Hi. I'm Dr. Chris Masterjohn of
chrismasterjohphd.com, and you are
watching Masterclass with Masterjohn.
And today we are in our tenth in a
series of lessons on the antioxidant
defense system. And what we're going to
be doing today is looking at how
glutathione transfers the burden of
supplying reducing power from the
antioxidant system to the system of
energy metabolism, and in doing so
implies everything that supports the
system of energy metabolism as equally
important to the antioxidant system as
everything in the antioxidant system.
Shown on the screen is a mini diagram
summarizing this principle. So 2 GSH can
be oxidized to form GSSG and the system
of energy metabolism is what recycles
GSSG back to GSH. Where this happens is
in an enzyme called glutathione
reductase; and in the diagram on the
screen glutathione reductase is shown in
blue and it is abbreviated GR. Glutathione
reductase requires two B vitamins for its
function. First of all, riboflavin
is connected to the nucleotide ADP in a
larger structure called FAD. And FAD can
carry two electrons and two hydrogen
ions. When it's carrying them, it's called
FADH2. We do the same thing for another
energy carrier called NADPH, and here we
have the B vitamin, niacin that's
connected to ribose, and ADP, and is
phosphorylated, and that's NADP+
when it's loaded with two hydrogen ions
and two electrons, it becomes NADPH and
one of those hydrogen ions is leftover
being carried in solution alongside it
ready to react with it.
Niacin is vitamin B3, riboflavin is vitamin B2.
Now NADPH is a diffusable energy carrier
that is not connected to the glutathione
reductase enzyme; whereas FAD is
covalently bonded to glutathione
reductase as what we call a prosthetic
group. If you imagine that you have a
prosthetic joint, that new hip is part of
you right, so FAD is the prosthetic
group of the glutathione reductase enzyme
and is part of the enzyme, it never leaves. So we could
say that the glutathione reductase
enzyme represents the interface between
the system of energy metabolism and the
antioxidant system. Glutathione is
properly part of the antioxidant system,
NADPH is properly part of the system
energy metabolism. It's carrying energy
from the system of energy metabolism,
bringing it to the glutathione reductase
enzyme, and FAD is standing at the
interface transferring that energy from
NADPH to glutathione. So the way this
happens, NADPH dumps off its reducing
power, FAD picks it up becomes FADH2,
FADH2 drops it off to GSSG, splits
that apart, reduces the sulfhydryl groups,
and generates 2 GSH. In order to
understand how NADPH is deriving the
energy from the system of energy
metabolism, we need to talk about what
NADPH is in a little bit more detail. Now
previously we talked about how we can
measure the reducing power of the
glutathione pool based on its redox
status measured in millivolts and the
more negative the number, the greater the
reducing power. And we talked about how
that was dependent on the concentrations
of glutathione and GSSG and their ratio.
We can apply that same principle of
redox status to looking at these energy
carriers such as NADPH, NADH, and FADH2;
And the first way
we can do that is to talk about their
standard redox potential, which is a way
of looking at the intrinsic reducing
power of the molecule itself. And when we
look at standard redox potentials, the
assumptions are listed at the bottom of
the screen, and they assume that we have
equal concentrations of the reduced and
oxidized form, technically one molar of
each; and they assume particular
temperature, pH, atmospheric pressure, and
so on.
We don't really care for the purposes of
this lesson about any of that stuff,
except to say that when we measure the
standard redox potential we are trying to
look at the intrinsic reducing power of
a molecule independent of its
concentrations.
So when we do that, we see that NADPH
and NADP+, has a standard redox
potential of negative 320 millivolts. NADH
and NAD+ has the same exact standard
redox potential, and the only
difference between those two molecules
is that NADPH or NADP+ has a phosphate
group added to it. So to say that the
intrinsic reducing power of each of
these redox couples is identical, is to
say that this phosphate group has no
effect on the intrinsic reducing power
of the molecule. If we compare them to
FAD, then FAD has a significantly less
negative reducing power. It has negative
two hundred twenty millivolts for a
standard redox potential. So if FAD
is less reducing, then it's not very
surprising that in the glutathione
reductase enzyme, the electrons flow from
NADPH, the more reducing of the two, to FAD, the
less reducing of the two. And then to
glutathione, even less reducing of the
three. The significance of the phosphate
on NADP is it allows our bodies to
regulate the pool of NADPH differently
from the pool of NADH. And to use a
totally different set of enzymes to
metabolize each one of those.
And so it allows a functional split
between the two redox couples, and the
NADP is typically maintained with, if we
take the cytosol of hepatocytes as an
example, liver cells, the NADP+ to NADPH ratio
tends to be about 0.1. That means there's
ten times more NADPH then NADP+. By
contrast, NAD+ to NADH ratio, in the same
compartment, tends to be about a thousand.
That means there's a thousand times more
NAD+ than NADH. That's a 10,000 fold difference
between the two ratios, where NADPH is
maintained primarily in the reduced form,
and NAD+ is maintained primarily in the
oxidized form. And what that does is
allow a split in functional purposes
where NADPH is used for reductive
anabolic purposes, and NAD+ is used for
oxidative catabolic purposes. That means
when we're breaking things down we're using
NAD+, and when we're building things up or when
we're recycling things, we're using NADPH.
Now this is going to be reflected in
their actual redox status. What I cited
before was the standard redox potential
that assumed equal concentrations one
molar of each. That's not the
concentrations that we find in liver
cells. And so just like we were talking
before, about how the cell can have
different redox status for different
pools of glutathione in different
compartments and those can change over
time based on the concentrations. The
same thing is true of NADPH; its true
redox status is going to depend on its
concentration at that moment, and it's
going to be very reducing. NAD+, its
true redox status is going to depend on
its concentration at that moment and
it's going to be very oxidizing. NADPH is
primarily getting its reducing power
from glucose through a shunt that is
split off from glycolysis. Shown on the
screen is a basic overview of what
happens in glycolysis. We have 10
enzymatic reactions that split the
glucose molecule in half, and oxidize it
to two molecules of pyruvate. Since those
molecules of pyruvate are oxidized,
what's doing the oxidizing is NAD+,
the oxidizing agent, the agent that splits
things apart like glucose is getting
split in half; and NADH is taking those
hydrogen ions and electrons and carrying
them to the electron transport chain to
produce ATP.
However, in glycolysis, we have the
opportunity for a shunt. And this term
shunt is taken from engineering. And if
you have a circuit where you leave the
circuit and you come back to the circuit,
that's a shunt. And so this can be called
the pentose phosphate pathway because
it's where we get pentose phosphates, or it
can be called the hexose monophosphate
shunt, because we take hexose phosphates
make pentose phosphates, and then
rearrange them and send them back to
glycolysis. And when it operates in that
closed circuit that's a shunt that
leaves glycolysis and comes back to
glycolysis. Whether you call it the hexose
monophosphate shunt, or the pentose
phosphate pathway, it's the same thing.
In this, which is summarized on the
screen, we're taking hexose phosphates to make
this is six-carbon sugar to make a
pentose phosphate which is a five-carbon
sugar. In the process, we're removing one
carbon dioxide and instead of oxidizing
the molecule with NAD, we use NADP+,
and in doing so, we make NADPH. And the
two NADPH that are formed in the
conversion of one hexose phosphate to a
pentose phosphate, is the major
overwhelmingly primary source of NADPH
in the cell. Now pentose phosphates serve a variety of
purposes. Our demands for five carbon
sugars include the ribose of RNA, the
deoxyribose of DNA, the five carbon sugars
are also found in all these energy
carriers that we were looking at before
like NAD, and FAD, ATP, NADP, coenzyme A,
which is a vitamin B5 derived molecule
that's shuttling around two carbon
units and other molecules. So we're
actually deriving two functions from
this pathway. One is to get NADPH, and
one is to get pentosases. The reason it
operates as a shunt is because what
happens when you need NADPH, but you
don't need any pentoses? NADPH is used not
only for the recycling of glutathione,
but also the recycling of folate, and the
recycling of vitamin K, and for the
synthesis of all kinds of things:
nucleotides, cholesterol, fatty acids.
So many processes rely on NADPH, that our
needs for it are higher than our needs for the
pentoses. So what happens is when we don't
need the pentoses, what we do is just
send them back to glycolysis. Summarized on
the screen, we can have six pentoses if we
arrange them into four hexoses and two trioses.
We can send the hexoses back to
glycolysis here, we can send the trioses
back to glycolysis here, and all of those
can undergo the subsequent metabolism to
pyruvate, and we were able to gain NADPH
out of that process. So, if we need a lot
of NADPH, and we don't need a lot of
pentoses, we just continually operate
this in a shunt and go back-and-forth,
back-and-forth, back-and-forth producing
NADPH every time you run the cycle. The
regulation of this pathway is primarily
dependent on our need for NADPH, because
when we use NADPH at a high rate, it
could, it gets converted to NADP+. NADP+ is a
reactant in the conversion of hexose
phosphates to pentose phosphates, and the
rate of a chemical reaction is always
directly proportional to the
concentration of reactants. And so we have,
when we have more NADP+ that alone
is sufficient to drive this reaction
forward at a greater rate, and to make
more NADPH whenever we need more NADPH.
So to summarize what this means,
glucose is the ultimate antioxidant
because it is providing the reducing
power that used to recycle glutathione.
Glucose donates reducing power to NADP+,
itself becoming a pentose and converting
NADP+ to NADPH. NADPH donates reducing
power to FAD on the glutathione
reductase enzyme.
FAD becomes FADH2, and that enables the
glutathione reductase enzyme to take
GSSG and convert it to 2 GSH, then GSH can
continue to support all of its roles in
the antioxidant defense system. Now this
doesn't necessarily mean
that more carbohydrate is better. And
that's because when you have an excess
of carbohydrate beyond your capacity to
store it as glycogen, you convert the
carbohydrate to fat, and the conversion
of carbohydrate to fat, called de novo
lipogenesis, consumes NADPH. What's shown on the
screen is, uh I love the title of this
study, it's called: "Glycogen storage
capacity and de novo lipogenesis during
massive carbohydrate overfeeding in man."
And what they did in this study was they
took people, they put them on a
low-carbohydrate diet and exposed them to
a lot of high-intensity exercise. That
brought their glycogen stores down as
low as it could possibly go, and then
they switched them to an eighty-six
percent carbohydrate diet, that was it
wasn't just high-carbohydrate, it was
hyper caloric, so well beyond their
normal needs for calories, such that the
total amount of carbohydrate in the
diet exceeded their total needs for
calories.
And what you can see is that, over the
first couple of days what happens is
first of all, they start burning all of
their energy as carbohydrate. You can see
they're burning 500 grams a day, 500
grams a day of carbohydrate, that's like
2,000 calories. So they're deriving most
of their energy from carbohydrate and
they're starting to put the excess in
glycogen. You can see, over the course of
day three to day seven, glycogen storage
capacity tops off and after day 7
they're not storing anything else in
glycogen because it's full. As glycogen
starts to get maybe a third full, or
between a third and a half full,
de novo lipogenesis starts happening;
and it starts increasing as the glycogen
storage gets full. Once the glycogen storage
gets full, de novo lipogenesis just takes over.
So whatever they, whatever they can burn
for energy they burn for energy, and all of
the excess gets converted to fat. Now the
study that I showed on the screen is
extreme.
I can't think of many situations in real
life where your total carbohydrate
intake would exceed your total need for
calories. I can think of maybe a food
eating contest where you eat as many hot
dogs as you can that have a lot of hot
dog buns, and I can think of some tribal
rituals of intentional fattening; but for
the most part, when people are operating
in a eucaloric diet or a slight caloric excess,
de novo lipogenesis is a minor
pathway. If you take people on a standard
American diet, they're making one to two
grams per day of fat from carbohydrate.
That increases to three to six grams for females,
during certain parts of the menstrual
cycle, and if you look at obese people or
people with certain diseases, that
you can maybe get up to three to six grams per
day with those conditions as well. If you
were to eat a very high carbohydrate
diet, such as a 70-percent carbohydrate
diet, and it's not hypercaloric, you can
probably push de novo lipogenesis up to
10 grams per day. I don't know of any
evidence that that in and of itself
compromises antioxidant activity, but
certainly you could say that if you're
in the range were you are increasing
de nova lipogenesis with increased
carbohydrate intake, then it's unclear
whether you're getting any net benefit
to NADPH, given the fact that you're
consuming it in the process of de novo
lipogenesis. In addition, the more
carbohydrate you have, the more insulin
you have. And when I say insulin, I mean
the higher the ratio of insulin to
glucagon. And when you have a higher
ratio of insulin to glucagon, you have
high levels of intracellular insulin
signaling that cause you to burn
carbohydrate for energy. And you do that
through glycolysis. So insulin is causing
the downstream metabolism of glucose to
pyruvate, which actually detracts from the
glucose available for the NADPH
production. If you restrict carbohydrate,
you're going to have lower insulin
signaling, so you're going to get less
conversion of glucose to pyruvate, and
that's going to preserve hexose
phosphates for the production of pentose
phosphates, and for the production of
NADPH. Additionally, when you're
restricting carbohydrate, you have other
sources of glucose and that's mainly
amino acids, and most textbooks will only
tell you about amino acids. Maybe ten
percent of your needs during this time
are being met by fatty acids, but in the
process of gluconeogenesis you take
amino acids or fatty acids and you make
glucose. That glucose is now available for the
pentose phosphate pathway. So glucose is
the ultimate antioxidant, but there's
probably a very wide range of
carbohydrate intakes that would allow
you to have enough glucose for the
pentose phosphate pathway because when
you restrict carbohydrate, even to the
degree that we would call it a
low-carbohydrate diet, you have
gluconeogenesis that allows you to get
more glucose and you have a decrement
in insulin signaling which preserves
glucose for the pentose phosphate
pathway. On the other end of the spectrum,
when you provide more glucose, you
have more dietary glucose available for
the pentose phosphate pathway, but you're
also increasing insulin causing you to
burn it for energy. And eventually you
get to the point where you're increasing
the conversion of carbohydrates to fat
which itself consumes NADPH. So what is
the optimal amount of carbohydrate?
I don't know the answer to that, but I suspect
that there is none in the sense that
there's probably an extraordinarily
large range of carbohydrate intakes that
can support the pentose phosphate
pathway, and it's only at the extremes of
either intake where you can start to
develop a problem. However, insulin
signaling itself plays an independent
role in increasing glutathione synthesis as
discussed before. So carbohydrate intake
is going to be more important to
antioxidant defense because it provides
the signal of insulin to make glutathione.
And variations of carbohydrate
intakes across the spectrum of what most
people are eating are probably going to be
much less important as influencers of
the glucose available for the pentose
phosphate pathway. Nevertheless,
we can look at things like niacin and
riboflavin and see that they are making
critical contributions to antioxidant
status. In the next lesson, we'll also come
back to look at how thiamine is another
B vitamin that's important for
supporting the pentose phosphate pathway
and energy metabolism in general. And
how even ATP production and everything that
supports that is critical to the
antioxidant defense system.
Alright, I hope you enjoyed this lesson.
Signing off, this is Chris Masterjohn of
chrismasterjohphd.com. And you have been
watching Masterclass with Masterjohn.
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