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PROFESSOR: In this session, we're
going to be looking at carbohydrate biosynthesis.
Please look at Storyboard 29.
Looking at Panel A, the next set of pathways
on which we're going to focus concerns
carbohydrate biosynthesis.
First, we're going to look at the pathway by which glycogen
is made.
As you know, glycogen is the polymeric form of glucose
that's very readily available for energy production.
The second pathway is gluconeogenesis.
The organs that utilize glucose as their metabolic fuel
prefer to have glucose at a concentration of about 100
milligrams per deciliter in the blood.
The challenge comes from the fact
that we eat only sporadically, and thus, levels of glucose
will go up and down depending upon the time that
has passed since our last meal.
When glucose levels drop, gluconeogenesis
is the pathway that's activated.
It takes non-carbohydrate precursors,
converts them to glucose, and then secretes the glucose
into the blood, ultimately to help
maintain a constant glucose concentration.
Looking at Panel B, our first topic
is the synthesis of glycogen. If you look back at my first two
lectures, I describe the structure of glycogen,
which is also shown here.
The piece of glycogen that I've shown
consists of a linear chain of glucose molecules connected
together through the 1 and 4 carbons.
Chemically, we call this an alpha 1, 4 linkage.
To the left of the glycogen molecule
is the non-reducing end and to the right
is the reducing end, which is connected by a tyrosine residue
to a protein called glycogenin.
Glycogenin is a variant of the glycogen synthase enzyme
we'll talk about later.
Glycogenin has the property that it
can synthesize a polymeric glucose
chain, such as the one shown, to boot up
the synthesis of glycogen.
In effect, glycogenin forms a primer molecule
such as the one shown that provides
a non-reducing end that can be extended by its sister enzyme,
glycogen synthase.
While I've drawn a linear glucose,
I want you to keep in mind, the branches
off of the six carbon of the glucoses in the chain
are possible.
As I mentioned earlier, glycogen is designed for fast breakdown.
Its glucose units will quickly enter the pathway of glycolysis
and generate ATPs in a manner of seconds.
Let's now look at Panel C. It's useful to review
the biochemical steps by which glycogen is broken down
because the exact same intermediates appear
in the reverse order in the synthesis of glycogen.
The key enzyme for glycogen breakdown,
or glycogenolysis, is glycogen phosphorylase.
Glycogen phosphorylase progressively will nip off
the non-reducing end--
that is the left-most sugar as shown--
producing oxonium ion intermediate.
And as we saw in my first lecture,
glycogen phosphorylase stereospecifically adds
inorganic phosphate to the bottom face--
that is the alpha face of the oxonium ion--
to give glucose 1-phosphate with this stereochemistry shown.
Once again, these same intermediates
are going to appear in the synthesis of glycogen.
Now let's take a look at the way that
glucose 1-phosphate interfaces with the other biosynthetic
and catabolic pathways.
Let's look at Panel D. This metabolic map
shows glycogen in the lower right-hand corner.
We can see how glycogenolosis results in glycogen breakdown
to glucose 1-phosphate, and in the reverse direction,
we can see how glucose 1-phosphate can be used to make
glycogen by way of two enzymes--
UDP Glucose Pyrophosphorylase, UGP, and Glycogen Synthase, GS.
Let's look a little deeper at other pathways
with which glucose 1 phosphate interfaces.
This schematic shows that glucose 1-phosphate
can be converted to glucose 6-phosphate
by phosphoglucomutase, PGM.
In this case, the phosphate is moved from the 1 carbon
to the 6 carbon of the glucose moiety.
The opposite reaction also occurs.
That is, if you have glucose 6-phosphate,
phosphoglucomutase will convert it to glucose 1-phosphate.
Glucose 6-phosphate is an intermediate in glycolysis,
gluconeogenesis-- which is the next pathway we're going
to look at--
and another future pathway, the pentose phosphate pathway.
All of this shows us that glucose 6-phosphate
is a crossroads and one of the branches that leads from it
and it is by way of glucose 1-phosphate.
Let's imagine a scenario in which we eat a meal.
Glucose appears in the blood as shown.
It is taken into the cell.
The enzymes hexokinase or glucokinase
will phosphorylate the glucose into glucose 6-phosphate.
If the glucose is not needed for glycolysis
or the other pathways that I mentioned,
phosphoglucomutase will convert the glucose
6-phosphate to glucose 1-phosphate,
and then in the pathway of glycogen synthesis,
glucose 1-phosphate will be polymerized into glycogen
for energy storage.
At this point, let's turn to Storyboard 30 and look
at Panel A. Now let's take a look
at the detail pathway by which glucose 1-phosphate is
converted to glycogen. At the left
is the structure of glucose 1-phosphate.
The first enzyme involved is UDP Glucose Pyrophosphorylase,
or UGP.
The second substrate in this reaction
is UTP, uridine triphosphate.
The UDP Glucose Pyrophosphorylase
catalyzes attack by the phosphate
on the 1 carbon of glucose 1-phosphate
on the alpha phosphorus of UTP.
The two products are pyrophosphate and UDP glucose.
The reaction is made thermodynamically irreversible
by hydrolysis of pyrophosphate by inorganic pyrophosphatase
into two molecules of inorganic phosphate.
The UDP glucose is the substrate for the next enzyme
in the sequenced glycogen synthase.
I'm going to divide the glycogen synthase
reaction into two parts.
In the first, we see cleavage of the bond
between the 1 carbon of the glucose
and the beta phosphate of the UDP.
This reaction liberates the UDP and generates the oxonium ions
shown in the brackets.
Structurally, this oxonium ion is the same intermediate
we saw in glycogen breakdown, but here, we're
using it as a biosynthetic reagent.
Let's look at Panel B. In this panel,
we continue the glycogen synthase reaction.
In Panel A, we generated the oxonium ion
of glucose, which is shown here, in Panel B in the lower left.
Glycogen synthase activates the hydroxyl group
on the 4 carbon of the terminal sugar residue.
That is the sugar on the non-reducing end.
The oxygen on the non-reducing sugar residue of glycogen
then attacks the bottom face of the oxonium ion
to give rise to a glycogen unit that has been extended
by one glucose residue.
I have put an asterisk on the 6 carbon
of the glucose residue that's been added to the growing
glycogen chain.