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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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September 6, 2013

Making the Bacteria Make Your Fluorinated Compounds

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Posted by Derek

Acetate is used in vivo as a starting material for all sorts of ridiculously complex natural products. So here's a neat idea: why not hijack those pathways with fluoroacetate and make fluorinated things that no one's ever seen before? That's the subject of this new paper in Science, from Michelle Chang's lab at Berkeley.

There's the complication that fluoroacetate is a well-known cellular poison, so this is going to be synthetic biology all the way. (It gets processed all the way to fluorocitrate, which is a tight enough inhibitor of aconitase to bring the whole citric acid cycle to a shuddering halt, and that's enough to do the same thing to you). There a Streptomyces species that has been found to use fluoroacetate without dying (just barely), but honestly, I think that's about it for organofluorine biology.
The paper represents a lot of painstaking work. Finding enzymes (and enzyme variants) that look like they can handle the fluorinated intermediates, expressing and purifying them, and getting them to work together ex vivo are all significant challenges. They eventually worked their way up to 6-deoxyerythronolide B synthase (DEBS), which is a natural goal since it's been the target of so much deliberate re-engineering over the years. And they've managed to produce compounds like the ones shown, which I hope are the tip of a larger fluorinated iceberg.

It turns out that you can even get away with doing this in living engineered bacteria, as long as you feed them fluoromalonate (a bit further down the chain) instead of fluoroacetate. This makes me wonder about other classes of natural products as well. Has anyone ever tried to see if terpenoids can be produced in this way? Some sort of fluorinated starting material in the mevalonate pathway, maybe? Very interesting stuff. . .

Comments (19) + TrackBacks (0) | Category: Chemical Biology | Chemical News | Natural Products


1. milkshake on September 6, 2013 10:37 AM writes...

there several genera of plants (hundreds of species), native to Australia and Africa that produce fluoroacetate as a toxin, enough to be highly lethal to mammals. I suppose these plants must have a decent tolerance to fluoroacetate. So why not use plant tissue cultures, or even whole plants?

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2. HTSguy on September 6, 2013 11:28 AM writes...

Or, for those who prefer handling bacteria, move the plant's resistant aconitase (if that's the mechanism of tolerance) over to the bugs.

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3. Oldnuke on September 6, 2013 11:56 AM writes...

And let's just substitute hydrofluoric acid for water in the culture media ... er, just where did that petri dish go? gr

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4. AHarsanyi on September 6, 2013 11:57 AM writes...

It is nice to see synthetic biology finding use for these fluorinated building blocks and as a fluorine chemist, I hope that this is a new area where fluorine can make an impact!

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5. annon on September 6, 2013 12:11 PM writes...

Interesting. Reminds me of a situation from a few years ago with a compound that had the potential for metabolic formation of fluoroacetate. During single dose PK evaluation of the compound in the dog, one animal spontaneously died; however, this was not shared with the team immediately, and came out upon later considerations Then, in rodent acute tox screen, several animals died without any previous symptoms, due to something that looked like acute heart failure.

The team was alerted to the possible formation of fluoroacetate as a known toxin that clogs-up the Krebs cycle with particular sensitivity in dogs & use as a coyote poison and to control dingos in Australia. The clinical physician did not want to stop efforts with the compound in favor of a backup, not wanting to believe the inherent metabolic problem. So, urine was collected in rats administered the compound, and the urine, neat, was evaluated by F-NMR therein showing peaks corresponding to three oxidation states for the acid (fluoroacetate), aldehyde and alcohol (fluoro-ethanol).

With this demonstration, the compound was finally buried into a deep hole!

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6. Chemjobber on September 6, 2013 12:39 PM writes...

@5: Wasn't there a JMedChem about such a problem a couple of years ago...?

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7. SP on September 6, 2013 1:06 PM writes...

You just need to evolve the targets that are inhibited by F (and consequently lethal) into mutants that can tolerate your modified inputs.

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8. Anonymous on September 6, 2013 1:17 PM writes...

@7: It would be difficult for any mutant enzyme to create F+ instead of H+ as a leaving group!

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9. Hap on September 6, 2013 2:14 PM writes...

It's in Chemjobber's Toxic Carnival post (Cox et al., J. Med. Chem. 2008, 51, 4239-4252).

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10. annon on September 6, 2013 3:20 PM writes...

#6 & 9:

This is certainly an interesting example, but not the one that I had experience with. Don't think it has been published.

An ironic side-story of our example was that the senior med chemist on the project did not agree with the interpretation of the F-NMR. It was obvious he was applying expectations from proton spectra, and that he had no experience with fluorine shifts & splitting relative to proton.

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11. annon on September 6, 2013 3:20 PM writes...

#6 & 9:

This is certainly an interesting example, but not the one that I had experience with. Don't think it has been published.

An ironic side-story of our example was that the senior med chemist on the project did not agree with the interpretation of the F-NMR. It was obvious he was applying expectations from proton spectra, and that he had no experience with fluorine shifts & splitting relative to proton.

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12. Hap on September 6, 2013 3:33 PM writes...

I wasn't assuming the article was the story you were referring to, just the one CJ referred to.

I never used it in lab, but 19F (and sometimes 31P) have long-range couplings in aromatic rings which can make peaks and isomers easier to assign (or possible). Trying to determine the regioisomer of a dimethylphenylphosphine wouldn't have been great with just 1H but the coupling constants with P that showed up in the NMR made the isomers distinguishable.

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13. D2o on September 7, 2013 9:47 AM writes...

This is not as dramatic but has Anyone ever tried to feed deuterated acetate/propionate to actinomycetes and gotten out per deuterated erythromycin? Surely Concert has thought of this

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14. gippgig on September 8, 2013 2:34 AM writes...

Not a polyketide, but look at nucleocidin.

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15. Harry on September 8, 2013 9:28 AM writes...

The place I used to work made a variety of fluoroacetates. Sodium Fluoroacetate went mostly to Australia and New Zealand for rabbit control. We also made Fluoroacetamide for a private-label rodenticide that went to a couple of the Gulf States (Quatar and Dubai). We also made small quantities of Fluoroacetic Acid. Our biggest product (and the precursor for the others) was Ethyl Fluoroacetate, which was used in the production of 5-Fluorouracil.

Eventually a more economical process was developed for making the 5-FU and the business dropped off dramatically.

The stuff is crazily toxic to canines, which is why it was such a good coyote poison.

One of my jobs for a while was packing the SFA into one lb cans for shipment. A normal order was around 100-200 lb. While we never had any poisoning episodes, I was always very edgy while handling the stuff, and constantly checked my PPE.

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16. gippgig on September 8, 2013 1:10 PM writes...

Anyone try 3-fluoro, difluoro, or trifluoropropionate?

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17. Nick K on September 8, 2013 9:30 PM writes...

I read somewhere that the Finnish Army poisoned wells in Karelia with sodium fluoroacetate during the Winter War with the Soviet Union (1939-40) to prevent their use by the invaders. Can anyone confirm this?

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18. sepisp on September 9, 2013 3:37 AM writes...

#17: I can't definitively deny it, but I have never heard of it. First, if it actually had happened, the Soviets would've never shut up about it. Second, the problem here is that the area was rather soon occupied again by Finnish returnees in the Continuation War. Cleaning the wells was one of the first things to do, and if that would've required any special equipment to remove the fluoroacetate, there would be records of it. Third, the Finnish Army did not retreat under fire. The decision to withdraw was done by politicians at a higher level, in peace negotiations. (Defense capacity was close to running out, but had not yet actually run out.) It seems unlikely that poisoning the wells would help with getting favorable peace terms.

To me it looks like a textbook example of Soviet propaganda. It's a bald-faced lie, the more blatant, the better.

Alternatively, there were fears that the Soviets would've poisoned the wells, but they were unfounded.

In the Continuation War, the army found four wells that were poisoned by the Soviets, but that was with mercury(I) chloride and arsenic. There were also isolated incidents of Soviet commanders using poison gases against orders from higher-ups. See‎

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19. Anonymous on September 9, 2013 3:45 AM writes...

@17,18: A quick Google search didn't reveal anything relevant, so not sure where that story comes from...

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