The three amino acids leucine,
valine and isoleucine
are the next ones I
want to consider.
Notice the branched-chain
amino acids, the BCAAs,
and they have some common
features among them in
their metabolism and some
unique features as well.
We start with them in their decarboxylation
by the attachment of a two-carbon piece
to a molecule known as
Now valine and leucine
attachment of this two-carbon
piece to pyruvate.
They have that in common.
The isoleucine pathway, by
contrast, involves the attaching
of this two-carbon piece to a
molecule of aplah-ketobutyrate.
The penultimate products that is the
precursors of these amino acids
then become the
Alpha-ketoisocaproate is a precursor of
leucine by a transamination reaction.
Alpha-ketoisovalerate is a precursor
of valine, again, by a transamination.
alpha-keto-beta-methylvalerate is a
precursor of isoleucine,
a third transamination.
Now, the synthesis of these amino
acids is important to balance.
One of the themes that we've seen in
metabolic pathways is the importance of
making the right amount, not too much,
not too little, of any given molecule.
And this is illustrated
in the slide that I
want to show here for
these three amino acids.
Now, the synthesis of these three
amino acids actually interacts
with the synthesis of the
breakdown pathway for threonine.
Threonine's breakdown involves
the enzyme threonine deaminase.
We can see that illustrated at
the top left of the screen.
The breakdown of threonine produces
the molecule alpha-ketobutyrate.
And if you recall from
what I said earlier,
alpha-ketobutyrate is the
precursor of isoleucine
that involves the transfer of a two-carbon
piece from thiamine pyrophosphate.
It's that transfer that produces the
precursor that ultimately makes
isoleucine and that's shown in the
sort of central part of the screen.
We remember that there is also a
transfer of a two-carbon piece
from thiamine pyrophosphate
to make its precursors
for valine and leucine.
So what we see is that this two-carbon
piece attached to thiamine pyrophosphate
is common to all three amino acids even
though they go in different directions.
Well, this, the way in which
these pathways interact with the
threonine deaminase pathway is
as we see on the screen here.
The starting material for isoleucine
requires the production of threonine --
the action of
And the starting material
for valine and leucine is
pyruvate which comes from
the glycolysis pathway.
There's the common
molecule of all three.
So how does the cell
balance these things?
The cell balances it by controlling
the activity of threonine deaminase,
the precursor of isoleucine -- that
makes the precursor of isoleucine.
High levels of isoleucine
will inhibit the enzyme.
Now, this is known as a
Feedback inhibition occurs when
a molecule at the end of a
metabolic pathway inhibits an
enzyme earlier in the pathway.
If the cell has too
it does not want to continue to make
the precursor alpha-ketobutyrate,
so it turns off the enzyme.
Well, if it turns off the enzyme, that
means that this balance that's shown
between alpha-ketobutyrate and pyruvate
shifts in the favor of pyruvate.
Now, pyruvate will get
to that two-carbon piece attached
to the thiamine pyrophosphate.
That will favor the production of valine
and leucine whenever isoleucine is high.
On the other hand,
when valine is high,
this will turn on the threonine
deaminase and shift the
balance away from pyruvate but
back to alpha-ketobutyrate
which now gets preferential
access to the two-carbon piece
to make the precursor
to make isoleucine.
It's a nice balance, too much of
one, favors the alternate pathway.
Now, the breakdown of the branched-chain
amino acids occurs through a
pathway known as the branched-chain
alpha-keto acid dehydrogenase complex.
That's a mouthful of a name.
We see the generalized reaction by
which this occurs at the very top.
We see the alpha-keto acid that
shown on the left schematically.
And we an R group in the lower
left part of that molecule.
That R group is a variable
portion of the molecule.
And the different things that can be attached
as that R group are shown for isoleucine,
leucine or valine, so any of those
can function as the R group there.
In this reaction catalyzed
by this enzyme,
the alpha-keto acid is
being decarboxylated to
form the molecules that
are shown on the right.
There is the decarboxylation.
And if this enzyme is
defective or deficient,
then what will happen is
a person who develops
what's known as mapla
syrup urine disease,
they're unable to break down that
precursor that's seen there,
and their urine will look
and smell like maple syrup.
Histidine is the last family of amino
acids I want to describe here.
And it's a family
that's all to itself.
There's no other amino
acid in this family,
so histidine stands unique
among all of the amino acids.
Its synthesis is
the most complex.
Histidine synthesis overlaps with
nucleotide metabolism in involving
ribulose-5-phosphate and also involving
phosphoribosyl pyrophosphate or PRPP.
Now, there are 10 complicated
steps that lead to histidine,
and I'm not going to go through
and describe each one.
The second enzyme of the pathway, which
is known as ATP phosphoribosyltransferase
is feedback inhibited by the end
product of the enzyme histidine.
So histidine as it accumulates
will turn off its own synthesis.