Unit 04

Review of Intermediary Metabolism

Video
Review of Intermediary Metabolism Part 2

Transcript

Slide 1

The HMPS is also called the pentose phosphate pathway, because it produces
five carbon or pentose sugars that are phosphorylated. It occurs in the cytosol of
various cells types, and the purpose of the pathway is to make the reducing
equivalent NADPH as well as five carbon sugars. One unique characteristic of
the HMPS is that it can follow two different routes depending on the body’s
needs. The oxidative route will produce both pentose sugars and NADPH, while
the non-oxidative route will only produce the pentose sugars. So, the difference
between them is that the oxidative pathway makes NADPH while the non-
oxidative pathway does not. The signal for taking the oxidative route is an
increase in oxidative stress, since NADPH is used in oxidant defence, as we will
see in unit 10. This signal is mediated by changes in the ratio of NADP+, which is
oxidized, to NADPH, which is reduced. This ratio is called a “redox couple”, and it
is an important indicator of metabolic health. In a healthy cell, there will be more
NADPH, which can be used in oxidant defence, in contrast to NADP+, which
signals that the cell is under oxidative stress. Both the oxidative and non-
oxidative pathways produce five carbon pentose sugars that can be used to
produce DNA and RNA that are used in cell growth and division. The HMPS is
active when someone is well fed, and blood glucose levels are high. It is
considered anabolic metabolism as it is building products required for cell growth
and division.

Slide 2

Let’s shift now from looking at pathways that use glucose to the further
metabolism of pyruvate produced in glycolysis. Under aerobic conditions, much
of the pyruvate will be metabolized to acetyl CoA in a reaction catalyzed by the
pyruvate dehydrogenase complex. This complex is actually comprised of three
enzymes, each of which catalyzes a different reaction, and which uses several
different nutrient cofactors, including thiamine, niacin, riboflavin, and pantothenic
acid, which are all B vitamins. We will look at the way this enzyme complex
works in more detail in unit 11, but for now, we will consider it simply as the
reaction that metabolizes pyruvate to acetyl CoA. The pyruvate dehydrogenase
reaction occurs in the mitochondrial matrix, so it is limited to cells that have
mitochondria, which excludes red blood cells. The pyruvate dehydrogenase
reaction can be thought of as having three substrates, which include pyruvate,

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oxidized NAD+, and coenzyme A. Coenzyme A is commonly shown as CoA-SH,
because it has a sulfhydryl or SH functional group. The pyruvate
dehydrogenation reaction also has three products, which include reduced NADH,
CO2, and acetyl CoA. The NADH produced in this reaction can donate electrons
to the electron transport chain and produce ATP via oxidative phosphorylation.
The CO2 is a waste product that can be eliminated from the body. And the acetyl
CoA is a molecule that is carrying two carbons in its acetyl group, which can
enter the TCA cycle or be used in fat synthesis. The pyruvate dehydrogenase
reaction takes place under aerobic conditions, but like glycolysis, it is always
active, regardless of blood glucose levels.

Slide 3

If the acetyl CoA produced by the pyruvate dehydrogenase reaction is to be fully

oxidized, it will enter the TCA cycle. This cycle is called the tricarboxylic acid, or
TCA cycle, because some of the substrates contain three carboxylic acid
functional groups. It is also known as the citric acid cycle, named after one of the
substrates in the cycle, or the Kreb’s cycle, named after the scientist who
characterized it. Although it is regenerative, it is generally considered that the first
reaction in the cycle is the one in which acetyl CoA reacts with four carbon
oxaloacetate to form six carbon citrate, or citric acid. We won’t consider all of the
reactions of the TCA cycle, but you should be aware of the fact that there is one
molecule in the cycle that produces the ATP equivalent GTP via substrate level
phosphorylation, and that there are several reactions that produce reducing
equivalents including NADH and FADH2, which can subsequently donate
electrons to the electron transport chain to produce ATP via oxidative
phosphorylation. Like the pyruvate dehydrogenase reaction, the TCA cycle
occurs in the mitochondrial matrix, and so does not occur in cells without
mitochondria like the red blood cells. An important point regarding the TCA cycle
is that it is an important point of integration with other metabolic pathways, with
intermediates regularly leaving and arriving to participate in other pathways.
Because molecules enter and leave the cycle, it is possible for the cycle to slow
down under certain conditions, such as when oxaloacetate is used in
gluconeogenesis. This will become clearer as the course proceeds and we look
at the integration of metabolism in more detail. Overall, the TCA cycle is
considered to be catabolic, but like glycolysis and the pyruvate dehydrogenase
reaction, it is always active, regardless of blood glucose levels.

Slide 4

Now that we’ve gone through the complete oxidation of glucose via glycolysis,
the pyruvate dehydrogenase reaction, and the TCA cycle, we have produced
products including ATP or ATP equivalents or reducing equivalents that can
donate electrons to the electron transport chain for production of ATP via
oxidative phosphorylation. At maximum efficiency, the electron transport chain
will produce 3 ATP per molecule of NADH and 2 ATP per molecule of
FADH2.This allows us to calculate the energy yield from different metabolic

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processes. The first part of this table shows the energy yield from the TCA cycle,
using a single acetyl CoA molecule. The cycle will yield a total of 3 NADH, 1
GTP, and 1 FADH2. So, the total yield of ATP from NADH will be 9; from GTP it
will be 1, since GTP is an ATP equivalent; and from FADH2 it will be 2. This
gives a total of 12 ATP produced per molecule of acetyl CoA per turn of the TCA
cycle. If we look at the second part of this table, we see energy yield per
molecule of glucose. In glycolysis, there was a net production of 2 ATP as well as
production of 2 NADH. This yields a total of 8 ATP considering that one NADH
will yield 3 ATP at maximum efficiency. The pyruvate dehydrogenase reaction
also yielded 2 NADH, which will yield 6 ATP at maximum efficiency. And if we
consider what we saw in the first table, which was that each acetyl CoA yields 12
ATP, since each glucose molecule yields 2 acetyl CoA molecules, a single
molecule of glucose will yield 24 ATP in the TCA cycle. In total, this means that
throughout the cumulative oxidation of one molecule of glucose, a total of
approximately 38 molecules of ATP will be produced.

Slide 5

The last metabolic pathway that we will look at is gluconeogenesis. This is the
production of glucose from non-glucose substrates, including lactate, pyruvate,
glucogenic amino acids, and TCA cycle intermediates. This means that there are
many substrates in the body, including protein, that can be used to support blood
glucose. The pathway of gluconeogenesis is primarily active when someone has
not eaten, and blood glucose levels are low, although it can also be active when
someone is eating a high protein or fat diet and glucose intake is greatly
decreased. Low blood glucose is the main trigger for gluconeogenesis, which is
activated by glucagon. Blood glucose has to be maintained in order to meet the
metabolic needs of the red blood cells, which are obligate users of glucose,
meaning that they can’t use any other substrates as fuel sources. The brain is
also an obligate glucose user under some conditions. As previously mentioned,
in gluconeogenesis, many of the same reactions of glycolysis occur, although in
the opposite direction. Since glycolysis occurs in the cytosol, it is not surprising
that gluconeogenesis occurs in the same cellular location. The irreversible
reactions of glycolysis are different in gluconeogenesis, and require different
substrates, products, and/or enzymes. As also previously mentioned, despite the
fact that gluconeogenesis is active when someone isn’t eating, it is an energy
consuming process, requiring 6 ATP to go through the entire pathway. It also
consumes 2 NADH, meaning that these molecules are no longer able to donate
electrons to the electron transport chain. Gluconeogenesis primarily occurs in the
liver, although there is some activity in the kidney, and it also produces CO2 as a
waste product.

Slide 6

As a leaving point, consider this figure, which illustrates the interactions between
the metabolism of proteins, carbohydrates and lipids. Although we focus in unit
04 on the metabolism of carbohydrates, in subsequent units we will consider in

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detail the metabolism of proteins and lipids, and you will see how these link
clearly with the metabolism discussed already. We can think of this as the “big
picture” of metabolism, and it is one of the important learning outcomes of this
course.

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