The New Scientist
February 1985; p. 20
SCIENCE: How Fluoride Might Damage Your Health
New evidence now supports earlier suspicions
that fluoride can damage your health. The anti-fluoride lobby has always
lacked solid evidence of the mechanism by which fluoride could be harmful.
American chemists have now used X-ray analysis to study a fluoridated enzyme,
and a disturbing picture emerges. Fluoride switches off the enzyme by attacking
its weakest links - the delicately-balanced network of hydrogen bonds surrounding
the enzyme's active site.
It has been known for many years that fluoride inhibits enzymes, preventing these natural catalysts carrying out their essential tasks. A new study describing, for the first time, the crystal structure of a fluoride inhibited peroxidase enzyme shows that the fluoride ion attaches itself to the iron atom at the heart of the enzyme and then disrupts the active site by attracting groups that can form strong hydrogen bonds to itself (Journal of Biological Chemistry, 1984, vol 259, p 12984). Ultimately, this inactivates the enzyme by changing its shape, or molecular conformation.
Hydrogen bonds are weak interactions between the hydrogen atom in O-H and N-H chemical bonds, and a second oxygen, nitrogen or fluorine atom. For example they are written O-H --- F- or N-H --- F- where the dotted lines indicate the hydrogen bond. The fluoride ion, is particularly good at forming such bonds because of its small size and negative charge. Hydrogen bonds are weaker than normal chemical bonds but many of them can hold complex systems together in very specific patterns. The best known is the hydrogen bonding that maintains the double helix of DNA. Hydrogen bonds are no less important in enzymes such as the iron-containing cyctochrome C peroxidase.
This yeast enzyme is of the heme type which means that the iron atom at its centre is complexed to a porphyrin in much the same way as haemoglobin. The enzyme catalyses the reaction which disposes of hydrogen peroxide, a dangerous metabolic byproduct, by converting it to water:
H202 + 2H+ + 2e- > 2H20
A lot of evidence has accumulated indicating that a particular histidine group (labelled as His-52) provides the hydrogen ions for this step and a nearby arginine group (Arg-48) is probably important in the electron transfer necessary for the reaction. Both His-52 and Arg-48 are linked to the active site of the enzyme via hydrogen bonds to water molecules (see diagram).
Steven Edwards, Thomas Poulos and Joseph Kraut, of the Department of Chemistry at the University of California in San Diego, prepared a crystal of the fluoride form of cyctochrome C peroxidase and looked at it using X-ray crystallography. The structure of the fluoridated enzyme was compared with that of the ordinary enzyme, so that changes in the active site could be monitored. These changes are small but highly significant (see diagram).
The free enzyme has a delicate network
of hydrogen bonds that is based on water molecules around the active heme
site. One water molecule is directly bonded to the iron atom. This water
is hydrogen bonded to His-52 and to a second water molecule which in turn
is hydrogen bonded to Arg-48. This fine molecular web awaits a peroxide
molecule which it captures and converts to water. How it actually does this
is not certain but the Arg-48 lies near to the surface of the enzyme and
it is this group which is thought to be responsible for guiding the incoming
peroxide to the active site.
In the fluoride-inhibited enzyme the Arg-48 has moved far away from the surface and much closer to the heme site. It is attracted by the presence of the fluoride, which is directly bonded to the iron atom, and which is capable of forming much stronger hydrogen bonds than the water molecule it has displaced. (200 pm closer in the case of Arg-48--quite a big jump in molecular terms.) His-52 has also moved closer to the active site, but this repositioning of Arg-48 now prevents it from doing its job - the fluoride blocks the enzyme. Many enzymes are inhibited by fluoride even when this is present only in parts per million levels. Luckily a healthy individual can easily cope with tiny doses of fluoride from food and drink, and this can strengthen the teeth and bones. But are other parts of our metabolism threatened?
In the current debate on the fluoridation of drinking water it is claimed by those in opposition to fluoride that it causes several maladies ranging from allergies through premature ageing to higher incidences of cancer. The more serious of these claims have recently been officially refuted in the publication Fluoridation of Water and Cancer (HMSO, 1984). And it would be very difficult to prove that fluoride could disrupt DNA in such a way as to make it cancerous. However fluoride might begin the process by interfering with the hydrogen bonding of DNA, as it does to cyctochrome C peroxidase.
The anti-fluoride MPs and their supporters seem to be a defeated political lobby. Suddenly they have been given proof positive of what fluoride does to the hydrogen bonding of one vital component of a living cell. But are they capable of understanding the weapon they have been handed by Edwards, Poulos and Kraut? However, all is not lost for there is one chemist in government who should understand hydrogen bonding and its importance. Let's hope she reads New Scientist.
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