Leah here from leah4sci.com/mcat and in this video we're going to look at Glycolysis starting
with phase 1 the investment phase
What is glycolysis?
Glycolysis comes from the word glyco which should remind you of glucose and lysis which
means to break, glycolysis is the reaction in which we take a 6 carbon glucose and break
into 2, 3 carbon pyruvates + energy, this is a universal metabolism pathway used not
only in humans but many other animals and even microorganisms.
Glycolysis is a very involved reaction and for the MCAT you have to know the names, the
structures and the enzymes and so I want to break this down where in part 1 we're going
to look at the investment phase where we put energy in, part 2 is the payout phase where
we now get some energy out, we'll summarize it all in part 3 from a logical rather than
a technical perspective.
Now before you worry about copying down all of the structures, the names and the enzymes
I've got you covered with a glycolysis cheat sheet which you can find on my website along
with the other videos leah4sci.com/glycolysis or see the link below.
The first step in glycolysis is to trap a molecule of glucose in the cell, specifically
the alpha D glucose.
As a reminder, humans can only utilize the alpha D glucose because we are very "baaaaaad"
at utilizing the beta, we are bad at utilizing beta but ruminant animals like cows and goats
and sheep they have microorganisms that help them digest the energy found in grass but
we don't.
In step 1 in order to trap the glucose in the cell, we add a negative phosphate group
onto carbon 6, the product is a glucose 6 phosphate or G6P, that phosphate group means
that glucose can no longer get back out through the glut transporter which is how it got in
to the cell and that means it's now available to be attacked by additional enzymes undergoing
additional reactions without escaping, step 1 in glycolysis is a 1 way reaction, this
means that once glucose is phosphorylated related this cannot be reversed by the same
enzyme and that means the cell is committing to continuing on the glycolysis pathway.
In order to complete this reaction the phosphate group which moving forward, i'm just gonna
show as a P with a circle, comes from a molecule of ATP, ATP stands for Adenosine Triphosphate,
it has 3 phosphate groups and when we take off the phosphate, we're left with ADP which
is Adenosine Diphosphate, it's missing that third phosphate that we put on glucose.
ATP is the primary source of energy in a living system, it's the currency, it's how you pay
for reactions and so by utilizing ATP, this is an investment step.
We're paying with phosphate to start this reaction and the enzyme that catalyzes the
reaction is called hexokinase.
I realized this is alot to memorize so when you're looking at the structures and especially
at the enzymes, don't just memorize the name, try to understand what the name means and
why this specific enzyme name hexokinase connects to this reaction.
The name hexokinase comes from Hexo or Hexose which is a 6 carbon, ose, sugar.
Anytime you see ase, that tells you it's an enzyme but Kinase specifically is an enzyme
that transfers a phosphate group.
In this reaction from ATP onto carbon 6 of glucose.
Most of the cells are going to use hexokinase but the reaction is slightly different in
the liver that uses glucokinase and that has to do with why the liver is utilizing glucose,
perhaps to store it where the rest of the cells are utilizing glucose to burn it for
energy.
Another reason for adding phosphate onto glucose is to destabilize the glucose molecule, glucose
unlike the other sugars is very stable in a chair conformation because all of the OH
groups are equatorial, adding a negative phosphate introduces some instability into the molecule
which allows it to open up, which allows us to proceed to the next step.
Step 2 is the reversible conversion from glucose 6 phosphate to fructose 6 phosphate.
F6P, if you're wondering how you went from a 6 member ring in glucose to a 5 member ring
in fructose, the answer is you can't.
You can't simply pull a carbon out of the ring, instead we have to go from the chair
or Haworth confirmation to the open form which we'll show in a fischer projection before
the reaction can proceed.
You'll notice that even with the phosphate group, glucose still favors the cyclic form
but everytime we form a glucose and it gets isomerized to fructose, Le Chatelier's Principle
dictates that another glucose will go from cyclic to linear form so it can react in another
and another which is how we get all of the glucose to react.
Let's take a look at what happened, notice that everything from carbon 3 onward is exactly
the same the isomerism happened at the top of the molecule where glucose had an aldehyde
on carbon 1 and fructose has a ketone on carbon number 2, what happens in this reaction is
the aldehyde on carbon number 1 is converted to an enol between carbons 1 and 2 through
keto enol tautomerization.
That enol is then tautomerized again so that we get the ketone on carbon number 2, once
we have a fructose 6 phosphate, we're able to reform the cyclic structure because remember,
in the cell there's always an equilibrium between linear which we shown in fischer and
cyclic which we shown in Haworth.
The enzyme that catalyzes this reaction is called a phosphoglucose isomerase.
Phosphoglucose because it acts on a phosphorylated glucose molecule and isomerase which ends
in ase telling us that it's an enzyme that creates and isomer, in this case we have a
constitutional isomer because if you count the atoms, nothing has changed between carbons
1 and 2 except that we've moved some atoms and bonds around.
Notice that we lost 2 hydrogens on carbon number 2 to form the ketone but we gained
2 hydrogens on carbon 1 when we lost the aldehyde.
Think of steps 1 and 2 as the warm up in glycolysis the cell knows it wants energy, it knows it
wants to proceed but up till step 2 it can still change its mind.
Step 3 is considered the rate limiting step of glycolysis because when the cell goes through
step 3 it is committed to seeing this all the way through, why is step a rate limiter?
In step 3 we're taking a molecule that already has a lot of energy invested and we're putting
even more energy in because we know we're going to get energy out later, how?
We take fructose 6 phosphate and add a phosphate group from another ATP molecule in a one way
reaction that gives us fructose 1,6 bisphosphate or F16BP.
That's a fructose molecule with bisphosphate, 2 phosphate groups, 1 each on carbon 1 and
carbon 6.
ATP, Adenosine Triphosphate having given up the phosphate is now left with only 2 for
ADP, Adenosine Diphosphate.
The enzyme that catalyzes this reaction is called phosphofructo kinase or PFK and is
considered the most important enzyme in glycolysis.
Phosphofructokinase comes from phosphofructo, a phosphate group on fructo and kinase as
you remember is an enzyme that catalyzes the addition of a phosphate group.
In this case a second phosphate group onto the fructose molecule.
Don't forget that the cyclic structure is an equilibrium with the open or linear form
that I drew here in fischer projection.
I want you to pay attention to what we have on this molecule, I want you to see how even
though the molecule isn't exactly symmetrical, if we break it down the middle we have about
the same number of atoms for groups, we have the same number of oxygens and the same number
of phosphates on both sides.
This is critical for the next step because now that we've invested all the energy, now
that we have the phosphate groups here, we want to get one step closer to 2 pyruvates
which means we have to find a way to break the molecule.
To break the molecule I put the two halves in different colors so that we can follow
their progress towards pyruvate.
In Step 4, Fructose 1,6 Bisphosphate shown here in 2 different colors will get broken
right here to give us dihydroxyacetone phosphate, DHAP and Glyceraldehyde 3 Phosphate, G3P also
sometimes called GAP.
If the names are confusing take a look at what we have, remember that to add the phosphate
group we needed an OH so the Dihydroxy refers to the OH that would have been there and this
OH as 2 OH's , Acetone because this right here is a 3 carbon ketone or acetone with
a phosphate on the OH.
Glyceraldehyde 3 Phosphate comes from a glycerol molecule which would have been a 3 carbon
chain with 3 alcohols but in this case it's a glycerol aldehyde with on carbon 1 instead
of one of the three OH's, 3 phosphate because that is on carbon number 3.
Now here's the problem with step 4.
Pyruvate, our ultimate goal is 1 molecule, in order to get to pyruvate, we need glyceraldehyde
3 phosphate but when we broke this molecule in half, every glucose gave us one good G3P
and one unusable DHAP, Dihydroxyacetone phosphate.
Given how important glucose is to this cell, we can't simply take the one and toss the
other, that would be a tremendous waste, that means half of the energy that you're eating
of your glucose consumption would be wasted and that is why in step 5 we have to find
a way to rescue all of the DHAP but first the enzyme that catalyzes this reaction is
called an Aldolase.
Aldolase tells us we have an enzyme that catalyzes an aldol reaction.
Aldol reaction?
Wait a minute, isn't that the reaction you learn in organic chemistry where you take
2 aldehydes and fuse them together to form a molecule that has both an aldehyde and an
alcohol for an aldol condensation?
Actually yes but in reverse.
If you look at these 2 molecules, we have an aldehyde that can react with this molecule,
the ketone can be an aldehyde or a ketone to give us an aldol which we have in fructose
1,6 bisphosphate but that's the reversed reaction.
Anytime you have a reversible reaction the enzyme name can come from the forward reaction
or as you saw here from the reverse reaction.
In step 5, we're going to rescue the dihydroxyacetone phosphate, this is not in a form that we need
so we want to find a way to convert the dihydroxyacetone phosphate to glyceraldehyde 3 phosphate and
that will be catalyzed by an enzyme called the triose phosphate isomerase or TPI.
From the name, we see that we have tri ose a 3 carbon sugar, the half is a 3 carbon sugar,
phosphate isomerase where isomerizing or moving the phosphate group but first what is the
difference between DHAP and G3P?
Carbon number 3 has a phosphate group that doesn't change, carbon number 2 has to convert
from a carbonyl to an alcohol and carbon has to convert from an alcohol to a carbonyl.
This should once again remind of that double keto enol tautomerization.
Carbon number 2 instead of a carbonyl gets C singlebound OH for the alcohol plus another
H and carbon number 1 is going to lose 1 hydrogen here, 1 hydrogen here, leaving it with just
1 hydrogen and the oxygen now gets the second bond to form the aldehyde.
This is just another way of drawing glyceraldehyde 3 phosphate where carbon 1 is the aldehyde,
2 is an OH and 3 has a phosphate.
Interesting note about TPI this is considered one of the few perfect enzymes in a biological
system because it's very efficient and has a very high turnover rate which if you think
about it is really important given that half of every single glucose molecule is not usable
until TPI turns it into G3P so that we can get the maximum energy out of every half of
glucose.
Now that we have 2 glyceraldehyde 3 phosphates, 1 from the initial G3P that formed when we
broke fructose 1,6 bisphosphate and the second from converting this unusable half, DHAP into
G3P so far, we invested, we spent money in the form of ATP, we put in all that effort
into taking glucose, changing it, breaking it, fixing the broken halves and now that
we have the 2 glyceraldehyde 3 phosphates we're ready to go onto phase 2, the payout
phase where we start collecting and taking energy out of glycolysis and that is exactly
what we're going to discuss in the next video
But first make sure you give this video a thumbs up, subscribe to my channel and hit
that bell icon so you don't miss out on any new videos then visit my website for the next
video along with the glycolysis cheat sheet which you can find on the link below or go
to leah4sci.com/glycolysis , again that's leah4sci.com/glycolysis .