00:01
Let's turn our attention now to thinking
about regulation, because, regulation is
very important for making sure that these two
pathways are not at loggerheads with each other.
00:11
Glycolysis goes as follows.
You start with glucose
2 ADPs, 2 phosphates and 2 NADs, and you
get the products shown below.
00:21
And in gluconeogenesis we are reversing the process
and if you add up all the different pieces that I
gave you in the pathway where we see that
we start with 2 pyruvates,
2 NADHs and then it take 4 ATPs
and 2 GTPs to make the glucose.
00:37
Well if you do the math what you will
see that it takes more triphosphates
to make glucose than you get out
of glucose when you break it down.
00:46
Well that makes sense there is no process that
is a 100 % efficient and this one isn't neither.
00:51
But the problem with that
arises, if we turn and we
try to run both these
pathways at the same time.
00:57
Glycolysis makes pyruvate,
pyruvate goes up to glucose,
glucose goes to glycolysis and we go in this circle that's
actually called a futile cycle, is what’s it called.
01:08
But this futile cycle does nothing
but burn ATP and GTP.
01:15
When you burn things what happens?
Heat,
and loss of essential energy that you need.
So the futile cycle should be avoided
and that cells have interesting things
setup to avoid that futile cycle.
01:30
ATP and GTP get burned as noted
but nothing but heat is produced.
01:33
Now if you are trying to generate heat that could be
useful. But usually you are not trying to generate heat.
01:40
So if we look at the regulatory enzymes,
in glycolysis and gluconeogenesis
and you are seeing the gluconeogenesis
once for the first time here.
01:48
We have discovered that many of these
have reciprocal effects or
opposite effects on one
enzyme compare to the other.
01:54
We see for example that PFK is
is activated by AMP.
02:01
That makes sense. Cells need energy.
They wanna get PFK going.
02:05
If cells need energy they
certainly don't wanna have
gluconeogenesis going because it's
gonna take energy to make glucose.
02:14
Notice that FBPase gets turned off by AMP.
02:20
Notice that PEPCK gets turned off by
ADP, that's a lower energy indicator than ATP.
02:25
And notice that pyruvate carboxylase is turned off by ADP.
02:31
So low energy things are turning off
gluconeogenesis things and turning on glycolysis.
02:37
Hexokinase is turned off glucose-6-phosophate.
That may not be apparent but
the k the times when glucose-6-phosophate is high is
when the cell has plenty of energy.
02:48
PFK is turned off by a
high energy compound, ATP.
02:51
And pyruvate kinase, the big bang
catalyzer, is also turned off by ATP.
02:59
Gluconeogenesis, on the other hand, is activated
by things that indicate high energy.
03:05
Now citrate is one of these things that
indicates high energy. With citrate,
the fructose bisphosphatase, FBPase is activated.
03:14
Another thing that indicates
high energy is acetyl-CoA.
03:19
Now acetyl-CoA you may remember is one of those
things that if it's produced on x-axis
can be a problem and you make fat when you have
high energy and if you have a lot of acetyl-CoA,
high energy. So these high energy indicators
are having opposite effects
on glycolysis and gluconeogenesis.
03:35
Now there is a couple of things here that don't really
have any relationship or any direct relationship to energy.
03:43
The most important of these is the molecule
called fructose-2,6-bisphosphate.
03:49
I mentioned in the glycolysis talk
that fructose-2,6-bisphosphate
was an activator of PFK.
03:55
And you will notice there is two + signs
by it. It's a pretty strong activator of PFK.
04:01
You will notice also that fructose-2,6-bisphosphate
has two - signs next to FBPase.
04:09
Those two enzymes
catalyze equivalent reactions.
04:13
The glycolysis direction were going down
from fructose-6-phosphate
to fructose-1,6-bisphosphate.
04:20
In the gluconeogenesis reaction we are going up from
fructose-1,6-bisphosphate back to fructose-6-phosphate.
04:26
They are catalyzing opposite things.
04:29
And notice that the regulators
having opposite effects on them.
04:32
It's turning off the gluconeogenesis enzyme at
the time it's turning on the glycolysis enzyme.
04:39
This reciprocal regulation is a very important
concept to understand in a metabolic control.
04:46
Now one of the things about fructose-2,6-bisphosphate
that I should mention is that
fructose-2,6-bisphosphate is made upon insulin stimulation.
04:55
When is insulin is made? Well
insulin is made when the liver
for example starts getting glucose from a meal.
05:04
And you might think, "Well with the meal do
I need to deal with all of that glucose?"
"Should I be burning it
like I am burning it here?"
Well it turns out that the liver has got a little
different circumstance then rest of the body.
05:14
The liver has a lot of
glucose and glucose can be toxic.
05:20
So glucose must be dealt with
and insulin is there to deal with glucose.
05:24
What insulin does is
it stimulates the uptake
of glucose and if you take up too much
of glucose you will have a problem.
05:32
So cells have to deal with
that access of glucose.
05:35
How do they deal with it? In
two ways. One is by burning it
with glycolysis and the other is by
storing it in the form of glycogen.
05:45
Insulin stimulates both of those
processes and result in the reduction
of glucose concentration inside of cells.
05:54
Now fructose-2,6-bisphosphate is broken down
by the opposite thing and the opposite
this is glucagon stimulation.
06:01
Glucagon says that there is
two little glucose around
and the liver is gotta
worry about two little glucose;
because, the liver is supplying
glucose to the rest of the body.
06:14
What is it doing? It favors gluconeogenesis.
And what does gluconeogenesis do?
It releases glucose for the body.
06:21
So the opposite effects
of insulin and glucagon
control the synthesis of fructose-2,6-bisphosphate and it
helps supply the body with its needs exactly as needed.
06:35
In this discussion I have gone through
the metabolism of other sugars
as well as the synthesis of glucose. And I
have talked about the ways in which these
pathways can be reciprocally regulated.
06:44
By balancing the pathways,
as I have described here
and using very simple concepts
of reciprocal regulation,
the cells in our body
can use and produce glucose
in the way that it needs.