclusion of electronic polarizability: theory and applications

Molecular modeling and dynamics studies with explicit inclusion of electronic polarizability: theory and applications

4. Alkaline phosphatase

Alkaline phosphatase inhibition by vanadyl-β-diketone complexes: electron density effects

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