00:01
Folates are important compounds
that donate one carbon units
to individual biochemicals
that are being synthesized.
00:09
And we will see how
that occurs here.
00:11
So folates are involved in single
carbon transfer reactions.
00:15
They are sometimes called vitamin B9,
although more commonly refer to
them as folic acid or folates.
00:21
Deficiencies of folates in
our diet can be very severe,
resulting in megaloblastic
anemia in adults,
cardiovascular disease,
birth defect in infants,
particularly failure to close the neural
tube during the process of development.
00:37
And these problems overcome
to a large extent
in recent years by supplementation
of folates in grains.
00:44
It's things such as our bread now contains
folate that didn’t contain folates before.
00:48
You can see two of different folates
on the right and as we'll see,
this is a whole family of compounds
but slightly different structures
involved in adding different
forms of one carbon units
to build a biochemical molecule.
01:00
There are many different
forms of folate as I noted
and they can differ in
both their oxidation state
and also in the configuration of
carbons they have to allow diversity
of forms of one carbon units that can be
added to a growing biochemical molecule.
01:16
Now, folates are important
in many metabolic processes.
01:19
We see them, for example, as
required in the synthesis
of purine nucleotides
for making RNA and DNA.
01:25
They’re also necessary for making thymidine
from the uracil containing nucleotides.
01:30
We've seen how they’re involved in other
lectures here in the synthesis methionine.
01:35
And they’re also important for the
interconversion of serine and glycine
in the metabolism of
those two amino acids.
01:43
You can see two different
forms of folates:
the N5, N10
methylenetetrahydrofolate on top
and the 5-methyltetrahydrofolate
on the bottom.
01:53
Now, if we look at the serine
and glycine metabolism,
we see one of the ways in which the
folates are actually interchanged.
02:00
You can see the reaction as described
on top where serine is interacting
with tetrahydrofolate to create glycine
and N5, N10 methylenetetrahydrofolate.
02:10
Well, here’s what it actually
looks like and what’s going on.
02:13
Now remember that this
had a fairly long chain
and I don’t have enough room on the
slide to show you the long chain.
02:18
So I’ve abbreviated it by putting an R
on the right side of the THF molecule.
02:24
The reaction that is important here occurs
within that molecule that
you can see on the screen.
02:29
But in this reaction, serine is actually
donating a carbon to the tetrahydrofolate.
02:35
And we can see that carbon has
been added between the nitrogens,
that are on the right
side of that molecule
In this case, the addition
is a methylene group,
the CH2 and the product of that
reaction is the amino acid glycine.
02:50
Meaning that after serine has donated
its group, glycine is what results.
02:55
Well, this turns out to
be a reversible reaction
If the cell needs to make tetrahydrofolate,
it can convert glycine into serine
and then convert N5, N10
methylenetetrahydrofolate into folate.
03:07
So this can go either way
depending upon the cell’s needs.
03:13
Folates are needed in purine metabolism,
where purine nucleotides
are being synthesized.
03:18
This reaction is a fairly mouthful of
reaction that you can see on the screen,
that I’m not going to read to you here.
03:23
In this reaction, another
mouthful molecule as you can see
combines with another folate to make
an additional long named molecule.
03:33
That is not important here.
03:34
What’s important is actually
what’s being added.
03:36
And what’s being added in
each case is a formyl group.
03:39
A formyl group, you
remember, is an aldehyde
and we can see that aldehyde
being added to the growing chain
in the green box on the upper right.
03:47
We can also see the similar
reaction occurring on the bottom
and there is the addition of
aldehyde that’s occurring.
03:53
We can see that in the bottom
reaction, we’re getting very close
to synthesizing a complete
intact purine molecule.
04:01
Now, folates, as I said, are very important
in the synthesis of thymidylate nucleotides
from uracil-containing nucleotides and
this is a very interesting reaction.
04:10
It looks a lot more complicated
than it really is.
04:13
We see on the left, on the
top, one of the folates,
so the folate is involved
in this reaction.
04:19
We see the uracil-containing
nucleotide on bottom.
04:23
There, in the green square,
is the methylene group
that is actually added to the
uridine-containing nucleotide
as the reaction
precedes to the right.
04:33
The intermediate is shown here
and what happens in this process
is we see this methylene group that
becomes attached to the uracil
and the attachment is shown
on the molecule on the right.
04:46
There is that.
04:47
Now what’s happened here is the
methylene group has been added,
but it has been converted
into a methyl group
which requires an additional reduction.
04:56
The reduction comes from the
oxidation of the tetrahydrofolate.
05:01
So we started from
tetrahydrofolate after we
oxidize it or ending
up with dihydrofolate.
05:07
And that turns out to
be very significant.
05:10
So the formation of dihydrofolate
is a bit of a problem for the cell
because the formation of
dihydrofolate is a dead end.
05:19
Dihydrofolate cannot readily be
converted back into the other folates.
05:23
We will see that process in just a
little bit unless itself is changed.
05:28
This reaction has to
recycle dihydrofolate.
05:31
We will see that there is an
enzyme involved in this process.
05:35
Now, dihydrofolate looks
like this and again,
the structure is an important
consideration here.
05:40
The important thing is dihydrofolate must
be reduced.
05:43
Remember it got oxidized.
05:45
Dihydrofolate has to be reduced
back to tetrahydrofolate.
05:49
And the enzyme that catalyzes this reaction
is known as dihydrofolate reductase.
05:54
It uses the electrons, NADPH,
to create tetrahydrofolate.
05:59
And as long as everything is preceding
normal, this reaction goes along just fine
and the cell replenishes is tetrahydrofolate
after it makes thymidine nucleotides.
06:09
Well, this enzyme turns out to be
the target for an anticancer drug.
06:13
And this target works because it messes
with the nucleotide
metabolism of cancer cells.
06:20
Tetrahydrofolate, of course, is
something that can readily be converted
into the other folates
unlike dihydrofolate.
06:26
So once this tetrahydrofolate has
been regenerated by this enzyme,
everything is fine.
06:31
The target of this medication that
is used to target this enzyme,
dihydrofolate reductase,
is known as methotrexate.
06:39
And as you look on methotrexate,
you see that it looks very similar
to the dihydrofolate
that's on the left.
06:45
It turns out that methotrexate
is a competitive inhibitor
of the dihydrofolate
reductase enzyme.
06:51
In the presence of methotrexate,
the enzyme will not function.
06:55
And when the enzyme does not function,
then tetrahydrofolate can’t be made.
06:59
Dihydrofolate is left as a dead end.
07:01
Well, after a few cycles of
making thymidine nucleotides,
this cell will run out of its folate so
will convert everything into dihydrofolate
and it can’t be produced outwards.
07:11
The reason that methotrexate works
in some cases as an anticancer drug
is because rapidly dividing cells
are needing nucleotides faster.
07:20
And if you give cells that are
rapidly dividing methotrexate,
for a short period of time, they will
be much more likely to die then cells
that are dividing more slowly and don’t
have such a rapid need for nucleotides.
07:32
Methotrexate is an important
drug in this medication.
07:35
It’s a fairly severe drug because it’s
using a hammer to really knock the cell
but for certain cancers
that are very aggressive,
this may play an important role.