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Regulation of Pyruvate Dehydrogenase

October 15, 2019

– [Instructor] Before
talking about the regulation that occurs inside the citric acid cycle, let’s take a moment and
step back and talk about what regulates the entry
into the citric acid cycle. So remember that a molecule called Acetyl-CoA is what really enters
the citric acid cycle and is oxidized into the
carbon dioxide molecules as it kind of goes around
in a citric acid cycle. And instead of writing out
the entire chemical formula I just want to abbreviate
this as a two carbon molecule with the coenzyme
A functional group. Which is actually a thiol
group, a sulfur group. So I’ll just write, two carbons with a sulfur coenzyme group for short. Now I want to remind you
what produces Acetyl-CoA. So remember we have
glycolysis and from glycolysis which begins the breakdown of glucose, we produce pyrate. And so it’s the pyrate that
travels from the cytosol into the mitochondria that’s
converted into Acetyl-CoA by a very special enzyme called pyruvate dehydrogenase. And remember dehydrogenase means we’re dehydrogenating or oxidizing our molecule. And so if we’re oxidizing it
shouldn’t surprise you then that this enzyme has a co factor indeed. It requires NAD+ , which is converted into NADH, or I should say reduced
into NADH as pyruvate is being oxidized into Acetyl-CoA. And I want to remind you that pyruvate is a three carbon molecule. So it’s losing a carbon molecule. You can see here because
Acetyl-CoA is two carbons but pyruvate is three
so a carbon must be lost during this reaction. And indeed, part of the
oxidation process releases a carbon dioxide molecule. And finally, I also want to note as well that of course, in order
to get this coenzyme A here we need to have that
as a substrate as well. Now one important point about this step, this entry point into
the citric acid cycle, is that this reaction,
in going from pyruvate to Acetyl-CoA, is irreversible. Which is why I’m kind of bolding
this unidirectional arrow here to tell you that while
we can take pyruvate into Acetyl-CoA, it’s not
possible to take Acetyl-CoA and turn it into pyruvate. And remember, that when we
say a reaction is irreversible that’s just another
way to say that we have a pretty large negative Delta G value. Now the big point I want to make is that because this reaction is
irreversible it makes it a nice target for the cell
and for lots of regulation. And remember that regulation often occurs on irreversible steps
because these are the steps that if you open basically, then the ball will keep rolling down the pathway. So we want to make sure that these irreversible steps are tightly regulated. But just as a quick
side note before we talk about the actual regulation, it’s also kind of nice to recognize that fatty acids can also
contribute to the production of Acetyl-CoA when they’re broken down. But because this reaction is irreversible, this Acetyl-CoA produced by fatty acids cannot contribute to the
production of pyruvate and therefor, cannot
contribute to the production of gluconeogenesis. Which remember, if you recall, occurs by using pyruvate
as one of the substrates. And so that’s why you
might hear some text books kind of quote this fact that fatty acids, or at least most of
them, cannot contribute to the production of glucose. All right, so let’s leave
that tangent for a moment and let’s return to our question which is, how is the production
of Acetyl-CoA regulated? And to answer this
question I’d first like to kind of just start off
with the big picture. Which is, what is the
purpose of Acetyl-CoA? And the two major purposes are one, which most people are familiar with which is entry into the citric acid cycle. And of course, the entry
into the citric acid cycle allows Acetyl-CoA to be
oxidized into carbon dioxide and produce the electron
carrier molecules NADH and FADH two which then enter the electron transfer
chain to produce ATP. All right, so that’s one purpose. But another purpose is also, remember how I mentioned that fatty acids can be broken down to Acetyl-CoA? Well Acetyl-CoA can also be used to produce fatty acids when
ATP levels are high. And so this is kind of this second major use of Acetyl-CoA in the body. And so keep these kind
of two major pathways for Acetyl-CoA in mind as we talk about how this step is regulated. Now I should say at this
point that the major form of regulation, in this case,
is allosteric regulation of the pyruvate dehydrogenase enzyme. So remember, that’s just
a fancy way for saying that there are molecules
that can essentially bind to a part of the enzyme
to make it work better. In which case it’s an allosteric activator or to make it not work as good, in which case it would be
an allosteric inhibitor. And, I kind of remember
that this is the main form of regulation in this
step because it really allows this step to kind
of assess the energy state of the body by looking at, kind of, what molecules it has floating around. And in fact, let’s go ahead and write out what some of the allosteric
activators and inhibitors are off this pyruvate dehydrogenase enzyme and you’ll kind of see what I mean when I talk about the
energy state of the cell. Now one important principle that I use to kind of remind myself what activates and inhibits this enzyme is to remember what products and substrates
are for this reaction. And I kind of, essentially, I think back to Le Chatelier’s principle and justify to myself that if we have an accumulation of substrates these are going to want to be allosteric activators. Essentially they want to push
this kind of reaction forward. And if we have an
accumulation of the products these are going to probably most likely be allosteric inhibitors, because they’re going to, you know, assign that too much is being produced and we can put a break on the reaction. And so indeed, the allosteric activators include the substrates CoA as well as NAD+ and even pyruvate. And then the inhibitors
include Acetyl-CoA of course, as well as NADH. Now a couple more allosteric
activators and inhibitors that might not be immediately obvious, but will make sense once we discuss them, are ATP is also a negative
allosteric inhibitor. On the flip side, AMP is
a allosteric activator. And additionally, fatty acids can also be an additional allosteric inhibitor and calcium can be an
additional allosteric activator. All right, so how can we reason out these final allosteric
activators and inhibitors? Well first simply realize that the levels of ATP and AMP again are getting at this
energy state as the cell. It’s a way for the body to assess if it needs to shuttle more Acetyl-CoA through the citric acid
cycle and then, you know, channel all of these
electron carrier molecules to the electron transfer chain or whether it has enough ATP and it can slow down the flux of Acetyl-CoA through the citric acid cycle. And so it should make sense to you that having a low-energy
state in the cell, indicated by lots of AMP,
should activate this, should alert the body to
produce more Acetyl-CoA. But if we have enough, if we have enough ATP
lying around, then the, you know, this reaction
can essentially slow down. Now this calcium here may
not be immediately obvious but I’ll remind you that, remember that exercising skeletal muscle involves the influx of a lot of calcium. So when you’re exercising of course your energy needs to go up and so in skeletal muscle this free calcium in the cell is kind of
a nice alert to say, you know what, we’re
gonna need more energy. Let’s start producing more Acetyl-CoA. And finally, these fatty acids, why do these fatty acids inhibit the production of Acetyl-CoA? Well of course I remind you here of the second purpose of Acetyl-CoA which is to produce the
synthesis of fatty acids. And so if we have enough
fatty acids in the body again it can be a signal
to the cell to say, you know what, we don’t
need any more Acetyl-CoA. We can slow this process down. So at the end of the
day there might be a lot of these allosteric
regulators to keep track of but just go back to the
basics and remind yourself what is a substrate, what is a product, and what the energy state of the cell is. And I think you’ll be able
to reason out most of these.

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  • Reply Johannes Schlüter June 5, 2014 at 1:36 am

    very very helpfull thanks

  • Reply Martin M June 17, 2014 at 10:39 pm

    Great video with excellent clarity. 

  • Reply Nataly González September 2, 2014 at 8:44 pm

    OMG! this is soooooo helpful for understanding the allosteric regulation of the PDH, thanks a lot =)

  • Reply GoogleIs StartinToSuck November 20, 2014 at 8:42 pm

    bloody annoying voice

  • Reply Bandari Al-jabri January 4, 2015 at 8:39 pm

    Your explanations are the best! biochem may not be so hard after all  thank  you!

  • Reply Alem April 11, 2015 at 4:19 pm

    I love those cute voices :3 jk jk.. good explanation! I might succeed in just 3 days of studying xD

  • Reply Nyan Cat May 3, 2015 at 2:32 pm

    You have said nothing about regulation.All you have explained is what the inhibitors  activators are for the enzyme. You should reconsider renaming your video. It is very misleading.

  • Reply bellamuhko June 13, 2015 at 7:15 pm

    This is a bit misleading, Pyruvate dehydrogenase is 1 enzyme in the pyruvate dehydrogenase complex, which is a 3-enzyme complex, using 5 co-factors not the 2 mentioned in the video.

  • Reply Michael Tsang June 21, 2015 at 3:26 pm

    She sound like asian.

  • Reply Keishla Jim August 10, 2015 at 9:23 pm

    Where is go the Co2 that  was remove of pyruvate?

  • Reply Abbas Sizar February 8, 2016 at 5:42 am

    to be honest i stopped watching khan academy because this voice can get irritating. I cant stand the lisp anymore 🙁

  • Reply Lisa Garrison April 24, 2016 at 6:03 pm

    This makes a lot of sense, thank you!

  • Reply Jianing Liang August 20, 2016 at 2:15 am

    super clear!

  • Reply Nada Dew December 15, 2016 at 9:17 am

    Thanks 😄

  • Reply marcus cooley January 5, 2017 at 11:18 pm

    Correction fatty acids can contribute to glucose. The glycerol from triaglycerol can be used to synthesize glucose via gluconeogenesis. Glycerol –> Glycerol phosphate –> DHAP-> glyceraldehyde 3 Phosphate.

  • Reply booloob May 21, 2017 at 12:42 am

    you are also not describing allosteric regulation

  • Reply Slwan Kadbeh September 10, 2017 at 12:50 am

    it's just about Allosteric Regulation. there are other important types concerning phos and dephos

  • Reply Aly Aly October 22, 2017 at 6:14 am

    Gosh your voice is annoying as hell. I can't concentrate cause of it!

  • Reply baldy hardnut April 8, 2018 at 11:28 pm

    Soooo basically link reaction…?

  • Reply Demi K April 20, 2018 at 8:30 am

    this girl talks so fast its fustrating

  • Reply Lazar Kulašević June 16, 2018 at 8:35 pm

    Who let Bernadette talk on KhanAcademy?

  • Reply 視覺美國頂級醫療技術 August 30, 2018 at 7:23 am

    Well explained. 2 enzymes other than pyruvate dehydrogenase are required for the reaction .. dihydrolipoyl transacetylase and D. Dehydrogenase. deficiency or missing those enzymes, it causes metabolism disease

  • Reply Gobinda Sethi February 12, 2019 at 5:16 am

    Work on the the voice

  • Reply Joe Nepram May 9, 2019 at 11:49 am

    Misleading video

  • Reply Lucila Alvarez September 7, 2019 at 12:15 am

    I have observed a tendency for ppl to copy & write the same idea someone else has commented on..for example about her voice which seems to be a very clear/understandable one in contrary to what all these negative comments r saying. I wonder how limited your own individual opinion spectrum has to be for that to happen…

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