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It’s been interesting to watch as microbiology’s own cold fusion debate has been raging. It began with an extraordinary claim about bacteria using arsenate as a replacement when phosphate concentrations are low (1). 

It progressed when at least two scientist / bloggers ( here, and here) (not bloggers! the horrror! how uncivil!) gave public “journal club” presentations on blogs (envision dripping slime).

It continued with the science journalists lamenting about having swallowed the hype.

And it seemingly ended with another scientist / blogger’s post that seemed to equate discussions of  scientific technique in the public eye with airing a family’s dirty laundry. One doesn’t discuss this this in public, you know. It just isn’t done.  It isn’t civil.

ResearchBlogging.orgCoupled to the arsenic debate is our very own tribal mythology of scientists who turned out to be right despite overwhelming skepticism (Peter Mitchell and the chemiosmotic hypothesis, Stanley Pruisner and prions, Ken Stuart and RNA editing, to name a few).  Even the New York Times had to jump in and join the fun.

I wondered if it wouldn’t be fun to “put my experiment where my” blog is and see what sorts of arsenic-based treasures I could find, without of course, ever leaving my computer.

My question was this: What arsenic-containing structures have already been shown to exist?

Without further ado, here are some lovely structures that I found that that do contain arsenic.

i-6dd4107ef76a4ef33230855becba547a-arsenic_DNA.pngFigure 1.  Arsenic and DNA.  Image by S. Porter.

The structure below was made by researchers seeking to understand how bacteria like E. coli  detoxify substances like arsenic (2). Many bacteria have systems to protect themselves from heavy metals like arsenic.  In E.coli, genes for arsenic resistance are turned on when arsenic enters the bacterium and binds to the ArsR protein. ArsR is a repressor protein that binds to DNA when arsenic isn’t around.  When arsenic appears, ArsR binds to the arsenic and releases the DNA.  Genes in the DNA are transcribed, leading to the production of proteins that pump arsenic of the cell and an enzyme is produced, arsenate reductase, that reduces arsenate to arsenite.

Figure 2 shows a synthetic protein that was designed to bind arsenic in a manner that would be similar to arsenic-binding proteins in E. coli.  The arsenic is bound to three cysteines in the center of the three coils.  I admit this structure doesn’t really address the debate. I just liked the image.

i-570a2023ddc40968ccf4ff7b1cd70aa7-arsenic_protein.png

Figure 2. Arsenic and synthetic peptides.  Image by S. Porter.

The next structure (Fig.3) shows a case where arsenate is replacing the third phosphate in a synthetic analogue of ATP (3).  The molecule in this structure isn’t a naturally occurring compound; it was synthesized in a lab, but the existence of this kind of analogue does show us that it is possible for an arsenate to substitute for a phosphate, at least in this one case.
  

i-2b677858a90ed16a1393c5f46baf52fe-arsenic_ATP.pngFigure 3. Arsenic and ATP.  Image by S. Porter.

The last image is from a DNA quadruplex structure (4).  This image shows two arsenic molecules bound to DNA.  This image demonstrates that arsenic can stick to DNA and supports RR’s suggestion that washing the DNA pellets in the NASA experiment might have washed off any bound arsenic.

i-59c9cac84cd36b0e9011e419c74586cf-arsenic_DNA_quadraplex.png

Figure 4. Arsenic and DNA.  Image by S. Porter.

What can we conclude? 

Arsenic can replace a phosphate in an analogue of ATP.  However, arsenic can also bind in a non-covalent manner to DNA.  This means we need more experiments to really know the answer and they need to rule out the possibility of the arsenic just being stuck.

References:

1.  Wolfe-Simon, F., Blum, J., Kulp, T., Gordon, G., Hoeft, S., Pett-Ridge, J., Stolz, J., Webb, S., Weber, P., Davies, P., Anbar, A., & Oremland, R. (2010). A Bacterium That Can Grow by Using Arsenic Instead of Phosphorus Science DOI: 10.1126/science.1197258

2.  Touw, D., Nordman, C., Stuckey, J., & Pecoraro, V. (2007). Identifying important structural characteristics of arsenic resistance proteins by using designed three-stranded coiled coils Proceedings of the National Academy of Sciences, 104 (29), 11969-11974 DOI: 10.1073/pnas.0701979104

3.  Bystrom, C., Pettigrew, D., Branchaud, B., O’Brien, P., & Remington, S. (1999). Crystal Structures of Glycerol Kinase Variant S58→W in Complex with Nonhydrolyzable ATP Analogues Reveal a Putative Active Conformation of the Enzyme as a Result of Domain Motion  Biochemistry, 38 (12), 3508-3518 DOI: 10.1021/bi982460z

4.  Hazel, P., Parkinson, G., & Neidle, S. (2006). Topology Variation and Loop Structural Homology in Crystal and Simulated Structures of a Bimolecular DNA Quadruplex Journal of the American Chemical Society, 128 (16), 5480-5487 DOI: 10.1021/ja058577

Comments

  1. #1 herp n. derpington
    December 14, 2010

    i really liked this post, it’s a view on the arsenate yell-fest i haven’t yet heard. well done.

  2. #2 Jeffrey Toney
    December 14, 2010

    Nicely done! Your research into existing nucleic acid structures containing arsenic is a welcome addition to the controversial “arsenic-based life form” blogosphere.

    A fellow Sb blogger.
    http://scienceblogs.com/deanscorner/

  3. #3 anonymous
    December 14, 2010

    Also, note that ADP-arsenate is unstable in water. I seem to recall that this explained both the Victorian “diet pill” usage of low doses of arsenate (not one to try at home!) and the increased body temperature of those patients… arsenate gets misincorporated into ADP-arsenate during ox-phos, but the energy is released quickly as heat. Essentially a futile cycle.

  4. #4 Sandra Porter
    December 14, 2010

    Thanks! nice to meet you Jeffrey! Welcome to the group!

  5. #5 Rosie Redfield
    December 14, 2010

    Nice work! Too bad Wolfe-Simon et al. didn’t take the same trouble before they published.

  6. #6 Sandra Porter
    December 14, 2010

    Thanks Rosie!

  7. #7 Andreas Zai
    December 14, 2010

    I’m not a Sb blogger, but I have hypothesized some interesting information on the topic of the arsenic binding to the DNA to create an alternatively DNA based life form. My hypothesis consists of DNA binding with methane rather than arsenic, but it is similar. You seem like a bright lot, and if you could check out my blog at http://sceintec.blogspot.com/ I would be grateful.

  8. #8 Curt F.
    December 14, 2010

    In response to comment #3:

    ADP-arsenate may well be unstable in water. I had the same thought and went to check the referenced paper for the structure of the inhibitor actually used.

    In the As-substituted analog actually used, the bridging group between the beta phosphate and the gamma “arsenate” (which is usually an oxygen in ATP) is replaced with CH2. I don’t know how to name that structure (arsane monoester?) but presumably that assists in its water stability.

  9. #9 Gustavo Helguera
    December 15, 2010

    What would be the effect of pH 9.8-10 of Mono Lake on the stability of the interaction of Arsenic with ADP or other molecules?
    Is the pH inside of the cell alkaline? I have seen somewhere that it can reach above 8 sometimes.

  10. #10 yannis zabetakis
    December 15, 2010

    many thanks for all the valuable info of this post and the great pics!

    keep the flag up!

  11. #11 Gerard Harbison
    December 22, 2010

    The ‘arsenic’ in the quadruplex is just cacodylate from the buffer; it’s a pretty standard ingredient in DNA preps. Probably not relevant to bio-arsenic.

    DNA is a polyanion. it binds cations, and then a secondary layer of anions.

  12. #12 Gerard Harbison
    December 22, 2010

    Interesting question this raises, though. Cacodylate in an EXAFS spectrum would look exactly like the signal described in their Science paper. Not everyone (actually, almost no one) who uses cacodylate knows it contains arsenic. i wonder did they use cacodylate in fixing their EXAFS sample of the bacteria and not realize it was a arsenodiester?

  13. #13 Paul Decelles
    December 23, 2010

    Does arsenic ever have a use in cellular processes as does selenium?

  14. #14 Teo Raab
    December 26, 2010

    Not to add to the As-DNA-extremophile debate endlessly, but may I ask why no attempt was made to do a vodka-extraction of pelleted bugs, half grown on As-media, half without ?!? Certainly the phosphodiester vibrations in the thermal IR occur at different frequencies from arsenodiesters ? Or was this expt tried without decent yield ?

  15. #15 Sandra Porter
    December 31, 2010

    @Paul: I don’t think arsenic plays a role in normal cellular processes, but bacteria certainly make an effort to bind to it and shuttle it out of the cells.

    @Teo: uh, vodka extraction would be fun, but pretty unusual. We typically use ethanol, but buy the reagent grade brand.

    @Gerard: I didn’t really make an effort to determine where the arsenic in the structures came from. It may very well have been the buffer. I just wanted to point out that you can find it sticking to DNA.

  16. #16 Pat Ryan
    January 1, 2011

    I live in the central valley of California. The water here is heavily concentrated with arsenic. I sell Purified Water & Ice with a TDS@4 after my purifying process. My lab reports show zero arsenic. This is a HUGE problem in our area and has been Hidden by BIG GOVT!!! I was just interested in your arsenic work. Theoretically arsenic could be attached to families in our area within their DNA molecules in a way that is to much arsenic. i.e. Cancer rates higher??? get back to me if u interested in this ARSENIC IGNORED AREA

  17. #17 Elliot Emerson
    January 4, 2011

    Sandra, Thanks for pointing out that although our culture reveres the rare scientific heretics who are right, it fails to note the existence of the huge number who are just plain wrong and won’t let any mere data convince them otherwise. I have named the following syllogism “AB’s fallacy” after a full professor who was one of its most dedicated practitioners: “Great scientists are misunderstood. I am misunderstood. Therefore I am a great scientist.”

  18. #18 gangaud
    January 8, 2011

    It appears that evidently scientists at NASA research have been researching a microorganism from Mono Lake in Jap California and have found that they seem to be the one organism on Earth able to develop and and reproduce utilizing the very toxic chemical arsenic. A lot to their shock, as a substitute of feasting on phosphorus as could be the same old case, plainly the little buggers are substituting arsenic within the make-up of their DNA, and that’s a no-no on the planet of earthly life types, the place arsenic will kill you many of the time.For More Info visit here

  19. #19 David Marjanović
    January 8, 2011

    This image demonstrates that arsenic can stick to DNA and supports RR’s suggestion that washing the DNA pellets in the NASA experiment might have washed off any bound arsenic.

    Uh, you mean “might not have washed off all bound arsenic, if any“, right?

    Cancer rates higher???

    Nope. Arsenic does not cause cancer. Its dangers lie elsewhere.

  20. #20 Sandra Porter
    January 8, 2011

    No. I meant what I wrote. It’s common practice when isolating DNA to wash the pellets to remove any bound salts.

    The pellets were NOT washed in the experiment, and arsenic was found.

    If the pellets had been washed, they might not have found any arsenic because it might have been washed off.

  21. #21 M Pagel
    February 18, 2011

    Most/all inorganic As that would be contaminating the DNA from natural sources would be in the As III form, which the uEXAFS seems to have excluded. Gerard’s suggestion seems on the surface plausible though – that’s an As (V) source. In any case, it doesn’t seem to me that all the data matches either a plausible As-DNA solution or the Cacodylic acid model. I expect (I haven’t looked at the structure in a pdb viewer) cacodylic acid would have a shorter As-C bond than their uEXAFS data suggest, as the As is directly bound to C (so the second-listed C distance would be completely out of the ballpark, and even the shorter As to C distance looks suspiciously long). Whereas in DNA, the second As to C distance is perfectly reasonable (about .01 angstrom off the expected value given sp3 O in the middle), but the first one is WAY too short for an oxygen to be intervening. That datapoint indicates to me that the As is “lodged” or in a binding pocket of something (protein? major groove of DNA?) and the interaction with a carbon is not via a neighboring C in primary molecular structure.

    Sorry for the two month late post:P