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Zap the Zinc

Zinc – can’t live without it, can’t get rid of it. That about sums up the situation with trying to figure out the metal’s many important roles in biology. A long, long list of proteins have zinc-binding functions (with the metalloproteases and the DNA-binding zinc-finger domains being two important ones that immediately come to mind). It’s been recognized as an essential human nutrient for over fifty years, and human zinc deficiency is a real problem in some parts of the world. That’s often caused by a diet high in phytic acid, which complexes zinc into a much less bioavailable form, although there are some rare inherited zinc deficiencies due to defects in zinc transporters themselves.

But while whole-organism depletion of zinc is known, taking this down to the cellular level is not so easy. That’s because it’s been hard to deplete culture media of zinc down to the levels where you really put the squeeze on the cells. They’re very efficient at importing any zinc available, and some of the methods you might use to get rid of it will alter the growth medium in other ways that will confound your results (such as depleting other metal ions which you then have to add back in).

This new paper, though, suggests a way to get the job done. The authors (a team at MIT’s chemistry department) had an ingenious idea. It’s known that there are proteins whose job is to sequester zinc in response to infection (to keep invading pathogens from using it) – so why not use these to clear it out of the culture medium? The S100A12 protein does the trick – immobilizing it onto resin gives you a way to filter your media and remove zinc from them almost completely. This worked on a number of different media, and even on human serum, etc. Surprisingly, you can actually regenerate the resin – treatment of the immobilized protein with 1M acetic acid liberates the zinc while leaving the protein itself undestroyed and ready for another round.

So what happens to cells grown in such de-zinc-ified media? After 36 hours, HEK293 cells are still alive (and indeed show no particular metabolic phenotype). But a detailed look shows that despite this placid exterior, the cells are furiously paddling under the surface. About 75% of all their gene transcripts were significantly altered by the depletion treatment. The pool of “labile zinc” in the cells, interestingly, wasn’t changed very much at all, which makes one think that they must work pretty hard to keep that in place.

Now that there’s an easy way to deplete zinc for such studies, we can look forward to more advances in “metallomics”. Stressing cells in this manner should reveal some new biology, as the massive response of the HEK293 cells in this work indicates. What happens when you do the same thing to cells from other tissue lineages? To cancer cell lines? To bacteria? We can now find out.

23 comments on “Zap the Zinc”

  1. Some Dude says:

    Nothing to do with Zn, but:
    Why do so many of your links appear as strikethrough (html del or s tag)? It’s a bit irritating. Initially I thought it was intentional corrections, but it’s either just a bug or you do something wrong when posting links.

    1. Anonymous says:

      I always assumed it was the high tech version of italics. They always make me laugh.

      1. dave w says:

        I thought it was just some weirdness in the rendering of something that was underlined in the original…?

    2. Hap says:

      I think a link used to be struck through when it was broken or expired, but this one isn’t, so I don’t know.

      1. David says:

        Page Source has the tag class=”broken_link” within the link code for the struckthrough ones. I have now exhausted my html knowledge.

        1. David Stone says:

          I notice that both “struck through” links are PMC articles, whereas the others aren’t. I’m wondering if there’s some automated link checker that gets invoked when the blog entries are published, but it’s being blocked by a “no robots” setting for PMC articles? So an automated checker might see the links as broken when they are in fact just fine for normal users.

    3. Mark Thorson says:

      I was thinking the same thing while reading the posting. This has been a problem for quite some time, but there are bigger annoyances on the net so I just accept it.

      1. Mark Thorson says:

        One of those bigger annoyances is the short fuse on the captcha for this website. I always have to prepare my comments in a text editor, copy them, then scramble to post before the timeout. Sometimes even then I can’t beat the timeout, especially if there’s already lots of comments to the posting. I’d like the timeout to be increased to something reasonable or removed altogether.

        1. b says:

          You can click the circular arrows beside the captcha to reload a new one, answer then post

          1. Hap says:

            Still better than late-era Corante, though.

  2. bhip says:

    de-zinc-ified….you, sir, are a wordsmith…

  3. Shanedorf says:

    One group is working on answering the bacterial question above. The crew at Forge Therapeutics in San Diego are working with zinc metalloenzymes to develop novel antibiotics for gram negatives

  4. Lisa says:

    Made our day to see you blog about our A12-related work! A bunch of us (PhD student at MIT in chemical biology) all read your posts!

    1. AnotherDude says:

      As a Wisconsin PhD, I’m glad to to see the Shoulders lab getting highlighted, too!

  5. Anonymouse says:

    Is there anything enzymes can’t do? It feels like every time I turn around they’re pulling off some kind of chemistry miracle.

  6. Insilicoconsulting says:

    sequester zinc so as not to be available to pathogens in an infection? But that’s quite the opposite of what’s recommended in flu and viral infections right? So microorganisms would be bacterial/fungal only..right?

    1. Aidan G Chappuis says:

      Well, yes. Bacteria and fungi reproduce outside cells, so removing nutrients starves them, but viruses hijack cellular machinery to reproduce and removing zinc would only have an effect if you killed most/all body cells with it, which would kill you. Far better to help the immune system deal with it.
      basically, bacteria/fungi are an invading army, who you can hurt by burning all the crops in their path before they can get them, but viruses are terror cells, and you cannot starve them without starving everyone, and should let the police/military deal with it.

  7. A world without zinc says:

    I can’t imagine a world without zinc.

    https://youtu.be/U1iCZpFMYd0

      1. Thoryke says:

        I was waiting for that one to show up…Thank you!

  8. Worth noting the really minor change in intracellular total, and labile, Zn levels. Also the scale: Extracellular Zn is about 1 millimolar; labile intracellular is measured in picomolar. All that Zn is bound up in proteins, that really don’t want to let go of it.

    1. NJBiologist says:

      Holy moly! That’s… six logs more aggressive than the regulation of intracellular calcium?

  9. steve says:

    Be interesting to see the effects on immune cells (the basis of the zinc supplementation for colds, etc). http://www.ncbi.nlm.nih.gov/pubmed/29186856

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