Arsenic

Lakeside of the Mono Lake with Tufa columns in...

Shore of Mono Lake, California; Image via Wikipedia

I’m sure everyone else in BIO230 is as excited as I am over yesterday’s big press conference by NASA.  I saw that today’s XKCD is certainly excited about it!  In case you had your computer off yesterday, or didn’t watch any TV or listen to the radio, here is the gist of the press release. Researchers examining bacteria isolated from Mono Lake, California, found a species that appeared to tolerate tremendous levels of arsenic in their environment. Arsenic is poisonous to all living cells (well, after yesterday, almost all living cells,) and in fact was used successfully by Paul Ehrlich as a form of chemotherapy in the treatment of syphilis. This compound, known as Salvarsan, was the first so-called “magic bullet,” a compound designed to specifically target the pathogen with minimal damage to the host. So what is so exciting about the NASA-funded discovery which came out yesterday?

Arsenic is directly below phosphorus in the periodic table, which means that the chemistry that occurs with phosphorus can also occur with arsenic. However, arsenic is a larger element with an additional electron orbital, so the substitution of arsenic in a molecule will have profound effects on its function. Phosphorus is one of the “Big 6” elements found in all living cells, which also include carbon, hydrogen, oxygen, nitrogen, and sulfur. Of those 6 elements, the macromolecules of life are composed mainly of the first 4, sulfur is almost exclusively found only in proteins. Phosphorus, on the other hand is found mainly in phospholipids and nucleic acids, and in nucleic acids (DNA and RNA,) phosphorus forms the backbone of the nucleic acid molecule. Small molecules such as ATP also have phosphorus as an essential part of the molecule. So if a cell has arsenic present, arsenic can chemically substitute for the phosphorus, but the cell will end up having nucleic acids or lipids which are non-functional.

We’ve learned in this course about organisms that tolerate environments which we would perceive as being inhospitable to life. Thermophiles can grow in boiling water, halophiles can grow in extremely high levels of salt, and acidophiles can grow under pH conditions that would degrade human flesh. Thermophilic bacteria have developed enzymes that are stable at high temperatures, things are different in the case of halophiles and acidophiles. If one carefully examines the cytoplasm of these organisms where the enzymes and other cellular machinery is found, you will find that the cytoplasmic environment of those organisms is actually very close to that found in our cells, and that there enzymes have pH and salt optimal conditions very much like our enzymes. How do they do this? The cells use active transport to maintain a constant internal environment of low salt and neutral pH. This active transport can require a tremendous amount of energy (ATP) to maintain.  So one might very logically assume that if an organism is arsenotolerant (can grow in high levels of arsenic, which is toxic!) that the mechanism for survival might be the same: the organism uses active transport to generate a cytoplasmic environment which is very low in arsenic. WRONG!

Animation of the structure of a section of DNA...

Image via Wikipedia

This is where the story gets really interesting. When researchers isolated this bacterium and grew it in the lab, they grew it in very high levels of arsenic, and found that it was very happy under those conditions. Furthermore, when they examined the DNA of these organism, they found that the DNA contained arsenic in the backbone of the molecule instead of phosphorus. This means that instead of actively trying to maintain a constant low physiological level of arsenic in the cell, these cells say “Bring it on!” and have developed a way to live with it. Although their biochemistry is only poorly understood as of now, in order to incorporate arsenic into DNA, these organisms must have enzymes that can bind to and catalyze reactions with precursors (ATP) that have arsenic in them instead of phosphorus. Also consider this: the structure of the double helix is essential for the transmission of heredity from generation to generation, and also as the template for the formation of messenger RNA in protein synthesis. Enzymes such as DNA polymerase and RNA polymerase must recognize the DNA double helix, bind to it, and catalyze an enzyme reaction. The distance between each base pair in this figure is 3.3 angstroms, and that distance is determined by the phosphodeoxyribose backbone. If we substitute arsenic for phosphorus, that distance will change, because arsenic is a bigger atom than phosphorus.  It is incredible that this new molecule will even work in a living cell, yet is does so very successfully for this bacterium.

What does this mean in the big picture? Our thinking about the requirements for life is that all living cells have fundamental requirements. Prior to yesterday, we would not have considered that arsenic-based chemistry would be amenable to living systems. We now have an example of how living systems are flexible enough to adapt to an inhospitable ecological niche, take advantage of resources in that niche, and flourish. Our definition of habitable biospheres has now been expanded.

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About ycpmicro

My name is David Singleton, and I am an Associate Professor of Microbiology at York College of Pennsylvania. My main course is BIO230, a course taken by allied-health students at YCP. Views on this site are my own.

Posted on December 3, 2010, in Important, Microbes in the News, Strange but True. Bookmark the permalink. 3 Comments.

  1. I don’t know; I believe I will reserve judgment on this story. Science stories that make the NYT front page and NPR “Morning Edition” always ring alarm bells for me. Two concerns immediately jump to mind:

    1) The atomic mass of As (74.92) is more than twice that of P (30.97). What does that pretty DNA picture look like with those P atoms replaced by As?

    2) There are differences in the disassociation constants for arsenate [e.g. H3AsO4 —> H2AsO4 + H+] and phosphate.
    AsO4 pK1 = 1.97, PO4 pK1 = 1.73;
    AsO4 pK2 = -6.30, PO4 pK2 = -6.55;
    AsO4 pK3 = -16.94, PO4 pK3 = -18.03
    source =Geochimica et Cosmochimica Acta 65(14):2361–2378 (2001)

    In the pH range of most cells those subtle pK differences should lead to differently charged phosphate molecules.
    At any rate, that’s my $0.02 worth.

  2. Tried to fix the HTML; hopefully haven’t altered any content. I am hoping that a colleague with electronic access to Science will forward a copy of the research article to me. I have helpfully included the direct link in the summary above. I agree with your skepticism

    I assume that the 3.3 Angstrom distance between bases would be larger if you substituted arsenate for phosphate between the deoxyribose. If we made a ball and stick model of DNA, wouldn’t it look potentially similar, but stretched out? I cannot imagine how a transcription factor, which will sit on one face of the DNA molecule would be able to fit in and recognize a sequence. One simple experiment would be to isolate arsenate-containing DNA, and subject it to restriction enzyme digestion. It should cut very poorly.

    Would the difference in dissociation constants be significant at physiologic pH (approximately 7?) I would think a more significant issue would be the strength of the arsenate ester bond in comparison to phosphate ester bonds. The utility of silicon as an analog of carbon (occupying the same relationship in the periodic table) is very poor, as longer polymers of silicon containing molecules are not as stable as analogous carbon compounds. My quick Google search didn’t turn up an obvious citation, but if the chemical analogy is the same, one would predict that adenosine triarsonate would not be as useful as ATP as a chemical building block or energy storage molecule; it wouldn’t be as stable. A simple experiment would be to measure the relative pools of AMP/ADP/ATP1 in phosphate-grown cells and AMAs/ADAs/ATAs2 in arsonate-grown cells. In the absence of any synthesis to replenish, the relative level of ATAs should be diminished.

    1adenosine mono, di, and triphosphate
    2adenosine mono, di, and triarsonate

  3. Note to BIO230 students: Please welcome Prof. Rivers Singleton, a microbiologist from the University of Delaware

    I am not sure what a “ball and stick” model would show; a “space filling” model would be better. I will try to do so with ChemDraw if I can find some time. The pK difference might be more problematic. Notice that the difference in pK2 and pK3 is greater than that of pK1 and pK2. That difference will most likely become greater as the pH becomes more alkaline. Since most cells have an internal pH slightly more alkaline than 7.0, the pK differential effect will increase (I think).

    I agree that the silicon comparison does not bode will for the logic behind the work. My ancient memory seems to vaguely recall that arsenic toxicity arose from uncoupling oxidative phosphorylation. Unfortunately, I do not recall if the uncoupling results from blocking the respiratory chain or the ATPase steps. However, the organism may be growing by fermenting glucose rather than via respiration. (They grow the organism either 40 mM AsO4 (with no added PO4 or 1.5 mM PO4 (with no added AsO4); maybe they are anaerobically respiring arsenate!!??)

    I do like your suggested test and am a bit surprised a reviewer did not suggest such an experiment. Invention of techniques like HPLC make such analyzes relatively easy. I am not really surprised that a peer reviewer didn’t suggest something like this hypothesis test.

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