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  • JOANNE STUBBE: So we've been talking

  • about iron metabolism in general in the first lecture.

  • And in the second lecture we started

  • to focus on iron metabolism in humans,

  • and the third set of lectures is going

  • to be iron metabolism and bacteria with a focus on hemes.

  • And the two things you want to talk about in the lecture today

  • are, how does iron get taken up into cells in humans,

  • with a focus on receptor mediated endocytosis,

  • and then we're going to start talking about hopefully iron

  • regulation--

  • how you sense iron, ion regulation

  • at the translational level.

  • By sort of a unique mechanism, at least

  • at the time of its discovery.

  • So in the last lecture, we introduced you

  • to some key features about iron chemistry

  • in general that we're going to use throughout this lecture

  • and next lecture.

  • So you need to go back and review your notes

  • if you don't remember that.

  • Or hopefully you've had it somewhere before,

  • and it's a review from you from freshman chemistry

  • or inorganic chemistry.

  • And so iron metabolism-- what do we know?

  • We know the average human being has 3 to 4 grams of iron.

  • We talked about this at the end of the last class,

  • of how is the iron distributed.

  • We all went through that most of our iron

  • is in our red blood cells in the form of hemoglobin.

  • But it's also-- so in the form of hemoglobin,

  • it also can be stored in proteins called ferritins,

  • which we're not going to spend much time on,

  • but I will introduce you to today.

  • And then many of you may know that red blood

  • cells die every 120 days.

  • And we'll see that the iron is really continually recycled,

  • and we'll talk a little bit about the mechanism

  • of how that's regulated.

  • So instead of excreting it, what happens is you recycle.

  • The iron unit's recycled by macrophages in the spleen.

  • And so the other place you see a fair amount of iron

  • is in the macrophages.

  • And the third place you see a fair amount of iron

  • is in the tissues, because myoglobin, again,

  • has to deliver oxygen to the respiratory chain.

  • So what I want to do now, and I'm

  • going to go back and forth between the PowerPoint

  • and notes.

  • And so some things I'm going to write down some things not.

  • Hopefully you have these cartoons in front of you

  • so you can write down some of the things

  • that I will say here, and say it again and say it again.

  • So this is sort of the big picture

  • that I took from some review.

  • And most of these big pictures have some issues with them.

  • But I think it still gives you the big picture.

  • So here's a duodenum, where we can take up iron from the diet.

  • And we'll talk about this in more detail,

  • but a key player in allowing the iron from the diet

  • to go into our system is going to be FPN--

  • that's going to be ferroportin, I'm

  • going to describe this again.

  • But you're going to see FPN over and over again.

  • It allows iron to be transferred in the plus 2 state,

  • and that's going to be important.

  • And so what we see, that if you look at iron from the diet,

  • there's not that much.

  • [AUDIO OUT] somebody's guess as to how much there is.

  • A few milligrams.

  • And the question is, where does it go in the bloodstream?

  • And it goes to a protein that we're

  • going to talk about that's a carrier for iron in the plus 3

  • state.

  • So we're going to see plus 2, plus 3 into conversions

  • over and over again.

  • And sort of what the strategy that

  • has evolved to be able to deal with these different oxidation

  • states is.

  • We'll see that this little protein, TF, is transferrin,

  • and we're going to look at transferrin

  • for a-- very briefly, but it binds iron 3 and bicarbonate,

  • and then delivers this to tissues,

  • and also delivers it to marrow.

  • And marrow, which is-- accounts for approximately,

  • by mass, 4% of the body weight, makes all of our red and white

  • blood cells.

  • So that's going to be important.

  • And so the marrow makes the erythrocyte,

  • the heme for the erythrocytes makes the erythrocytes,

  • and the erythrocytes are the red blood cells

  • that have all the hemoglobin.

  • So out of the 4 grams, you have 2 and 1/2 grams of hemoglobin.

  • And then these red blood cells die every 120 days,

  • and instead of just discarding everything, they're recycled.

  • And they're recycled by the macrophages in the spleen.

  • And somehow you want to take the iron from these red blood cells

  • and reuse it.

  • And so there's a series of reactions that happen.

  • Ultimately you get iron 2, and the iron 2-- here's

  • again our iron 2 transporter, ferroportin, is

  • going to take the iron that's recovered and put it

  • back into transferrin, where, again, it can be distributed,

  • depending on the sensing of iron.

  • Now, the major player in the sensing and storage of iron

  • is the liver.

  • So the liver, we're going to see there's

  • a protein there not indicated on the slide called ferritin,

  • and ferritin binds 4,500 molecules of iron.

  • And this is also-- the liver is the organ that generates,

  • biosynthesizes the key regulator of iron homeostasis,

  • which is a peptide hormone that we're not

  • going to spend a lot of time on, but I'm

  • going to show you what it does.

  • So that's called hepcidin.

  • And what we'll see is hepcidin in some way controls

  • the levels of ferroportin.

  • So we also see that we lose some iron daily,

  • but the iron losses are small.

  • So we have a lot of iron units, but the iron

  • is continually recycled, and the question

  • is, how does that happen?

  • So I just want to look at one place where,

  • in the duodenum, where we're going to take up iron.

  • So what I'm going to do is--

  • this is a cartoon of what I just showed you in more detail.

  • But I'm going to focus on iron absorption from the diet.

  • And I want to make a couple points

  • about this, which are general.

  • And so what we'll see is we have enterocytes,

  • so this is an enterocyte.

  • And you have an apical brush border membrane.

  • And then you have a second membrane

  • which is going to get us into the bloodstream.

  • So this is called a basolateral membrane.

  • So we get iron from our diets mostly in the plus 3 state.

  • But to do anything with iron, probably

  • because of the ligand exchange issues

  • we talked about last time, the rate constants for exchange

  • are much slower with iron 3 than iron 2.

  • So from the diet, we have iron 3.

  • And iron 3 needs to be reduced to iron 2.

  • And that can be done-- we'll see this is going

  • to happen over and over again.

  • And this can be done by a ferric reductase.

  • And what we will see is in this membrane,

  • we're going to have an iron 2 transporter.

  • So in addition to the ferroportin

  • I just briefly introduced you to,

  • and will introduce you to again, we

  • have an iron 2 transporter, that's called DMT 1.

  • Again, the acronyms are horrible.

  • But it's a divalent predominantly iron

  • 2 metal transporter.

  • And we're going to see, when we think

  • about regulation of iron homeostasis,

  • this is going to be a key player.

  • Because it takes iron from the diet into our cells.

  • And in this membrane of the enterocyte, what

  • we will see is that we have--

  • and this is what you saw in the previous slide--

  • you have ferroportin-- so I'm only

  • going to write this down once.

  • But this is going to take the iron 2

  • and then transfer it into, ultimately,

  • the carrier in the bloodstream, which

  • is going to be transferrin.

  • So here we have iron 2, but for it

  • to get picked up by transferrin, it gets oxidized to iron 3.

  • So what you're going to see over and over again

  • is going back and forth between iron 2 and iron 3.

  • And so this gets oxidized to iron 3.

  • And these proteins-- there's a copper iron oxidase.

  • And if you look at the handouts, you'll

  • see that this is also called--

  • again, I don't expect you remember the names.

  • What I think is key here is that you need to transfer this

  • to the plus 3 oxidation state.

  • So now what happens in the plus 3 oxidation state--

  • so let's go over to the next board here--

  • we have a protein called transferrin,

  • and we'll look at this a little bit.

  • And transferrin is going to bind iron in the plus 3 state,

  • but it also requires bicarbonate.

  • So in the blood, is that unusual that you

  • would require bicarbonate?

  • Or why might you require bicarbonate?

  • What do you know about blood cells and hemoglobin?

  • So we have iron 3 that's regenerated enzymatically,

  • through some kind of oxidation reduction equipment.

  • And we're going to see this, again, over and over again.

  • And they each have different names,

  • so that's confusing as well.

  • But you're cycling between 2 and 3.

  • And then transferrin, we have a structure

  • of this picks up the iron in the plus 3 state,

  • and also picks up bicarbonate.

  • So where do you think that bicarbonate

  • comes from in blood cells?

  • AUDIENCE: CO2.

  • JOANNE STUBBE: Yeah, so it comes from CO2.

  • Why?

  • Because a major function of red blood

  • cells is to transfer CO2 from the tissues back to the lungs.

  • So CO2 is not there, at pH 7, it gets rapidly hydrated to form

  • bicarbonate and protons.

  • And so this is unusual.

  • I think this is one of the few systems where you have-- we'll

  • see bicarbonate as a ligand.

  • So in addition to these enterocytes, which again

  • are involved in iron uptake, we also

  • have macrophages in the spleen.

  • And so this, again, is due to the diet.

  • And this is due to basically recycling--

  • iron recycling.

  • And so what you have is macrophages in the spleen,

  • and you have in the macrophages dead red blood cells,

  • which I'll abbreviate RBC.

  • And so the idea is we want to get the iron out

  • of the red blood cells somehow to reuse it.

  • So that's the goal.

  • And so somehow in a complicated process, we get iron 2 out.

  • And then iron 2--

  • here we have our friend ferroportin,

  • that I just showed you in the previous slide,

  • is going to take and put into the extracellular mirror

  • in the plasma the iron 2.

  • So what happens to the iron 2?

  • We just saw over here, the iron 2 gets oxidized to iron 3.

  • The same thing is going to happen over here.

  • So we have iron 2 that needs to get oxidized to iron 3.

  • And again, let's just call it a copper iron oxidase.

  • I'm not going to go through the details.

  • And then what happens to the iron 3?

  • So the iron 3 then gets picked up by the transferrin.

  • And then depending on what the needs are the cell,

  • the transferrin can deliver.

  • If you have a lot of iron, it could deliver it back

  • to the liver.

  • We'll see that's the storage place for the iron.

  • So the iron 3 transferrin needs to get taken up,

  • just like we saw with cholesterol.

  • Or if we need iron in some other tissues,

  • we'll see that there are receptors for iron 3

  • transferrin that can, again, take iron into the cells

  • to meet the needs of the cell for iron requirement.