Fluorine is the smallest and most reactive halogen, a relative of chlorine, bromine, and iodine. Chloride is ubiquitous in salts and in the ionic milieu of our bodies, and iodine has found a central role in metabolism in virtually all species. Even bromine has various biological roles, though mostly in microorganisms. Fluorine, however, has found no role at all, despite being relatively common- more abundant in rocks than chlorine, let alone bromine or iodine. Its only part to play is as a noxious ion to get rid of. And all organisms have ways to get rid of it, via both active and passive trasporters. More on that below.
Humans, in their wisdom, however, have found some remarkable uses for fluorine. Modern chemistry uses it a great deal, to make very tough chemicals like Teflon, Lipitor, and Lexapro. Virtually nothing displaces fluorine from carbon bonds, so its compounds, while very useful, also end up as rather persistent waste products. More interesting, however, is our practice of ingesting fluoride (the ionic form of fluorine) in small amounts for oral health. This has been a subject of tremendous controversy and conspiracy theorizing for decades. But the benefits couldn't be more clear- teeth are much tougher from trace topical exposure to fluorine, which works its way into the crystal structure of enamel.
However, ingesting fluoride is another matter. It is reputed to cause kidney problems at higher concentrations, but there is very little epidemiology to support claims that these risks start at low concentrations.. anywhere near the levels used in drinking water supplementation. Similar to observations of bone deformities and tooth fluorosis, the syndrome of too much fluoride common in geologic regions with excess fluoride, there would have been observations of rampant kidney or other disorders. But that doesn't seem to be the case, other than very sketchy reports. At any rate, the therapeutic dose of fluoride put in water supplies is about 30 micromolar, while the newest regulations in the US establish a conservative cap of about 100 micromolar, in light of the lack of any use for higher concentrations, and the occasional problems from higher natural exposure, top which the artificial amount adds.
So we can't do much with fluorine, biologically speaking. Indeed it is generally toxic, messing with the phosphate chemistry that is central to all life. How do we get rid of it? There are three mechanisms, overall. In animals, our kidneys take care of it, using clever ion transport to excrete excess fluoride. (Recall that the first step of the kidney's work is to remove all the small solutes from blood plasma, and then later to selectively bring back the important things we want, like sugar, some salts, lactate, water, etc. The remainder that is not actively re-absorbed includes such oddities as fluoride.)
But other organisms that live directly in the soup, i.e. microorganisms, all need to take specific and active measures on the cellular level against fluoride. An important point in this chemistry is that fluoride has a significant acid-base preference. HF forms at relatively high pH (pKa of 3.4, much higher than HCl, which stays ionic to pH 1 and below, an oddity of fluoride's chemistry), which means that in moderately acidic environments, external HF can easily form and diffuse into cells as an uncharged entity, and there, under more neutral conditions, dissociate and be trapped as F- ions. This leads to chronic over-loading of cells with F-, (up to 30X over external levels), which can be remedied by a protein channel (second mechanism) that lets these ions back out passively, while not letting out other ions such as the closely related chloride. The third mechanism, exclusively used by bacteria, is active antiport, (H+/F-), using the stored energy of the proton gradient (high outside, low inside) to drive F- excretion.
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| Structure of two copies of E. coli-derived Fluc, a passive fluoride channel/exporter. The proteins are blue and yellow, respectively, the membrane represented by black lines, and the fluoride ions are modeled as gray or red balls. Given the symmetry of the proteins and their passive role, the orientation (up/down) makes no difference. The channel is formed at the interfaces between the two proteins. |
A recent paper described the simple passive transporters that are ubiquitously used for fluoride export in microbes. They are odd in that it takes two proteins to form a functional transporter. The channel through which the F- ion passes is on the surface between the two proteins, in a symmetric structure that forms two channels (above). In eukayotic microbes like yeast cells, two such genes have become fused to form one gene encoding a protein that retains dimeric symmetry, but one of whose channels has become non-functional / vestigial.
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| A close-up view of one of the channels, showing some of the key individual amino acids that coordinate / bind to the fluoride ion as it travels along. This close physical and electrostatic coordination insures that nothing that is not fluorine can get through. Notably, part of the job is done by uncharged phenylalanine residues, (blue and orange ring structures), which are usually regarded as hydrophobic, but have a slight face/edge polarization that can be exploited by strong ions |
The channel is, understandably, very tight, with intensive coordination all along the way, particularly with uncharged phenylalanines which provide an unusual side-ways polar coordination that is proposed to make the channel particularly specific to F-, vs Cl-. And it is very selective- over 10,000-fold selective for F- vs Cl-. Replacing these phenylalanines with the hydrophobic amino acid isoleucine reduces F- transport to negligible levels. It would have been interesting to ask what a less bulky and less hydrophobic replacement like glycine or threonine does to the channel's activity, perhaps making it significantly less selective, while still functional.
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