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Enzymes and Fluorines

It hit me, one day during my graduate career, that I was spending my nights, days, weekends, and holidays trying to make a natural product, while the bacterium that produced the thing in the first place was sitting around in the dirt of a Texas golf course, making the molecule at ambient temperature in water and managing to perform all its other pressing business at the same time. This put me in my place. I’ve respected biosynthesis ever since.
But there are some areas where we humans can still outproduce the small-and-slimies, and one of those is in organofluorine compounds. Fluorine’s a wonderful element to use in medicinal chemistry, since it alters the electronic properties of your molecule without changing its shape (or adding much weight), and the C-F bond is metabolically inert. But those very properties can make fluorination a tricky business. If you can displace a leaving group with fluoride ion to get your compound, then good for you. Too often, though, those charges are the wrong way around, and electrophilic fluorination is the only solution. There are heaps of different ways to do this in the literature, which is a sign to the experienced chemist that there are no general methods to be had. (That’s one of my Laws of the Lab, actually). The reagents needed for these transformations start with a few in the Easily Dealt With category, wind entertainingly through the Rather Unusual, and rapidly pile up over at the Truly Alarming end.
But at least we can get some things to work. The natural products with fluorine in them can be counted on the fingers. A fluorinase enzyme has been isolated which does the biotransformation on 4-fluorothreonine S-adenosyl methionine (using fluoride ion, naturally – if an enzyme is ever discovered that uses electrophilic F-plus as an intermediate, I will stand at attention and salute it). And now comes word that this has been successfully engineered into another bacterial species, and used to produce a fluorine analog of that bacterium’s usual organochlorine natural product.
It isn’t pretty, but it does work. One big problem is that the fluoride ion the enzyme needs is toxic to the rest of the organism, so you can’t push this system too hard. But the interest in this sort of transformation is too high (and the potential stakes too lucrative) to keep it from being obscure forever. Bring on the fluorinating enzymes!

11 comments on “Enzymes and Fluorines”

  1. Curt F. says:

    A fluorinase enzyme has been isolated which does the biotransformation for 4-fluorothreonine (using fluoride ion, naturally – if an enzyme is ever discovered that uses electrophilic F-plus as an intermediate, I will stand at attention and salute it).
    If I understand things correctly, this statement is a bit off. I think the fluorinase enzyme catalyzes the substitution of fluoride for the methionine moiety of S-adenosyl methionine. The resulting fluoro-deoxyadenosine is processed several other enzymes which have unique specificities but which do not mess with the fluoro substituent (http://dx.doi.org/10.1016/j.chembiol.2008.10.012). Eventually fluorothreonine (or other more complex fluorinated products) can be produced, but the substrate for fluorinase itself is S-adenosyl methionine.
    It may seem a minor point, but to those souls who spend their days trying to link up disparate enzymes to create artificial metabolic pathways, its a world of difference.

  2. Bruce Hamilton says:

    “The natural products with fluorine in them can be counted on the fingers.”
    My recollection is that there are about 40, mainly carboxylic acid derivatives ( eg fluoroacetate ), but Gordon Gribble did a really nice, and informative, review of naturally-occuring fluorine compounds several years ago.
    Forty fingers?, that could be a great help in the lab picking up test tubes..

  3. barry says:

    calicheamicin?

  4. P says:

    “The natural products with fluorine in them can be counted on the fingers.”
    On the fingers of a fluorine chemist, no less!

  5. retread says:

    “There are heaps of different ways to do this in the literature, which is a sign to the experienced chemist that there are no general methods to be had. ”
    The same applies in medicine. Anytime you find a disorder with multiple treatments (say over 5) you can bet that none of them are much good. I once tried over 30 recommended treatments for postherpetic neuralgia in one poor lady. None of them worked.
    Skeptics will bring up epilepsy and Parkinsonism, but there are many epilepsies and many anticonvulsants have very similar mechanisms of action in common. In Parkinsonism there are hordes of dopamine agonists.

  6. chiraljones says:

    I’m most intrigued by the “Laws of the Lab.” Can you please pass along the rest of these, “ten commandments” style? And what ranking does “your yields shalt not exceed published yields” come in?

  7. sjb says:

    Some of the infamous Lowe’s Laws can be found at http://pipeline.corante.com/archives/lowes_laws_of_the_lab/

  8. Chiraljones says:

    Wow I’m not all here sometimes…
    Thanks! Also looks like my (least)favorite law is secondmost recent.

  9. Exactly, retread. Considering the prevalence of Type 2 diabetes in the general population, it’s surprising that better than 90% of the patients get either metformin or a sulfonylurea, though the glitizones are starting to make inroads into the market. All the other drug players are on the fringe. It’s because the mainline medications actually work.
    Ditto weight loss. Ditto exercise. All patients who can do these things are told to do them, because they actually work.
    Low-glycemic diet? Most patients get told to do it, becaues it helps some.
    Low-carb diet? High-carb diet? Mediterranean? Atkins? Palm Beach? Though most advocate restricting calories and including lots of soluble fiber (things which work!), the diets recommended for diabetics are all over the map. I’ve concluded this is because none of them is particularly better. I do about 40% calories from carbs myself, on the utterly unscientific theory of moderation in all things.

  10. J says:

    There have been other attempts at enzymatic fluorinations – e.g. http://www.ncbi.nlm.nih.gov/pubmed/19011638.

  11. Dave_n says:

    The very first publication from the ARC’s Unit of Nitrogen Fixation in the UK in the early 1960s was on a fluoroacetate-metabolizing Bacillus if my ancient memory serves me correctly. Fluoroactate was incorporated into Krebs cycle intermediates. Dave_n

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