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The Invisible Fight for Iron

One of the things that I have always liked about the sciences is that you get a behind-the-scenes look at what’s really going on in the world (which is something I emphasized in various entries in The Chemistry Book). If you’re not a biologist or chemist, one of those little-known but crucial things is how much life depends on an element that most creatures have trouble getting. That’s iron, which is absolutely required for many enzymes, including those handling key steps in metabolism and (famously) for oxygen-carrying proteins. But it’s not in short supply because it’s scarce. There’s iron all over the place, in quantities large enough to stain whole mountain ranges and color the dirt red as far as you can see. But it’s locked up as one of some of the most insoluble lumps in all of inorganic chemistry, the iron oxides and hydroxides. In the ocean, iron is often a limiting factor for plankton growth, and you can create a spectacular bloom with a helicopter and a load of soluble iron salts. (This has been suggested as a possible route for carbon sequestration, but as that link will show you, it’s not so simple – the amount of carbon sequestered also depends on the available silicon for diatoms to form).

There are bacteria that make a living off of iron oxidation states (there are bacteria and fungi making a living off of most any source of chemical energy you can imagine), but they all have to deal with the huge insolubility of the higher oxidation state Fe(III) compounds. In recent years, iron oxide nanoparticles have become an area of study, and it looks like these are (for better or worse) more bioavailable for bacteria than the usual iron oxide forms when released into the environment. A lot of bacteria (the ones that aren’t working the iron oxidations states in particular) are quite keen on sequestering whatever iron they can get, thus you have a whole class of natural products (the siderophores) that coordinate the metal to an almost unbelievable extent.

This is an issue in human bacterial infections, because our own bodies are not wasting much iron, either. The free concentration of iron in human tissue (outside of what’s bound up in hemoglobin, iron-based enzymes and the like) is estimated to be about ten to the minus twenty-fourth molar, so there’s not much to go around. And even at that, one of the responses to a bacterial infection (nutritional immunity) is to pull back sources of iron even more. Here’s a recent overview of the field, which presents some interesting ideas for antibacterials. Bacteria are especially good at taking up heme species, since those are the most abundant iron compounds in higher organisms, and blocking these pathways definitely puts a strain on them. Another set of targets involves interfering with the biosynthesis of the siderophore compounds themselves. Yet another possibility is to give a patient iron-coordinating compounds that will compete for whatever iron is around and make it less available for the bacteria, but that’s one that you’d want to be careful with, since we need the stuff, too.

And there’s another iron-centric strategy that’s being tried – conjugating known antibiotics to known siderophores, in the hopes that bacterial will take in this Trojan horse in their constant search for iron.  (Interestingly, bacteria are not above “siderophore piracy”, leaching off the hard work of neighboring bacteria by vacuuming up the iron complexes others have produced – actually, bacteria are not above any survival strategy whatsoever, which is one of the things that makes fighting them so difficult).

These kinds of ideas have gotten more traction in recent years, because the traditional routes to antibacterials have not been as productive as we need them to be. I’m glad to see it, having worked in antibacterials myself for a bit, because we’re going to need all the help we can get, and it’s been a long time since the fluoroquinolones (not to mention the beta-lactams or the tetracyclines). Antibacterials would seem to be the prime example of an area in which the low-hanging fruit has been definitively stripped off the trees, and we need ladders, cherry-picker trucks, and whatever else can be brought in to find more. Good luck to the iron-targeting people – we’re all going to need it.

37 comments on “The Invisible Fight for Iron”

  1. Douglas Kell says:

    This also pertains to a lot of chronic inflammatory diseases NOT traditionally seen as infectious. I am not going to paste all my OA reviews on this (http://dbkgroup.org/publications/), but start with http://content.iospress.com/download/journal-of-alzheimers-disease/jad160318?id=journal-of-alzheimers-disease%2Fjad160318 for just one. (And if you doubt me, remember ulcers…)

  2. PS Brookes says:

    The free concentration of iron in human tissue is estimated to be about ten to the minus twenty-fourth molar

    I find that hard to believe. Using Avogadro’s 1 mole = 6 x 10^23 molecules, thus 10^-24 M would be about 6 free molecules per liter, which is about 400 free irons per human body. That seems a little extreme?

    1. David Borhani says:

      PS Brookes: This value is based, I believe, on equilibrium iron (III) solubility calculations. Iron is incredibly insoluble, hence bacterial, etc. siderophores, and human proteins such as transferrin.

      Somewhat similarly, there is essentially no free Zn+2 inside cells. That is not due to insolubility, but rather the low-ish total Zn+2 concentration coupled with high concentrations of Zn+2 chelators.

    2. Morten G says:

      There’s also reported binding affinities between siderophores and iron in the range of 10^-56. I find that unlikely (and possibly not measureable?).

      1. sgcox says:

        Indeed. Any experimental technique covering the dose response will put homeopathy to a shame. One molecule in the volume of the Galaxy ?

      2. Anon says:

        FYI, there are other (indirect) ways of measuring such tight binding constants without requiring an equilibrium, such as measuring on and off rates in a flow system, e.g., with SPR (Biacore).

        1. sgcox says:

          Simple biotin-streptavidin(Kd=10(-14)) stays forever on Biacore chip, Kd of 10(-56) would take time of Universe to get accurate measurement. I suspect people simply divide on zero and come up with these values.

          1. Anon says:

            Then maybe AFM, literally pulling the iron from it’s ligand and measuring the force? Theoretical delta G calculations? Calorimatery? Spectroscopy?

            Whatever, no idea, but as long as it’s not theoretically impossible, then it’s theoretically possible. Just needs a dash of creativity.

          2. different anonymous says:

            For siderophores and other strongly-chelating molecules, I believe they typically look at equilibria in comparison to lower-affinity chelators.

            There’s a 2009 Inorg Chem paper describing this process for a couple of siderophore examples, here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2790009/ They look at siderophore-iron equilibria in the presence of somewhere between 2- and 10-fold excess EDTA.

    3. Mark says:

      Fe(III) in water is largely going to be present as Fe(OH)3 and FE(OH)2+, albeit not very much of each). You can measure the concentrations of these, and then also measure the equilibrium constants for dissociation down to Fe(OH)++ and Fe+++ – I can easily believe that the free concentration for Fe+++ could be very small indeed, if that’s what was meant.

      On a related note, the solubility product for HgS is around 10^-54…

  3. enotty says:

    One can only hope. Free iron bad. Transferrin good.

    1. Mol Biologist says:

      There was a night or a problem that could defeat sunrise or other hope. Bernard Williams

      https://en.wikipedia.org/wiki/Heme_oxygenase

  4. Wile E. Coyote, Genius says:

    One of the issues with a spectacular algal bloom is that yes, it may sequester carbon, but it takes the free oxygen in the water to zero and all the fish suffocate.

    1. Anon says:

      Erm, sequestering carbon means net photosynthesis vs respiration, and thus a net release of oxygen. So I believe you are talking shite without any cerebral involvement. To put it bluntly!

      1. Wile E. Coyote, Genius says:

        From Wikipedia: “When phosphates are introduced into water systems, higher concentrations cause increased growth of algae and plants. Algae tend to grow very quickly under high nutrient availability, but each alga is short-lived, and the result is a high concentration of dead organic matter which starts to decay. The decay process consumes dissolved oxygen in the water, resulting in hypoxic conditions. Without sufficient dissolved oxygen in the water, animals and plants may die off in large numbers. Use of an Olszewski tube can help combat these problems with hypolimnetic withdrawal.”

        Maybe I wasn’t precise, but the result is the same.

    2. Anon says:

      PS. To be fair, I do understand that algal blooms only sequester carbon temporarily as they are soon eaten by marine creatures and converted back into CO2 by respiration (and THAT is actually what ultimately causes oxygen consumption), but that could be avoided by filtering out the algae, drying it down and locking it away from the food chain so that the carbon is sequestered permanently. Problem solved. 😉

    3. Anon says:

      PS2: Dredging the algae out the ocean and dumping it to dry in the desert may be an economical way to do this? At least relatively economical. That may even be a good way to re-fertilize otherwise sterile ground. Two birds with one stone!

  5. BG says:

    You can have some of my iron. I have hereditary hemochromatosis that was found through routine blood screening. My body absorbs too much iron and i get rid of it through phlebotomies.

    1. Ken says:

      Sounds like you are highly adapted for hookworms.

    2. 💩 says:

      I think you mean lobotomy

    3. dwywit says:

      I’m heterozygous but still have to watch my levels. I’ve managed to keep it under control through diet (very limited amounts of beef, lamb, goat, and eggs), so I enjoy pork and chicken a bit more these days.

  6. kriggy says:

    Thank you for the review. We had Marvin J. Miller from Notre Dame giving a talk at my uni and it was super interesting. I hear that someone would take the topic of sidenophores so I could work on those but sadly not.

  7. Anon says:

    So what does this say about vampires? And why hasn’t anyone mentioned this yet?

    Come on, get with it, guys!

  8. milkshaken says:

    most cancer cells overexpress transferrin receptor, and are thus prone to over-accumulate iron in vivo if bolus of soluble Fe(III) is administered. The cancer cells seem to deal with the overload by biocrystallization of excess iron inside the vacuoles – similar to malaria parasites. I think this offers opportunity to develop artemisin-derived antimalarials against cancer sensitized by iron supplementation

    1. JimM says:

      The cancer cells seem to deal with the overload by biocrystallization of excess iron inside the vacuoles – similar to malaria parasites.

      The hemozoin crystals used by the malaria parasite have enough paramagnetic susceptibility to line up in an externally imposed magnetic field — which is the basis of a relatively new diagnostic technique.

      If the crystals used by cancer cells share that susceptibility, I wonder whether a strong externally imposed, polarity switching high frequency magnetic field could spin the crystals and heat the cancer cells enough to kill them without much of an effect at all on non-cancerous cells.

      1. milkshaken says:

        the formed Fe nanoparticles in tumor mass are definitely visible on MRI as contrast

      2. Peter Saul says:

        Have you any references to this?

      3. Peter Saul says:

        Have you any references to this? ps

  9. Mol Biologist says:

    I am wondering how oxygen-carrying proteins turnover can be related to HIF Prolyl Hydroxylase activities since last one also starving for Iron.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3361910/

  10. Biomaven says:

    In anemia of inflammation, high hepcidin levels block iron transport. EPO actually makes this worse, hence the need for concomitant IV iron and the need for high EPO doses in these patients.

    Fibrogen’s Roxadustat (HIF-1 stabilizer) has been shown in large Phase 2 trials to reduce hepcidin level and allows effective anemia treatment of these patients without IV iron.

    Incidentally, in Alzheimer’s, hepcidin levels are 3x normal:

    Aging Dis. 2017 Apr 1;8(2):215-227. doi: 10.14336/AD.2016.0811. eCollection 2017.
    Serum Hepcidin Levels, Iron Dyshomeostasis and Cognitive Loss in Alzheimer’s Disease.
    Sternberg Z1, Hu Z2, Sternberg D1, Waseh S3, Quinn JF4, Wild K4, Jeffrey K4, Zhao L5, Garrick M6.
    Author information
    Abstract
    This pilot study examined the status of the master iron regulatory peptide, hepcidin, and peripheral related iron parameters in Alzheimer’s disease (AD) and mild cognitive impairment patients, and evaluated the relationship between iron dyshomeostasis and amyloid-beta (Aβ), cognitive assessment tests, neuroimaging and clinical data. Frozen serum samples from the Oregon Tissue Bank were used to measure serum levels of hepcidin, ferritin, Aβ40, Aβ42 using enzyme-linked immunosorbent assay. Serum transferrin levels were determined indirectly as total iron binding capacity, serum iron was measured and the percent saturation of transferrin calculated. The study variables were correlated with the patients’ existing cognitive assessment tests, neuroimaging, and clinical data. Hepcidin, and iron-related proteins tended to be higher in AD patients than controls, reaching statistical significance for ferritin, whereas Aβ40, Aβ42 serum levels tended to be lower. Patients with pure AD had three times higher serum hepcidin levels than controls; gender differences in hepcidin and iron-related proteins were observed. Patient stratification based on clinical dementia rating-sum of boxes revealed significantly higher levels of iron and iron-related proteins in AD patients in the upper 50% as compared to controls, suggesting that iron dyshomeostasis worsens as cognitive impairment increases. Unlike Aβ peptides, iron and iron-related proteins showed significant association with cognitive assessment tests, neuroimaging, and clinical data. Hepcidin and iron-related proteins comprise a group of serum biomarkers that relate to AD diagnosis and AD disease progression. Future studies should determine whether strategies targeted to diminishing hepcidin synthesis/secretion

    1. Anon says:

      “Incidentally, in Alzheimer’s, hepcidin levels are 3x normaL”.

      I just read that quickly, thinking, “wow, that’s *really* normal”.

      Need coffee.

  11. Eric says:

    I’ve seen iron competition proposed (darned if I can recall where) as a hypothesis for why bleeding a patient might, sometimes, help.

    (Thanks be that we don’t live in a world where the best available antibiotic is bloodletting.)

    1. milkshaken says:

      when it comes to reducing iron load in the body, regular bloodletting beats the chelation therapy.

      1. Anon says:

        Not to mention a very effective way of treating high blood pressure.

  12. eub says:

    Another fun metal ion trick: it’s possible that concentrations of nickel in the surface biosphere drive the Earth’s atmospheric CO2/methane balance and hence its temperature. Nickel is the central metal ion of the archaean enzyme cofactor F430, which the methanogens use to do their thing.

    So volcanoes bringing up nickel-iron may have fed nickel to the deep-sea methanogens and heated the earth as part of the Permian-Triassic Great Dying.

    1. Morten G says:

      So you’re saying that fossil fuels are heating the planet via the release of nickel into the atmosphere? And here I thought the main problem with the toxic metal ions released into the atmosphere was that they were toxic. The more you know I guess.

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