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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.