Leah here from leah4sci.com/MCAT and in this video we'll start with an introduction to
red blood cells and Hemoglobin.
You can find this entire series by visiting my website leah4sci.com/Hemoglobin.
You'll be required to study many different metabolic pathways for the MCAT but you don't
wanna study them individually.
You want to understand how they all tie together.
And when it comes to Oxygen that is a key component that ties everything together because
Oxygen is what allows us to survive as multicellular organisms by allowing us to produce much higher
levels of energy compared to what the individual cells are capable of producing anaerobically.
Let's look at survival starting with Glucose.
Wit each we digest the glucose and we break it down into two molecules of pyruvate.
In order to harvest some energy through the process of like glycolysis.
But we don't get that much energy from Glycolysis instead we take the molecules of pyruvate
and we break them down ultimately into carbon dioxide through the krebs cycle which still
doesn't give us that much energy.
But in the process of breaking down pyruvate in the krebs cycle we harvest high energy
electrons which are carried as NADH and FADH2, those electrons are taken to the electron
transport chain and turned into energy to oxidate phosphorylation.
In order to keep the Electron Transport Chain going we need molecule to accept those electrons
and that's where Oxygen comes in.
Oxygen is a terminal electron acceptor which binds to those electrons, binds the protons
and is released as water.
Without the Oxygen the entire electron transport chain will stop, the krebs cycle will stop
and suddenly the production of ATP is slowed down.
ATP is the energy currency of the cell.
That is how you pay for the energy of reactions and that is how you have energy to do what's
required to survive.
Now that you see why Oxygen is so important, let's see how it gets to the cells.
When you breath in air you get Oxygen and many other gasses but let's focus on the Oxygen.
It enters the lungs and from the lungs it gets picked by the red blood cell which will
transport it to the rest of the body.
The red blood cells are also known as erythrocytes where erythro comes from the word red and
cyte is cell.
The red blood is a biconcave disk and I like to think of it as a life saver candy but without
the hole in the middle.
So looks like a tube that you can sit on and that tube will go into the bloodstream helping
to transport Oxygen.
The red blood cell is a very interesting cell like all the other cells in your body it has
the lipid by layer and then it has a cytoplasm but what it doesn't have is mitochondria and
it doesn't have a nucleus.
When the red blood cells are made in the bone marrow they do have a nucleus that would be
the pre red blood cell because the nucleus has DNA and DNA codes for proteins and protein
will carry out the functions that a growing cell needs to grow.
But as the red blood cells matures it has to lose its nucleus so that they'll have more
space to carry a very very critical protein and that is hemoglobin.
The other critical thing lacking is mitochondria.
Think of mitochondria as the powerhouse of the cell.
That's where the bulk of ATP in the cell is being made but the mitochondria which has
the electron transport chain requires Oxygen.
Do you really want the cell that carries Oxygen to other cells? to potentially eat up the
Oxygen along the way?
I don't think so.
So the red blood cells will rely on Glycolysis for their energy so that they can focus on
very simple task of just carrying Oxygen to the other cells.And if the cell isn't taken
up by a nucleus, isn't taken up by a mitochondria it has so much more room for Hemoglobin which
is what we really care about.
In fact, about 35 percent of the red blood cell is occupied by Hemoglobin which you can
write as Hgb or simply Hb and what's so special about Hemoglobin?
Hemoglobin is the protein that physically carries the Oxygen.
Hemoglobin is a very interesting protein and it's one of the most studied protein.
It comes from the word Hemo which refers to the heme prosthetic group which you have in
that molecule.
And globin which is a globular or just glob of a protein.
Adult Hemoglobin is a tetramer of Alpha two Beta two subunits.
Tetramer means that it has tetra four subunits, two of them are Alpha and two of them are
Beta so if you think of the structure of the protein the tertiary structure would be the
Alpha polypeptide chain or the beta polypeptide chain but the quaternary structure the ultimate
three dimensional structure comes from all four sub units being connected to make one
giant globular protein.
Let's contrast this with Fetal Hemoglobin which is Alpha two Gamma 2 and that is critical
to allowing the fetus to get Oxygen from the parent but more on that later.
I drew a scribbled version of the hemoglobin molecule just to give you the idea of what
we're looking at.
Notice we have two red and two blue subunits representing the Alpha and the Beta and let's
pretend that they're very similar to each other.
Notice you see a lot of Alpha helical structures in its secondary structure and that it's a
pretty much giant glob.
The black circle of the center of each sub unit represents the porphyrin ring.
This is a prosthetic group meaning it's not made up of Amino Acids but it's bound to the
protein to help with the structure for function and in this case the porphyrin ring which
is the heme group is critical because this is where you bind iron and iron in turn will
bind Oxygen and Oxygen is the ultimate goal of the Hemoglobin molecule.
I also want you to notice this nice hole in the center of the hemoglobin and that's going
to be critical when we talk about the binding of 23BPG.
Here's a close up of the heme group.
Notice that you have the iron 2 plus Fe+2 in the center bound to four Nitrogens in the
imidazole ring.
Imidazole comes from the amino acid histidine which is on the polypeptide chain and that
will be critical for the structure later on.
In addition to binding the four Nitrogen atoms, the iron will also bind all two.
You think of structure of Oxygen, we have Oxygen double bound to another Oxygen atom.
Two pi bonds and two lone pairs.
This is the ideal molecules that iron wants to bind.
But there are other competitive ligands that can try to bind.
For example carbon monoxide is a poison, let's see why.
If we draw the structure for carbon monoxide or CO you'll notice that it looks very similar
to Oxygen.
It's two atoms directly bound to each other with sigma and pi bonds and even though the
molecule has a net neutral charge don't let this trick you.
If you want a quick formal charge, Oxygen should have 6 electrons directly bound and
here we have all five.
Six minus five is plus one which is not of our concern with.
But carbon which should have only 4 bound electrons has five.
And four minus five is minus one.
That negative carbon will trick you into getting bound instead of Oxygen but because of the
negative charge it doesn't want to leave.
Carbon monoxide has a two hundred and fifty times stronger affinity for the heme group
than does Oxygen which means that if a carbon monoxide gets in it's very hard for an Oxygen
to kick it out.
Cyanide is another similar structure that also binds competitively.
Cyanide is CN minus, the only difference between carbon monoxide and cyanide is that even though
carbon has a negative one charge, Nitrogen is neutral because it wants 5 electrons and
it has five electrons.
Base on this you can imagine that cyanide is also a poison.
Looking at this heme group, notice all the pi bonds that you have.
This is an aromatic system, remember that one of the characteristics of aromaticity
is planar or flat.
But when this heme group does not have Oxygen bound it tends to look a little dome or Packard.
Hemoglobin doesn't necessarily like binding Oxygen and this is called the T-state which
stands for Taut.
It's so taut, it's so tight it doesn't want to allow an Oxygen into this group.
But if hemoglobin is in the lungs and there is a very high concentration of Oxygen that
sheer volume or partial pressure of O2 is going to force one of the ultra molecule to
bind.This will take that dome shape and flatten it out back into the structure that we see
here and this puts the hemoglobin into the r state which is much more relaxed.
It's so relaxed it doesn't mind binding Oxygen so when one of the heme groups binds to Oxygen
and it becomes more relaxed what happens is you get a very very slight movement in the
molecule when it goes from dome to flat.
It pulls up on the histidine which pulls that entire molecule and we're talking less than
an angstrom.
And if you remember an angstrom is one times ten to the minus ten meters.
It's a tiny tiny change but this induces the next subunit on hemoglobin to change and the
next one and the next one and suddenly they all want to start binding Oxygen so you go
from hemoglobin that doesn't like Oxygen to a hemoglobin that is desperate for Oxygen.
This concept is called Cooperative Binding or simply cooperativity.
And I think of this as peer pressure.
Just imagine a bunch of kids standing of a lake and they want to go swimming but no one
wants to be the first one jumping in.
So they said you jump in first, no you jump in first.
And then finally you have one kid that just gets pushed in and he gets in the water and
suddenly, uh this doesn't look so bad now they all want to jump in.
One Oxygen binds when it doesn't want to goes from T to R state and now they all want to
bind.
And this is great in the lungs because you need hemoglobin to pick up that Oxygen so
that it can go to the rest of the cells.
In addition to Oxygen binding to iron and the competitive inhibitors like carbon monoxide
and cyanide there were also Allosteric molecules that can bind to hemoglobin.
Remember that Allo means other and when you have an Allosteric ligand it's something that
binds to a non active site if you're thinking of an enzyme.
Hemoglobin is a protein not an enzyme but it still has allosteric binding sites which
are not specifically on the heme group.
These ligands can influence the hemoglobin stability to take up oxygen or release Oxygen.
The molecules that'll bind at the Allosteric site include protons and this will come from
having a low pH.
Carbon dioxide which is released by the cells from respiration and 23BPG which is another
very interesting molecule.
Not only will they affect hemoglobin stability to bind Oxygen, they're also going to change
the way they look at the hemoglobin curve and that's exactly what we'll discuss in the
next video which you can find along with the entire series by visiting my website leah4sci.com/hemoglobin.