I want to start a discussion here talking
about the alpha-ketoglutarate family,
also called the glutamate family
because all of the amino acids
that are made in this family
include glutamate and
alpha-ketoglutarate as precursors.
Now, this is a very good place
to start our discussion
because the alpha-ketoglutarate
family starts with the process
that's very central to many
amino acid metabolic processes.
And this pathway is known
So, transamination occurs
when an alpha-keto acid
is converted into an amino acid.
And that requires a donor of amine group
which is in this case
described as amino acid X,
and that amino acid X after donating its
amine group becomes an alpha-keto acid.
So, we sort of see this swapping.
Well, that's a lot of words.
Let's take a look at what
actually happens in the process.
So, we see here alpha-ketoglutarate,
our precursor of all the amino acids
in this family that I've described.
We see to its right the
amino acid aspartate.
Aspartate is the donor of the amine
group that will help to make glutamate.
We see in this process that's
starting at the top on the left,
glutamate on the bottom left
and the process aspartate or aspartic acid
becomes oxaloacetate on the lower right.
So, this is now showing us structurally
what's happening with the words
that I've showed in
the previous slide.
The alpha-keto acid number
one is alpha-ketoglutarate.
The amino acid number
two is glutamate.
The amino acid number one, our starting
amino acid or amino acid X, is aspartate.
And our final alpha-keto
acid X is oxaloacetate.
We can actually see very simply
what's happening right here.
We see the oxygen on
And we see the amine
They're basically swapping.
And here's that swap that they do.
The oxygen goes from
alpha-ketoglutarate to oxaloacetate
and goes from aspartate
to make glutamate.
This is central to transamination
and every transamination that I've
described will have exactly this going on.
The molecules and other
transaminations will differ
in terms of what the starting materials are
but all that's happening are the
swapping I've described here.
So having understood now of what
the process of transamination is,
we can begin to understand metabolism
that's happening among many amino acids.
The next amino acid that I want to
describe the synthesis of is glutamine.
And glutamine turns out to be
central to amino acid metabolism
for a very different reason.
And it actually relates to another
lecture I will give in this series
relating to the urea cycle.
And we'll see what's happen here.
Glutamine is really important for what
I've describe as nitrogen metabolism
And when we talk about nitrogen metabolism,
we're really talking about something
that all amino acids have to have.
The amine of course containing a nitrogen.
Well, not all nitrogens get on to amino
acids as a result of transamination.
It's a very common way,
but not the only way.
In making glutamine, glutamine is
made on a very simple reaction
from glutamate as we see here.
And we've already seen
how glutamine is made.
The enzyme that catalyzes this reaction
is known as glutamine synthetase.
As you can see it requires ATP.
But we see that the nitrogen
source here is ammonia
or in this case ammonium ion which
is the same in aqueous solution.
This ammonium ion is produced as a byproduct
of breakdown of other amino acids.
And that's pretty straight
forward except when we consider
that ammonium ion or
ammonia is toxic.
So, people talk about detoxing
and all that sort of things
when they talk about their bodies
and their health and so forth.
And they, a lot of the cases, don't
understand what that actually means.
But we talk about
This is a reaction that
actually detoxifies ammonia
because it's grabbing free
ammonium which is toxic
and putting it on to amino
acid to make glutamine.
Now, this enzyme that catalyzes this
reaction is a very complicated enzyme.
We're not going to go into
all the details of it
but suffice it to say that this
reaction is important to control.
Cells don’t' want to make
too much of anything
and so this reaction is
important for grabbing ammonium
but if the cells makes too much
glutamine, it will have other problems.
So, therefore it's important to control
how much glutamine is being made.
This enzyme is regulated by
a wide variety of things
and some of them are shown
on the screen here.
These are things that
inhibit this enzyme.
The molecules that I have
drawn the boxes around
are all molecules that
are made from glutamine.
We see histidine and tryptophan
among the amino acids.
We see AMP and CTP
among the nucleotides.
And we see carbamoylphosphate and
glucosamine-6-phosphate among other molecules.
All of these are
made from glutamine.
So, why is it important that these
things inhibit the glutamine synthetase?
The reason it's important is because
as they start to accumulate,
it means that the cell
has abundant glutamine.
If they get too high,
glutamine's too high.
If they get too high, they
turn off this enzyme.
So, there's a balance
that's actually happening
in controlling the
synthesis of glutamine.
Now, the alpha-ketoglutarate family
is important because, as I said,
we have to control how many different
things are made particularly of glutamine.
So glutamine is very central to metabolism
of all the amino acids that's happening.
has multiple sites
and that's actually how it controls
the synthesis of glutamine.
Those multiple sites are
not for making glutamine
but rather for binding inhibitors.
So, you saw on the last slide
about 10 different inhibitors
that can affect the enzyme.
And there are multiple sites
on the glutamine synthetase;
one for each of the
So, as we look at the amount of
inhibition that the enzyme exhibits,
it's actually a function of how many of
those sites are bound to inhibitors.
The more inhibitors are present,
the more sites will be bound
and the more the enzyme
will be inhibited.
It's important that the enzyme
not have a simple on/off
control as we had
seen other enzymes.
But rather that we have
an up-down regulation
where we make it more
active or less active
depending upon how much these
are the molecules are needed.
The glutamine synthatase is important,
as I've said, for removing ammonia.
And this is important in many places in
the body but particularly in the brain.
As we'll see in some of the
other lectures in these series,
the accumulation of ammonia in the brain has
very important problems neurologically.
Ammonia is produced by reducing nitrites
which can be found in the diet,
by amino acid metabolism and also by
photorespiration which occurs in plants.
In the liver, glutamine oxidation,
by glutamate dehydrogenase actually
releases ammonia for release --
I'm sorry, for synthesis of urea.
And urea is the excretion product
by which we get rid of excess
amines that appear in our body.
In addition to allosteric regulation of
glutamine synthetase that I've just described,
glutamine synthetase can also be
regulated by covalent modification.
And we can see that occurring
on this slide right here.
Looking at the enzyme in
the unadenylated form,
which is the form before
the modification occurs,
we see that it is the most active or
the more active form of the enzyme.
The addition of an adenyl
group comes from ATP
and the reaction that you can see here,
catalyzed by adenylyl transferase.
This reaction is facilitated by an
additional protein known as P sub A.
The unadenylated form
of glutamine synthetase
that is the covalently
modified form is less active.
So we see this addition of this adenylyl
group actually helps the enzyme --
helps to control the enzyme in a
different way besides allosterically.
The adenylyl tranferase can in
fact remove the adenyl group
as I've described here using a
different protein called P sub D.
And this reaction is a phosphorolysis
which actually uses a phosphate
to remove the adenyl group from the
adenylyl glutamine synthetase.