T<scp>he</scp> B<scp>iochemistry and</scp> P<scp>hysiology of</scp> M<scp>etallic</scp> F<scp>luoride:</scp> A<scp>ction,</scp> M<scp>echanism, and</scp> I<scp>mplications</scp>

Li, Liang

doi:10.1177/154411130301400204

Cited by 117 publications

(79 citation statements)

References 142 publications

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“…Fluoride inhibition of certain enzymes has been linked to its mammalian toxicity and to its therapeutic action in dental health. The growth of Treponema, Actinomyces, Fusobacterium, and Bacteroides species is inhibited by millimolar concentrations of fluoride and this has been linked to fluoride inhibition of acid and alkaline phosphatases (30). The proton translocating enzyme F o ATPases of oral bacteria are also inhibited by fluoride at millimolar concentration (31).…”

Section: Discussionmentioning

confidence: 99%

A Trojan horse transition state analogue generated by MgF ₃ ⁻ formation in an enzyme active site

Baxter

Olguín

Goličnik

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

113

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Identifying how enzymes stabilize high-energy species along the reaction pathway is central to explaining their enormous rate acceleration. ␤-Phosphoglucomutase catalyses the isomerization of ␤-glucose-1-phosphate to ␤-glucose-6-phosphate and appeared to be unique in its ability to stabilize a high-energy pentacoordinate phosphorane intermediate sufficiently to be directly observable in the enzyme active site. Using 19 F-NMR and kinetic analysis, we report that the complex that forms is not the postulated high-energy reaction intermediate, but a deceptively similar transition state analogue in which MgF 3 ؊ mimics the transferring PO 3 ؊ moiety. Here we present a detailed characterization of the metal ion-fluoride complex bound to the enzyme active site in solution, which reveals the molecular mechanism for fluoride inhibition of ␤-phosphoglucomutase. This NMR methodology has a general application in identifying specific interactions between fluoride complexes and proteins and resolving structural assignments that are indistinguishable by x-ray crystallography.enzyme mechanism ͉ fluoride inhibition ͉ NMR structure ͉ phosphoryl transfer ͉ isosteric isoelectronic ͉ transition state analogue P hosphate transfer reactions play a central role in metabolism, regulation, energy housekeeping and signaling (1). As phosphate esters are kinetically extremely stable, efficient catalysis is crucial for the control of these cellular processes. Although model studies have taught us much about the intrinsic chemical mechanisms (2), our understanding of the origins of the enormous enzymatic rate accelerations involved, up to a factor of 10 21 (3), is far from complete (4). A snapshot of an enzyme in a high-energy state would be immensely useful, as it would allow the very interactions that bring about catalysis to be observed (5). However, is this realistic given how elusive high-energy intermediates and transition states (TSs) inevitably are? The direct observation of TSs for simple organic reactions has required ultrafast lasers with femtosecond resolution (6) and no physical or spectroscopic method is available to observe the structure of TSs of enzymatic reactions directly. Thus transition state analogues that bind tightly in an enzyme active site have been of paramount importance in defining the structural and energetic framework for catalysis (7,8).An observation that appears to challenge this paradigm arises from structural studies with ␤-phosphoglucomutase (␤-PGM, EC 5.4.2.6): namely, that a high-energy phosphorane on the reaction pathway has been observed directly by x-ray crystallography, demonstrating how the enzyme interacts with a very high-energy, metastable species (9). The latter also apparently demonstrated that the enzyme catalyzed reaction proceeds through an addition-elimination mechanism, a reaction pathway not observed in solution for phosphate monoester anions. However, the observation of an enzyme "caught in the act" is surprising: the demands of turnover mean that the enzyme would gain no apparent advant...

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Section: Discussionmentioning

confidence: 99%

A Trojan horse transition state analogue generated by MgF ₃ ⁻ formation in an enzyme active site

Baxter

Olguín

Goličnik

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

113

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“…Aluminium fluoride (AlF x - ) acts as a transition stage phosphate analog also capable of inhibiting several phosphatases [38]. AlF x - forms spontaneously in aqueous solutions in the presence of aluminium (Al 3+ ) and fluoride ions.…”

Section: Resultsmentioning

confidence: 99%

“…This proposal is supported by the finding that the Al 3+ chelator DFOM failed to reverse AlF x - -evoked response, if added only after pretreatment of brain sections with AlF x - (and NaF). AlF x - is known to mimic the chemical structure of phosphate and therefore affects the activity of several phosphoryl transfer enzymes [38]. As a phosphate analog, AlF x - might bind to the P i recognizing binding pocket of the LPPs and by this mechanism lead to irreversible inhibition.…”

Section: Discussionmentioning

confidence: 99%

Lipid phosphate phosphatase inhibitors locally amplify lysophosphatidic acid LPA1 receptor signalling in rat brain cryosections without affecting global LPA degradation

et al. 2012

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BackgroundLysophosphatidic acid (LPA) is a signalling phospholipid with multiple biological functions, mainly mediated through specific G protein-coupled receptors. Aberrant LPA signalling is being increasingly implicated in the pathology of common human diseases, such as arteriosclerosis and cancer. The lifetime of the signalling pool of LPA is controlled by the equilibrium between synthesizing and degradative enzymatic activity. In the current study, we have characterized these enzymatic pathways in rat brain by pharmacologically manipulating the enzymatic machinery required for LPA degradation.ResultsIn rat brain cryosections, the lifetime of bioactive LPA was found to be controlled by Mg2+-independent, N-ethylmaleimide-insensitive phosphatase activity, attributed to lipid phosphate phosphatases (LPPs). Pharmacological inhibition of this LPP activity amplified LPA1 receptor signalling, as revealed using functional autoradiography. Although two LPP inhibitors, sodium orthovanadate and propranolol, locally amplified receptor responses, they did not affect global brain LPA phosphatase activity (also attributed to Mg2+-independent, N-ethylmaleimide-insensitive phosphatases), as confirmed by Pi determination and by LC/MS/MS. Interestingly, the phosphate analog, aluminium fluoride (AlFx-) not only irreversibly inhibited LPP activity thereby potentiating LPA1 receptor responses, but also totally prevented LPA degradation, however this latter effect was not essential in order to observe AlFx--dependent potentiation of receptor signalling.ConclusionsWe conclude that vanadate- and propranolol-sensitive LPP activity locally guards the signalling pool of LPA whereas the majority of brain LPA phosphatase activity is attributed to LPP-like enzymatic activity which, like LPP activity, is sensitive to AlFx- but resistant to the LPP inhibitors, vanadate and propranolol.

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“…The occurrence of only 21.35 % of free F − anions and 60.40 % of AlF 2 + complex was reported at pH6 (Jackson et al 2002). The AlF 2 + and AlF 3 complexes were identified as the main species at pH4 (Li 2003).…”

Section: Introductionmentioning

confidence: 97%

“…Acidity of the solution strongly affects the form and stability of various Al-F complexes (Corbillon et al 2008;Jackson et al 2002;Li 2003). In general, an increase in pH facilitates the dissociation of the complex species occurring at pH≤7.…”

Section: Introductionmentioning

confidence: 99%

Analytical Problems with the Evaluation of Human Exposure to Fluorides from Tea Products

Janiszewska

Balcerzak

2012

Food Anal. Methods

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Tea (Camellia sinensis) is a plant exhibiting high tendency for accumulation of fluorides. Up to 98 % of fluorides are accumulated in the leaves used for the preparation of widely consumed tea infusions. Fluorides from tea leaves are released into infusions, which make the second after drinking waters important source of fluorine for humans. A narrow margin between acceptable fluoride concentration and health risk requires a reliable examination of a large variety of tea products for fluoride contents. Large differences between the published results obtained by the use of different analytical techniques have stimulated studies on possibilities and limitations of different analytical procedures used for fluoride quantification in tea infusions. The applicability of ion selective electrode (ISE) and ion chromatographic (IC) methods to the determination of fluorides in the presence of aluminium, the element highly accumulated by tea trees affecting the amount of free fluoride ions occurring in tea infusions, was examined. The efficiency of different total ionic strength adjusting buffer (MES with citrates or tartrates and citrate) for the elimination of aluminium interference with fluoride detection by ISE method was compared. The applicability of three different chromatographic columns, Metrosep A Supp 4 and Metrosep A Supp 5 (both from Metrohm) and IonPac AS9-HC from Dionex, to the isolation of free fluoride signals from the signals of interfering species, including acetates and formates, which can occur in tea samples, were examined. The contents of fluoride in various tea commercial products evaluated by ISE and IC methods applied are compared.

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The Biochemistry and Physiology of Metallic Fluoride: Action, Mechanism, and Implications

Abstract: Fluoride is a well-known G protein activator. Activation of heterotrimeric GTP-binding proteins by fluoride requires trace amounts of Al 3+ or Be 2+ ions.

Cited by 117 publications

References 142 publications

A Trojan horse transition state analogue generated by MgF ₃ ⁻ formation in an enzyme active site

A Trojan horse transition state analogue generated by MgF ₃ ⁻ formation in an enzyme active site

Lipid phosphate phosphatase inhibitors locally amplify lysophosphatidic acid LPA1 receptor signalling in rat brain cryosections without affecting global LPA degradation

Analytical Problems with the Evaluation of Human Exposure to Fluorides from Tea Products

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The Biochemistry and Physiology of Metallic Fluoride: Action, Mechanism, and Implications

Abstract: Fluoride is a well-known G protein activator. Activation of heterotrimeric GTP-binding proteins by fluoride requires trace amounts of Al 3+ or Be 2+ ions.

Cited by 117 publications

References 142 publications

A Trojan horse transition state analogue generated by MgF 3 − formation in an enzyme active site

A Trojan horse transition state analogue generated by MgF 3 − formation in an enzyme active site

Lipid phosphate phosphatase inhibitors locally amplify lysophosphatidic acid LPA1 receptor signalling in rat brain cryosections without affecting global LPA degradation

Analytical Problems with the Evaluation of Human Exposure to Fluorides from Tea Products

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A Trojan horse transition state analogue generated by MgF ₃ ⁻ formation in an enzyme active site

A Trojan horse transition state analogue generated by MgF ₃ ⁻ formation in an enzyme active site