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THE BIOCHEMISTRY AND PHYSIOLOGY OF METALLIC FLUORIDE: ACTION, MECHANISM, AND IMPLICATIONS

Faculty of Dentistry, University of Manitoba, 780 Bannatyne Avenue, Winnipeg R3E 0W2 , MB, Canada; umlil{at}cc.umanitoba.ca

View larger version (18K): [in this window] [in a new window]   Figure 1. A section of the Periodic Table. For the elements related to phosphate or its analogs, their symbols, atomic numbers, oxidation states, and electron configurations are highlighted.

View larger version (16K): [in this window] [in a new window]   Figure 2. (A) Structural similarities among AlF4-, BeF3(OH2)-, and phosphate group. All three compounds exhibit tetrahedral geometry. BeF3- has an electron-deficient beryllium atom. Be completes an octet by accepting a pair of electrons from a water molecule. (B) The originally proposed -phosphate model for AlF4- and BeF3- activation of heterotrimeric G proteins. AlF4- and BeF3- bind with GDP and mimic the -phosphate of GTP. Notice that, to mimic the ground state of -phosphate, AlF4- has to lose one F-. Compare this theoretical model with the revealed transitional geometry of AlF4- in Fig. 3A (derived from Bigay et al., 1987). Reprinted with permission from Oxford University Press and The European Molecular Biology Organization.

View larger version (13K): [in this window] [in a new window]   Figure 3. (A) Schematic illustration based on the crystal structure of Gi1•GDP•AlF4-, the coordination sphere, and contact distances (Å) of AlF4- with active site residues, β-phosphate and magnesium. Notice that, in contrast to the tetrahedral geometry of a ground state phosphate, AlF4- forms a square planar complex that is octahedrally coordinated to a β-phosphate oxygen and to a putative water molecule as the trans-axial ligands. (B) Model of the active site of Gi1 at the transition state in the phosphohydrolysis reaction. Notice the true trigonal bipyramidal geometry of the -phosphate at its transition state (derived from Coleman et al., 1994). Reprinted with permission from the journal Science and The American Association for the Advancement of Science.

View larger version (20K): [in this window] [in a new window]   Figure 4. Schematic illustration based on the crystal structure of Ras•GDP•AlF3•GAP. The important elements of catalysis and their interaction with AlF3 (-phosphate) at the transition state are shown. Aluminum fluoride forms a trigonal bipyramidal complex. RasGAP stabilizes the transition state by supplying the critical arginine (Arg 789) in trans to neutralize the developing charges. In heterotrimeric G protein, such a critical arginine (Arg 178 in Gi1) is supplied in cis from the Gi1 itself (see Fig. 3A) (adapted from Scheffzek et al., 1997). Reprinted with permission from the journal Science and The American Association for the Advancement of Science.

View larger version (29K): [in this window] [in a new window]   Figure 5. Speciation of Al-F complexes in aqueous solution. Mole fraction of total Al(lll) vs. pF.pF = - log[F-], where [F-] is the ambient fluoride molar concentration. F complexes with Al were measured at two pH values, dashed curves for pH 4 and solid curves for pH 7.5. Symbols on curves designate the number of fluoride groups (F) or hydroxy groups (h) bound to Al(lll). Thus, h4 represents Al(OH)4-; F4 represents AlF4-; and hF3 represents (OH)AlF3- (adapted from Martin, 1994). Reprinted with permission from Elsevier Science.

View larger version (14K): [in this window] [in a new window]   Figure 6. G protein hypothesis in bone cells. In osteoblast-like cells, fluoride forms a complex with aluminum (AlFx), which interacts with GDP to form a GTP-like molecule. Activation of the Gi protein stimulates the tyrosine phosphorylation of signaling proteins by an unknown protein tyrosine kinase (PTK), such as the recently identified Pyk2. Activation of the MAPK pathway through the Ras pathway leads to enhanced cell proliferation (adapted from Caverzasio et al., 1998). Reprinted with permission from Elsevier Science.

Critical Reviews in Oral Biology & Medicine, Vol. 14, No. 2, 100-114 (2003)
DOI: 10.1177/154411130301400204


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