In our tour of the main pathways of
energy metabolism, we have looked at
glycogen synthesis and breakdown. In this
video, we'll consider how glucose is
metabolized in glycolysis to pyruvate,
and in fermentation to lactate or
ethanol. For the most part we're not
going to go through the individual steps
of these processes, and you are not
responsible for knowing the individual
steps for the test. If you're curious, you
can find the steps of glycolysis and
fermentation in a textbook or in
countless places on the internet. What we
do expect you to know on the test are
the starting materials and end products
of these processes, and under what
circumstances the pathways are
upregulated or downregulated. The overall
reaction carried out in the ten steps of
glycolysis is shown here. Glucose, a
6-carbon monosaccharide, is broken down
into two 3-carbon molecules called
pyruvate. During this process, there's a
net production of two ATP molecules from
two ADPs, and two inorganic phosphates.
Conversion of glucose to pyruvate is
oxidative, meaning that electrons are
taken from the carbons. These electrons
are transferred to NAD+ to make two
NADH molecules. What happens to these
product molecules? Well, the two pyruvates
can be oxidized further in the
mitochondrion in processes that will
allow synthesis of ATP. I'll talk about
that in a future video.
The two ATP molecules are useful as
sources of chemical energy, as I
previously described, and the two NADH
molecules donate their electrons to
molecules in the electron transport
chain in a process that ultimately
results in production of more ATP. We'll
go over that process in a future video
as well. A key point here, though, is that
glycolysis results in production of ATP
and compounds that can be used to make
ATP. One thing to note is that other
monosaccharides, such as galactose or
fructose, can be converted to
intermediates in glycolysis. So we can
get these products of pyruvate, ATP, and
NADH from
other monosaccharides, not just from
glucose. So how is flux through
glycolysis regulated? To answer that we
should look to the energetics of the
pathway. The Gibbs free energy values of
the metabolites in each step of
glycolysis are plotted on this graph. You
may recognize this graph from a video I
made about regulation of metabolic
pathways, when I introduced the graph but
I didn't say where it came from. I hope
you remember from that video that the
irreversible reactions, the reactions
with large negative delta G values, are
the targets of regulation of any
metabolic pathway. In glycolysis, those
reactions are the first, the third, and the
tenth reactions. These reactions are shown
on the right side of the screen here, and
are catalyzed by the three enzymes shown. To
illustrate the regulation of glycolysis,
I want to focus on the enzyme catalyzing
the third reaction, phosphofructokinase.
This enzyme is allosterically inhibited
by ATP and allosterically activated by
ADP, AMP, and inorganic phosphate. The
cellular concentrations of these
compounds reflect how much available
energy the cell has. When ATP
concentration is high, then the cell has
a lot of energy, and there's not much
need to do glycolysis, which is mainly
about making more ATP. When ADP, AMP, and
phosphate concentrations are high, then
the cell is low on energy, and glycolysis
is favored as a way to make more ATP.
Another regulator of phosphofructokinase
is citrate, which allosterically inhibits
the enzyme. Citrate is a metabolite in
the citric acid cycle, which is another
pathway used ultimately to make ATP. When
the concentration of citrate increases,
it means that movement of molecules
through the citric acid cycle is slowed,
implying the demand for ATP is low.
Therefore the cell slows down glycolysis,
which is used mainly to make ATP. And
finally, fructose-2,6-bisphosphate
activates phosphofructokinase. Now
this compound is not an intermediate
in glycolysis,
but its concentration does
increase in response to the presence of
the hormone insulin in the bloodstream,
which, as you remember, is a signal that
blood glucose concentration is high. So
this allosteric regulation of
fructose-2,6-bisphosphate is a way for insulin
in the blood to affect energy metabolism
in the cell by increasing flux through
glycolysis in response to high blood
glucose. Hexokinase and pyruvate kinase
are regulated according to similar logic.
When glucose is abundant, or ATP is
needed, the pathway is activated, but when
ATP is not needed, the pathway is
inhibited. Now, for glycolysis to continue,
you need a supply of the starting
materials. In particular, you need a way
to regenerate NAD+ from NADH. If oxygen
is present, this is not a problem.
Our cells have electron transport
pathways that remove electrons from NADH
and transfer them to other molecules,
with molecular oxygen being the ultimate
electron acceptor. During this process,
NADH is converted back to its oxidized
NAD+ form and is ready to pick up
more electrons in glycolysis. But if
oxygen is not present in the system,
our cells have nothing to transfer the
electrons to, and eventually all the NAD+
in the cell would be converted to
NADH. There would be no NAD+ left for
glycolysis to continue, meaning the cell
would not be able to use glucose to make
ATP. Certain cell types, such as skeletal
muscle cells and some microorganisms,
have developed mechanisms to regenerate
NAD+ even in so-called anaerobic
conditions, when no molecular oxygen is
present. A pathway that uses a starting
material to make ATP without net
oxidation is called a fermentation. In
one type of fermentation, which is used
in muscle cells, glucose is converted to
pyruvate, and then the pyruvate is
reduced to lactate. The electrons from
this reduction come from NADH
produced earlier in the process. So
the net amount of NAD+ in the cell does
not change, nor does the number of
electrons on the six carbons that
originally came from the glucose, but ATP
has been produced. A second strategy, used
by some microorganisms, is to convert
glucose to pyruvate, and then convert the
pyruvate to carbon dioxide and
acetaldehyde. The acetaldehyde is reduced
to ethanol, consuming NADH made earlier
in the process. Again, ATP is produced
without changing the net oxidation state
on carbon. The two fermentation pathways
are summarized on this slide. Now, note
that fermentation refers to the entire
process of converting glucose
to lactate, or glucose to ethanol and
carbon dioxide, not just the final steps
in these processes. Fermentations produce
ATP without net oxidation of the
starting materials and are a way to make
ATP under anaerobic conditions, when
molecular oxygen is not present. In the
next video, I'll describe how cells make
glucose, and the process of
gluconeogenesis.
