Now, in going through heme synthesis,
what's remarkable is how we can start
with very simple molecules and make
the complex heme ring as we will see.
The first step of the synthesis
begins with the simple compound,
succinyl-CoA and glycine.
Succinyl-CoA is from the citric acid cycle
and glycine is a simple amino acid.
The combining of these two molecules
together creates aminolevulinic acid.
The first intermediate on
the way to making heme.
This reaction is a decarboxylation
that releases both the carbon dioxide
and the Co-A part of the
molecule as we see here.
The enzyme catalyzing
this reaction is
aminolevulinic acid or ALA
synthase as we call it.
ALA synthase is found in almost all non-plant
eukaryotes and also in some bacteria.
Now the enzyme is found in
the mitochondria and that's
important because that's where
the succinyl-CoA is located.
The synthesis of the enzyme
is tightly controlled
by the presence of
iron binding proteins.
We don’t want to be making
this if iron is not available.
So, if iron binding
proteins are abundant,
that means there's iron
to put in and make heme.
The second step in the process
of making heme involves the
condensation of two of these
molecules of aminolevulinic acid.
The product to this reduction creates
porphobilinogen as you can see here.
And we already start to see complex molecules
resulting from these interactions.
This reaction splits out
two molecules of water and
it's catalyzed by the enzyme
Porphobilinogen synthase is sensitive to
magnesium concentration and also to pH.
It's also very easily
inactivated by heavy metals.
And because of this, it
is actually the source of
our sensitivity in our
body to lead poisoning.
When you heard lead poisoning,
it's affecting this enzyme.
And that's pretty severe as you can
imagine because if you couldn’t make
heme because this enzyme was deficient,
you would be in big trouble.
Four porphobilinogen molecules
combine with splitting out
of ammonia to create the next
Here are the four porphobilinogens
and here's the hydroxymethylbilane.
Now, I've gone through and
marked in the molecules
we'll see in a second
where these came from.
The reaction involves
the addition of water,
the loss of four protons and
the loss of four ammonias.
Again, ammonias need to be dealt with and
I've talked about that in another lecture.
The enzyme catalyzing this is
And we can see here that the molecules
are joined through their amine rings.
here and here.
So, each box contains one of the
The reduced activity of the enzyme
results in intermittent porphyria.
And intermittent porphyria, as
we will see, can cause some
really unusual things in terms
of behavior in a person.
In the next reaction,
uroporphyrinogen III is made
and this is the first cyclic
intermediate of the pathway.
Here's the precursor molecule from the
last reaction, hydroxymethylbilane.
This is a simple reaction involving the
loss of water to make uroporphyrinogen III.
The reaction is catalyzed by the
enzyme uroporphyrinogen III synthase.
In this reaction, we
can see what happens.
The green box on the left shows the
place where the reaction occurs.
And on the right, the water has been
lost and a bond has been created
to basically fasten together the
bottom part of the molecule.
This now creates a central
ring structure in the middle.
Hydroxymethylbilane can also
spontaneously cyclize to
form a related compound known
as uroporphyrinogen I.
We won't follow that here.
A deficiency of this enzyme is associated
with another kind of porphyria
known as congenital
In the next step of the process,
decarboxylation of the uroporphyrinogen
III gives us coproporphyrinogen III.
That is a pretty
mouthful of word.
Uroporphyrinogen III on the left
goes to coproporphyrinogen III
by the splitting out of
these four carbon dioxides.
We see that happening here.
Here's where the carbon
dioxide comes from.
And here's what's produced
after it has been lost.
Here's where the second one
comes from and the product.
The precursor and the product, and
the precursor and the product.
The enzyme catalyzing this reaction is
uroporphyrinogen III decarboxylase.
Now, this enzyme is notable
because it has an extraordinarily
high rate of catalysis compared
to the same uncatalyzed reaction.
In fact, this rate increase of 1024
is the highest of any known enzyme.
Mutations in this enzyme cause
familial porphyria cutanea tarda
In the next step
of heme synthesis,
coproporphyrinogen III is converted
to protoporphyrinogen IX
through two sequential steps
of oxidative decarboxylation.
And we can see these here.
Here's the coproporphyrinogen III and
here's the protoporphyrinogen IX.
This reaction involves
lost of two waters and the two
carbon dioxides that I mentioned.
Coproporphyrinogen III oxidase
catalyzes this reaction.
Here's the precursor on
the left and here's the
product after the
decarboxylation has occurred.
The precursor on top and the product
after the decarboxylation has occurred.
Reduced amounts of coproporphyrinogen III
oxidase leads to hereditary coproporphyria.
Coproporphyrinogen III oxidase is a
mitochondrial, iron-carrying enzyme.
In the seventh step
of this process,
protoporphyrin IX is formed from
protoporphyrinogen IX by oxidation.
It's the protoporphyrin
IX that is the precursor
in which the iron is
inserted to make heme.
Protoporphyrin IX is, I
said, the precursor.
It is the precursor
of the hemes,
cytochromes and also the hemes
that's used in chlorophyll.
We can see that reaction
The protoporphyrinogen IX on the left
and the protoporphyrin IX on the right.
In this reaction, three
molecules of oxygen are added
and three molecules of hydrogen
peroxide are produced.
You may recall that hydrogen
peroxide is a reactive
oxygen species and can cause
problems if it accumulates.
It's for this reason that the cell
has an enzyme called catalase that
breaks down hydrogen peroxide and
prevents from having toxic effects.
The enzyme catalyzing this reaction
is protoporphyrinogen oxidase.
We see the reaction
going on here.
In the green box on the left, we see
the central portion of the molecule
and we see the result in
structure on the right.
Now, at first glance, not a lot has
happened but in fact six atoms
of hydrogen have been extracted
from the molecule on the left.
If look carefully, you'll
see that there are
several double bonds that
have been created and a
couple of very visible
hydrogens that have been lost
to make the final product
of protoporphyrin IX.
Protoporphyrinogen oxidase is found
in the inner mitochondrial membrane.
Variegate protoporphyria is caused by
mutations in protoporphyrinogen oxidase.
The final step in the synthesis of heme
is of course the insertion of the iron
atom into the middle of the porphyrin group
that we've been constructing so far.
We see on the left the protoporphyrin, or
the protoporphyrin IX as it's also called,
with an empty space
in the middle.
On the right, we see the
product, heme B which has
had an atom of ferrous iron
inserted in the middle.
The iron is inserted
as we can see above.
This results in the
loss of two protons.
There's electronic rearrangement
that occurs in getting that
iron in there and I won't go
through that at this time.
The enzyme catalyzing this reaction
is known as ferrochelatase.
And ferrochelatase is another enzyme that's
found in the inner mitochondrial membrane.
Other hemes may require
and if you recall, those
were reoccurring away from the rings outside
of the structures that we see here.
They're fairly minor in
the scheme of things.
I've been talking about the individual
reactions and I've said that they occur in
the mitochondrion or whatever, but I have
not exactly shown you where they are.
So, I thought it would be helpful if
I provided a figure that illustrated
the individual reactions and the
enzymes and where they are located.
In the central part of the
figure, we see the mitochondrion
with its matrix and with
its inner membrane.
Outside that mitochondrion
is the cytoplasm.
And we see that some of the
reactions occur in the matrix.
The process actually
The molecules are moved out in the cytoplasm
where some of the enzymes are located.
And then some of the molecules
are moved back into the
mitochondrial matrix where the
other enzymes are located.
Ultimately what happens in this synthesis
of heme is that heme is moved out of the
mitochondrion to the inner mitochondrion
membrane where you see the heme located.
It's there that it's
attached the globins chains
to make molecules like
for example hemoglobin.