The topic of this set of lectures is
that of the metabolism of bilirubin.
Bilirubin of course is a
breakdown product of heme and
heme is one of the components
of our red blood cells.
Catabolism of heme actually begins
in the spleen because it's in the
spleen where the red blood cells
are taken out of the blood supply.
In this process, damaged blood
cells are recognized by the spleen
and these damaged blood cells have
contents that have to be processed.
One of the more important components of
those blood cells, of course, is heme.
Heme is shown in the
structure in the lower left.
Now the reduction of heme is the
very first step in the process
of converting heme into what will
ultimately become bilirubin.
The first step in the
process involves the
production of biliverdin
as you can see here.
And this reduction reaction
uses electrons from NADPH.
It also uses oxygen.
And this oxygen is actually
oxidizing a part of heme.
So this is a complicated
that's actually happening
to make biliverdin.
Well the reaction is complicated, but
the product is not very complicated.
As you can see, biliverdin
looks very much
like heme does on the
left with the exception
of the top bond that has been broken
where two oxygens have been substituted.
Heme is converted in this
reaction by the enzyme known as
heme oxygenase that makes
this overall process happen.
And again, we see the
involvement of molecular oxygen
as we have seen in numerous
other metabolic processes.
There's the top bond that's
been broken and there's the
production of the two oxygen
atoms that I described earlier.
Now the increased activity of heme
oxygenase is important because
it's a signal to the body to
start making more ferritin.
What is ferritin?
Ferritin is a protein that
grabs and stores iron.
Iron in the body is
something that the body has
to be very careful of
allowing in the free form.
This ferrous iron that we see here,
Fe+2 or ++ as it shown here.
This ferrous iron can participate
in reactions and cause some very
serious byproducts that the cell
of the body doesn't want to have.
So being able to contain this
within ferritin is important.
So increased activity of heme oxygenase
correlates with the production of ferritin.
And the reaction we've just seen, there
was a reduction at the center joint
that broke the conjugation and allow
for flexibility in the molecule.
And the reaction we'll see here,
biliverdin is converted into bilirubin.
And this involves breaking the bond
of the very bottom of the molecule
to allow the production of two of
the molecules that you see here.
In the reaction, NADPH is
used as a source of electrons
to reduce the biliverdin
into the bilirubin.
We see this bond that's here, that
has been reduced in the process.
And the reduction of this bond
changes the double bond, which is
shown on the left, to the single
bond, which is shown on the right.
Again, increasing the
flexibility of this molecule.
This reaction is catalyzed by an interesting
enzyme known as biliverdin reductase.
Now the formation of bilirubin is part of the
reactive oxygen species reduction cycle.
Now this reactive oxygen species
reduction cycle turns out
to be really interesting component
of bilirubin metabolism.
We'll see how this happens
in just a second.
But this recycling system
allows bilirubin to overcome
a 10,000 fold excess of
reactive oxygen species.
Now I'm going to remind you that
reactive oxygen species, of course,
are molecules that have free
radicals involving oxygen.
These free radicals cause
enormous problems in cells.
They can cause mutations.
They can cause formation of a lot of
products that the cell doesn't want.
And this all happen in the
absence of an enzyme.
So cells have a lot of things that they use
to control the amount of reactive oxygen
species produced, and this bilirubin as
seen here is an important component of it.
So, so far what you've seen is that heme is
converted to biliverdin by heme oxygenase,
and biliverdin is converted to
bilirubin by biliverdin reductase.
Bilirubin can be further
process and excreted
which I'll talk about
later in this lecture.
Or alternatively, bilirubin can
be oxidized back to biliverdin.
And this oxidation actually maps
up reactive oxygen species.
And we can see that there's
sort of a circle that's here.
You may remember from an earlier
lecture in this series that there
was a circle involved in the
production of peroxide chain reaction.
This was actually causing peroxides to form
in metabolism, I shouldn’t say metabolism,
but in the oxidation of fatty
acids that was very undesirable.
That cycle kept throwing out additional
peroxides that cause problems.
Here is a cycle that is containing
the reactive oxygen species.
Now this cycle counteracts other
cycles that cause problems.
So this cycle is very important for cells
to help manage reactive oxygen species.