#16 Biochemistry Blood Clotting/Carbohydrates I Lecture for Kevin Ahern’s BB 450/550

Ahern: How’s everybody doing? Student: Amazing. Ahern: Amazing. Everybody’s doing amazing. You’re speaking of
everybody here, alright. Okay, so we’re not too
far from finishing up regulation of enzyme activity. When I finished last
time, I had started, at least introduced the
topic of blood clotting and as we will see, blood clotting is another
system that uses zymogens. It is a system that, in
addition to using zymogens, uses an interesting scheme
or an interesting strategy that we will see later and
it’s what I call a cascade and the cascade system
is used in other enzyme control systems and the
beauty of a cascade system is that you can mobilize an
effect very, very rapidly. Okay, what does that mean? So if I think about the Cascades, the Cascade maintain
range and I go climbing the Cascades and I
get up to a high point, the higher I get up,
the more I see that the cascading
waterfalls get smaller because I’ve got a
smaller source of water. As I go down the mountain, the
further I go down the mountains, the waterfalls and
everything get bigger because the streams
start coalescing together. That cascading system,
one stimulating another, stimulating another,
stimulating another, is a very, very
effective way to make things happen very rapidly, okay? As I said, we’ll see
another example of it, but this shows a very involved
system for blood clotting. I’m not going to take
you all the way through, in fact I’m only
going to emphasize a couple major points in it. But sufficed to say
that a cascading system, if we think about a signal, let’s say it’s a damaged
tissue or a damaged blood vessel in some way. That signal has to be
amplified and the reason it has to be amplified
is because as I said at the end of the
lecture last time, we really need to
stop that blood flow before we lose too much blood. If we don’t, then the
person will bleed to death. So we have to have a system
that works very rapidly and is very effective, alright? So a small signal here,
if this is an enzyme, this enzyme activities
another enzyme and this enzyme in turn
activities a bunch more enzymes, and this bunch of
enzymes activates an even bigger bunch of enzymes, and at every step
along the cascade, the signal gets bigger
and bigger and bigger. The beauty of this is
it happens very rapidly, it’s happening in
our blood stream. And so the main thing
that we have to do in order to protect ourselves
via a clotting mechanism is to make sure
that we have plenty of zymogens in our blood stream. Things that are not
yet clottable but can be very quickly be
turned into a clot. Now, that’s the good side. The bad side is the same thing. We have a blood
stream that’s full of things that can form a clot. And so if the system screws up, then we can very rapidly
form a clot and kill ourselves if we have the clot forming
in the wrong place, alright? So there’s a Ying and a
yang to blood clotting. We’re going to focus mostly on
the good side, I guess the Yin. I wasn’t going to say
good, but on the positive side of the blood clotting, which is the forming of the clot, and I’ll also talk about
how we dissolve a clot. So just like I said before, if the body has a way
of turning a system on, it’s also going to have a
way of turning a system off. If it makes blood clots,
it’s got to be able to dissolve those
blood clots as well. We’ll talk about both of those. Okay, so like I said, I’m not
going to go through this pathway in detail and no I’m
not going to ask you to regurgitate this
pathway to me, alright? The important aspects
of this pathway are actually down here
for our purposes, okay? We don’t really
care much of up here. For our purposes,
we’re going to focus on what’s happening
down here, okay? Now as we start with things
on the left, or things, I should say on
things on the left, but things that are coated
in this sort of pinkish color, these are inactive zymogens,
or inactive factors. So when I see for
example, prothrombin, prothrombin is a zymogen. It is inactive, it is
incapable of acting. By the way, most of these
guys on here are proteases. One protease activating
another protease, activating another protease,
activating another protease and that last protease is going, which happens to be thrombin, is going to convert
the clotting material from an inactive form
to an active form, meaning that the
clotting material will start to make a polymer. So once this guy right here
gets converted to fibrin, fibrin is a
self-assembling polymer. That’s very important. It’s a self-assembling polymer. In the absence of
this activation, fibrin is floating through
your blood stream all the time. Or fibrinogen is floating
through your blood stream all the time doing nothing. That’s what you want it to do. You don’t want it to clot
unless you got an issue. Well, this raises a
couple of concerns. One is we want plotting to
occur in a specific place, we don’t want it occurring
randomly in our body. And our body, I’ll
show you one way, has a way of knowing
where to put that clot. There are several things in
place that help to do that but I’m going to tell
you about one of them at the molecular level. So our focus for right in is
going to be on the prothrombin to thrombin and the
thrombin catalyzing the conversion of
fibrinogen to fibrin, okay? Alright, so let’s consider that. Where was I at here, there we go. First of all, we have to consider
the structure of fibrinogen. So fibrinogen is the inactive
polymerizing material. When it gets activated,
then it will form polymers. Well it’s kept inactive by the
action of these two things here. This label with its
capital B and this guy down here with its capital A. These we can think of as
knobs that basically stop the polymerization process. During the
polymerization of fibrin, what we will see is these
knobs get clipped off and they yield ends that can link into these things
that we see here, okay? You see this little hole? The B will fit into
that little hole, so I can take one fibrin
molecule that’s got a B and stick it into the hole
of another one that’s got this. The As will stick
into the gammas, okay? So what thrombin is doing is
it’s clipping off the knobs. It clips this guy off,
it clips these guys off and now we’ve got some ends that the pieces can start
sticking together. The tinker toys, as it were, can start building themselves
into a bigger structure. Alright, so that actually
occurs in this mechanism that you see here, okay? In this case, the
alphas are linked up with the gammas as
we can see here, okay? The alphas and the gammas
have been stuck together. We don’t see the betas
going into the Bs, into the beta
structures and the reason is because that goes
in the 3rd dimension. We could imagine that
this polymer is going to stick back out
towards us, right? So we have this guy
sticking in here, this guy sticking in here, this
guy sticking let’s say in here, and now we get a three
dimensional structure. So coming back out at us, we got all these
things tied together. Now that’s, what’s amazing is A, that happens very rapidly, okay? It happens very, very rapidly, and second, it is a
pretty good structure, but it’s not a perfect structure. What does that mean? Well, what you see on the screen is a sort of a two
dimensional display of what we call a soft clot. A soft clot, why do
we call it a soft clot? Well, it’s the very
first thing that forms when there’s been
damage, there’s been a cut and you’re losing blood. The very first thing that happens is what’s called a soft clot. And the reason we
call it a soft clot is that these
interactions are not, underline not, covalent. These are hydrogen bonds. It’s soft because, yes, it helps to put all
the pieces together, but it’s not very sturdy. It doesn’t hold things real well. We can imagine we get a few
hundred or a few thousand of these hydrogen bonds, it’s really going to start to
add up to a reasonable structure, but for a good
protection, we want to have what’s called a hard clot, okay? To get a hard clot, we have to
make covalent bonds, alright? So what you see in
terms of that initial polymerization reaction
only makes hydrogen bonds, it does not make covalent bonds. The covalent bonds require
action of another enzyme, okay? The other enzyme is known
as a transglutaminase and it catalyzes a
reaction like this. The side chain of a
glutamine and the side chain of a lysine can be joined
together to make a cross link. This is a covalent bond. Now this is not happening in
those little knob structures. This is happening just
between the strands when they get
adjacent to each other, if there is a lysine
next to a glutamine, this transglutaminase will
join these bonds together. When we make these
covalent bonds, we’ve converted a soft
clot into a hard clot, okay? We’ve converted a soft
clot into a hard clot. If you watch a scab on your hand, you’ll notice that
when it first forms, it’s different than
what it looks like a couple of a hours later, okay? It goes from being literally
soft feeling to being hard. The scab does that. Now as I said, the remarkable
thing is this happens in the order of
minutes and this happens and the place you wanted. It’s rare that you’re
forming clots at places in your body where you
don’t want to have it, okay? And it’s water tight. Those are really remarkable
features of blood clotting. Well how do we know, how does
the body know where to make that? How does the body know
where to do it, okay? One of the ways in which
the body uses information about how to do it is by a
modification to prothrombin. Prothrombin. Remember prothrombin is the
zymogen form of thrombin. It’s the inactive
form of thrombin. But the body has a way
of collecting prothrombin at the site of the wound. As a way of collecting prothrombin
at the site of the wound, I need to tell you
about that, okay? So that happens as
a result of action. Of prothrombin, let’s
see, let’s go here. Here’s what I want to show you. In order for prothrombin
to get gathered at the site of the wound,
it has to be modified. So prothrombin gets
modified by vitamin K. Vitamin K is known as the
clotting vitamin, all right? Vitamin K is required
by an enzyme that puts an extra carboxyl group on
the side chain of glutamate. So prothrombin has
several glutamates. This enzyme that uses vitamin K, grabs a hold of prothrombin,
grabs a hold of vitamin K and it puts additional
carboxyl group on the side chain
of glutamate, okay? Here’s a regular
glutamate side chain, here’s the addition of a new
carboxyl group on it, okay? So in black, you see the
regular, I’m sorry going up here, the regular side chain
of glutamate, all right? And now this guy’s had an extra
carboxyl group added to it. Why is that important? Well it turns out that when that extra carboxyl group gets added, prothrombin can all of a sudden
bind calcium very, very well. It can bind calcium
very, very well. With only one carboxyl group, prothrombin doesn’t grab
calcium worth a darn, all right? But with two carboxyl groups, they sort of gang up on
calcium and hang onto it, okay? One doesn’t do it,
two are positioned perfectly to bind calcium,
calcium is charge plus 2, each carboxyl group
is charge minus 1, they form a very nice bond. Why is that important? Well at the site of the
wound, we’ve got cutting, we’ve ruptured open cells and we’ve exposed a
bunch of calcium, okay? So right at that
site of the wound, we’re going to have an
abundance of calcium there and that calcium is going
to attract prothrombin. Prothrombin will be concentrated
at the site of the wound. Now, prothrombin sits
there and waits for all of the other zymogens
to get activated to get activated and finally it gets
activated, making thrombin. And what’s thrombin going to do? Well thrombin is gonna
convert fibrinogen into fibrin and right in the
site of the wound, that polymer is going to form. So there’s other systems the
body uses but one is this one. It’s vitamin K dependent,
it’s why we have to have vitamin K to have efficient
blood clotting, okay? Yes? Student: So
when…[inaudible question] Ahern: Okay, so there’s
many causes of stroke, but one of the most
common causes of stroke can be the formation
of a clot in a place that would stop blood
flow to a vital organ like the heart or
the brain, okay? And yes, those do happen
and those are a problem and to prevent the
formation of clots in places where you don’t want them, people are given what
are called blood thinners and I’m going to talk about
that in just a second, okay? Yeah, please. Student: So if you’re a
hemophiliac, what goes wrong? Ahern: If you’re a
homophilic, what goes wrong? There’s several
places in the scheme where you can be lacking
an enzyme genetically. So if you’re lacking
a critical enzyme, and there’s several places
where this can happen, if you’re lacking
a critical enzyme in that activation
pathway, you may not be able to convert zymogens
and that’s going to stop the whole cascade and
you’re literally going to bleed to death if you
don’t have that factor. But there’s several places
where that can happen. Okay, so a very
interesting phenomenon, a very important phenomenon,
it has a molecular basis, when I talk about vitamin K, this is what vitamin
K looks like, okay? Vitamin K is needed by
that enzyme that puts the carboxyl groups
in the side chains of glutamate of a
prothrombin, all right? Blood thinners, okay,
the things that people refer to as blood thinners,
resemble vitamin K. And the enzyme
binds those molecules and when it binds
those molecules, it cannot put a carboxyl group on the side chain
of prothrombins. Would you describe these guys or competitive or
non-competitive? These are competitive. They resemble in
some way vitamin K. They’re competing
for the same site. Warfarin is also
known as rat poison. That was the original
use of warfarin. Oh my God, if I poison rats, am I going to get
blood all over my house? No, do you know why? Internal bleeding, yeah. So when you really
thin the blood a lot, what happens is the most
common thing that happens is the slightest
bruise can kill you. So people that get put
on blood thinners, okay, are, they have to do what
we call titrate the thinner. We don’t want to give
them too much thinner because we will kill them if
we thin their blood too much. They will bleed to
death internally. So a physician who’s
giving a person thinners will measure what’s the
clotting ability of this person. You’re trying to lower
it but not stop it because you don’t want
to completely stop it or you’re going to
kill the person, okay? Warfarin and dicumarol both are
very effective in this respect. They both do reduce the
clotting ability and people, for example, who had a
stroke or have other problems. I have relatives
who have phlebitis. Phlebitis is a clotting
disorder in the legs and they get put on blood
thinners to keep them from forming these clots
in their legs and again, they have to balance
the right amount so they don’t give them too much. At the same time,
they want to stop the clotting as much as they can. Student: A DVP? Ahern: I’m sorry? Student: A deep vein thrombosis. Ahern: A deep vein
thrombosis, uh huh, yeah. Okay, all right, let’s see here. What was I going to say? All right, so that’s how we
form clots and that’s a fairly cursory look of
how we form clots. I also want to say a word
about how we get rid of clots because as I said, the body
has to not only make things, it has, if it has something,
a switch, to turn something on, it has to have a switch
to turn something off, and so how does it get
rid of clots that it forms? Well it turns out
our body has an enzyme that does this very, very well. The enzyme that dissolves
blood clots is also a protease. And it’s known as plasmin. PLASMIN. Plasmin. And plasmin is present
in the blood stream, not as plasmin,
but as plasminogen because we want to
have that available so that we can
activate it when we want to dissolve the clot
and make that, alright? Now how do we
activate plasminogen? Well that’s activated by
another enzyme known as TPA, which also stands for
tissue plasminogen activator. Tissue plasminogen
activator is also a protease. We see a lot of
proteases involved here. And the effect of this
protein is remarkable. Now TPA has the historical note that it was the first
genetically engineered protein that was made
available for human use, okay? It was actually the first
protein that Genentech, you’ve heard of Genentech,
that was the first protein, they were the first one
to get that approved. TPA is a very powerful molecule. It needs some activation as well and we’re not going to talk
about how all that occurs, but TPA basically,
if you give TPA at the site of a blood clot, it will activate
plasminogen at that site and effectively
break down the clot. Now it’s not given routinely
because as you can imagine you could have some
problem turning this on like giving people
too much blood thinner. But at the site of a clot,
this guy can convert a plugged artery in the
heart to complete flow through in a matter of minutes. So for a person who has a
blocked artery because of a clot, TPA can be a life saver. In some cases, TPA is
actually given to people after they’ve had
a stroke in hopes that if there are small clots
in the brain or something, that they can be dissolved
very quickly and readily. That they can actually
alleviate the effects of a stroke and in many cases, that actually can have
a very positive effect. As I said, it’s used very
carefully because again, it’s a very, very
powerful substance and we don’t want to
be indiscriminately breaking down clots that might
otherwise be protecting us. Yes, sir? Student: I know that in
situations like you’re describing, they describe that
as a clot buster. What portion of that is TPA, or are there other
components that we use? Ahern: His question is, when
you hear the term clot buster, does that refer to
TPA or other things? And there are other things
that can be used as well, but TPA, the term clot
buster is just a generic term. TPA is definitely
a clot buster, yes. Yeah, back there? Student: How long does TPA
remain active in the bloodstream? Ahern: That’s a very
good question. How long does TPA remain
in the blood stream? And I don’t honestly know
the answer to that question. So that’s the activation. The inactivation
of blood clotting, it’s a pretty phenomenal
process I think. If there are no other questions, I’ll move forward
to carbohydrates. One other question back here. Elliot? Student: What was the enzyme
that catalyzes the vitamin K? Ahern: Yeah, his question
is what enzyme catalyzes the carboxylation of prothrombin. I didn’t give you
the name of that so you’re not
responsible for that. Vitamin K is a cofactor
for that enzyme, though. all right, we turn our
attention now to a subject that most students tend to like because this subject is
something I’ve covered before in organic chemistry. This structure of carbohydrates and it’s almost all
focused on structure. So we’ll say a lot about the
structure of carbohydrate, there are a lot of
terms that are here, and it’s very straight
forward kind of stuff. So I’m going to go
through it sort of quickly but also hopefully not too
fast to run over you with that. We talked about carbohydrates. Carbohydrates are obviously
important molecules for us. Carbohydrates are one of
our main sources of energy. They are in fact our primary
source of quick energy. Carbohydrates include sugars,
they include polymers of sugars, and they also include
modified forms of those sugars. The term carbohydrate
actually tells us what the structure
of the molecule is. Carbo referring to carbon,
hydrate referring to water. Carbo-hydrate is basically the
structure of these molecules. For example, look at
the structure of glucose, the structure of
glucose is C6H12O6. You don’t have to write that down but I could easily
write that CX H20X. In its case, the X is 6. That’s a 6 carbon sugar. Well it would be C4H8O4. So it’s a hydrate of carbon,
that’s what a carbohydrate is. Water to carbon. Probably never
thought of that before. Well the first term
I want to introduce you to with respect
to carbohydrate, and by the way, we also
use the term carbohydrate, we use the term saccharides. Saccharides are the
same as carbohydrates. SACCHARIDE. Saccharide. A saccharide literally means and I think it’s
Latin, sweet taste. Sweet taste. So carbohydrate,
saccharide, same thing. Well let’s look at a
couple of structures of very simple
carbohydrates or saccharides. These are three carbon molecules. In this case, we
would have C3H6O3. We notice that they are similar
in structure but not identical. We see first of all that this guy is a ketone and these guys
over here are aldehydes. Ketones vs. aldehydes, right? And if you look at
the two on the right, they are both aldehydes but
they are slightly different in their three
dimensional configuration. We remember that a carbon
that has 4 different groups attached to it can
have those groups attach in three dimensional space
in two different ways. And here’s where
you’re going to like biochemistry
because biochemistry, very simple people, we
like to think of the terms D and L to describe those. And you’ll see this is
a great simplification in terms of describing
their overall structure. The ketone doesn’t
have, in this case, doesn’t have a symmetric carbon. There is no carbon that has 4
different groups attached to it, so there’s only one form
of this three carbon ketone. A carbohydrate that
has a ketone bond in it is called a ketose. KETOSE. Whenever you see the letters
“ose” at the end of a name, we’re talking about
a carbohydrate. A ketose is a general name for
a carbohydrate that has ketones. Fructose is a specific ketose. And I’ll show you
the structure of that. On the other hand, if instead
of having a ketone bond in it, that the carbohydrate
has an aldehyde bond in it that structure is
known as an aldose. ALDOSE. And again, that’s a general
term for a carbohydrate that has an aldehyde bond in it. We can further delineate
the names of these guys by describing the numbers
of carbons that they contain. The guys I just showed you
are three carbon molecules. They’re known as trioses. I could describe them as an
aldotriose, or a ketotriose, depending upon whether
they had an aldehyde or ketone bond in them. If they have four carbons,
they’re known as a tetrose, five a pentose, 6 a hexose,
7 a heptose, 8 an octose. We don’t generally
see carbohydrates with single units containing
more than 8 carbons. But we will see polymers
of some of them that have 6. Now when we look at the different
structures of carbohydrates, we see that there
are a variety of names that can be used
to describe these. Let’s start down here. This guy down here
shows those two aldoses that I showed you before. One is known as
D-glyceraldehyde, the other is known
as L-glyceraldehyde. You’ll notice the structure. C3H6O3. They are mirror images of
each other because again, that relates to the
three dimensional arrangement of those
structure, those substituents on the asymmetric carbon. We draw them in simple terms. We’re going to then draw
them three dimensional. We can draw them like
this where we take the asymmetric carbon
and we put the hydroxyl on the right side vs. putting
the hydroxyl on the left side. In general, when we look at
the structure of carbohydrates, and we decide if it’s D or L, we look at the
next to last carbon. If the OH is on the left side
of the next to last carbon, it’s an L sugar. If it’s on the right side
of the next to last carbon, it is from the
bottom, it’s a D sugar. If we orient the OH on
the left side of the next to the last carbon from
the bottom, it’s an L sugar. If we orient it on the
right side of the next to the least carbon from
the bottom, it’s a D sugar. Two carbohydrates
that are mirror images of each other are
called enantiomers. Yes? Student: Are there
biases in proteins? Ahern: Are there biases? Do we see carbohydrates
being in one vs. the other? We do tend to see many more in
the D form than in the L form. Yes, we do. But it’s not as strong as we see with amino acids
and other things. But D is very strongly favored. Two molecules are enantiomers if they’re mirror
images of each other. These guys are mirror
images of each other. Now, [inaudible] uses this
term “constitutional isomers.” I don’t like that term,
so we’re not even going to hold you responsible for that. What is a stereoisomer? Stereoisomers are
molecules that have the same general structure,
that is they’re both C6H12O6. They’re both aldoses. But they’re not mirror images. Look at this. This guy is not a
mirror image of this one. They are stereoisomers
of each other. And another term is
used, it’s not on here, actually it is right here,
they are called diastereisomers. DIASTEREOISOMERS. So stereoisomers will
include enantiomers. They will also include
diastereoisomers. Now notice what I said had
to be for a diastereoisomer. They had to be the
same kind of sugar. In this case, they
had to both be aldoses. They had to have the
same number of carbons but they’re not mirror
images of each other. Yes, sir? Student: [inaudible] Ahern: I’m sorry? Student: There are 7
oxygens instead of 6. Ahern: Oh, that’s a
very good question. That’s actually incorrect. I didn’t even notice that. Obviously the book didn’t either. That should only be an H, yeah. Good eyes, wow. I’ve stared at this I
never noticed that before. When I was working on a textbook, I was an author, a
co-author on a textbook about 10 years ago and I
was on the third edition of the textbook and
so they, you know, I was reading all the
things that the other authors were writing and so forth and we use a lot
of the same figures in our textbook
that have been used in the previous edition
of this textbook. And so I look at this
one and this one figure and I said, “this is ridiculous, “it’s a carbon
that’s got 5 bonds.” [class laughing] And so I go to my
co-authors and I said, “this carbon has 5 bonds.” And they said, “oh my
God, it’s been in the past “2 editions and nobody’s
ever noticed it.” So you found 5 bonds, so
you found an extra oxygen. Good. We should contact,
we’ve seen other errors in this edition of the
textbook, so that’s kind of bad. This is the first time
this figure has been used in this edition of the textbook, so we didn’t used
to have this figure. I kind of like this figure
and there’s my little… Now, two other terms. Stereoisomers include enantiomers and they include diastereomers. Diastereomers include epimers. And epimers are two
sugars that again have the same kind, they’re
both in this case aldoses. They have the same
number of carbons. They only differ in
configuration by one hydroxyl. So if we look at this guy
on the left, on the left. On the right, on the right. On the right, on the right. The only place they
differ is right here. These two guys are
epimers of each other. They’re not mirror images. They’re not mirror
images of each other. They’re epimers. They’re only different in the
configuration of carbon number 2. Last, anomers are
also diastereomers. And anomers arise from
the different configuration that comes upon cyclization. I haven’t said anything
about cyclization so I’m going to show
you that in a minute. I’m going to introduce
the term to you right now and then I’m going to come back and show you more
detail in a minute. You should know what
an enantiomer is, you should know diastereomer is, you should know
what an epimer is, you should know
what an anomer is, you should know what
a stereoisomer is. Just some basic terms
of carbohydrates. Here are some common
monosaccharides that we see. We call them monosaccharides
because they’re not polymerized. They’re only existing
as a single unit. Glucose is a monosaccharide. Fructose is a monosaccharide. Galactose is a monosaccharide. Ribose is a monosaccharide. Deoxyribose is
actually an oddball because it’s lacking an oxygen. That’s why we have
the deoxy part. We show it to you
here because obviously this an important
constituent of DNA. It’s what gives DNA
the D part of its name. When we start looking at
sugars, carbohydrates here, you started thinking, “okay,
is Kevin going to make us “know all these structures?” Well there are hundreds of
possible carbohydrate structure, that pained look that says, “I really don’t want
to know that, right?” I’m not going to make
you know all those. But I will make you
know the structures of the important ones. And the reason I make you do that is you’re going to need to
know them in other classes. So you should know
the straight chain and the ringed structure
forms of glucose, galactose, fructose, and ribose. Ring and straight chain, glucose,
galactose, fructose, ribose. Now these actually
are quite common. They’re quite
similar to each other. Let’s look at glucose
and fructose for example. The only difference
between them is glucose is an aldose and
fructose is a ketose. Because if we look at the
configuration of the OH groups, this one is lacking
an OH in position 2, so we go to position
3, it’s on the left. Position 4 on the right,
position 4 on the right. Glucose and fructose
are identical except for whether they’re
ketose or aldose. Galactose is an
epimer of glucose. It’s an epimer of glucose. The only place that
galactose differs in configuration from
glucose is right here. These are very easy to
learn in terms of structure. I learned glucose is
right, left, right, right. Right, left, right, right. I can always draw
glucose and then remember that this guy’s
going to be identical. I remember that
galactose is going to differ at carbon number 4. 1, 2, 3, 4. There’s the difference. So you can put these
to memory pretty easily. Now, you learn in
organic chemistry, I trust that these 6
carbon or 5 carbon rings have a geometry
such that they can actually come back around
and interact with each other to make ring structures. The ring structures
are named according to their resemblance to
a couple of molecules. Pyran is a molecule that looks
like what you see on the top. It has 6 carbons, I’m
sorry it has 5 carbons and it contains an oxygen. Furan has 4 carbons
and contains an oxygen. This is a 6 membered ring,
this is a 5 membered ring. We use these names as our
way of describing sugars. Sugars that form six-membered
rings we refer to as pyranoses. Notice I said 6-membered rings. 6-membered rings have
5 carbons in them. Sugars that form 5-member
rings are known as furanoses. 4 of those are in there. Can a 6 carbon sugar
form a pyranose? Can a 6 carbon sugar
form a furanose? Yes. We’re only counting them
with carbons in the ring. Other carbons can be
sticking off as we will see. Okay, so how do these form? Well, aldoses form a structure
known as a hemiacetal. A hemiacetal arises by reacting
an aldehyde with an alcohol. An example would be glucose
can make a hemiacetal structure because glucose is an aldose. A hemiketal arises
from taking a ketone and reacting it with an
alcohol to make a hemiketal. And fructose is a ketose. So it can form a hemiketal. Let’s watch this
cyclization process happen. The cyclization process happens
as you can see right here. Here’s the 6-member glucose. The 6-membered
glucose has a geometry such that this hydroxyl
group on carbon number 5 right here can get very
close to that aldehyde group on carbon number 1. When it does, it can
make a ring structure. And it turns out it can
make 2 rain structures because what’s
happening is this guy, which only had 3 members on it, now is going to
have 4 members on it. We don’t have the double
bonded oxygen anymore. If it forms in this configuration
such that the OH is down, we refer to that configuration
as the alpha configuration. If it forms such that
the hydroxyl is up, we refer to it as the beta. Now, at this point, I can
tell you these two guys we see here on the
right are anomers. Their only difference is
whether they are alpha or beta. Everything else is the same. So we can have
alpha-D-glucopyranose, we can have
beta-D-glucopyranose. Those two will be anomers. But if I had alpha-D-galactopyranose
and beta-D-glucopyranose, they would not be
anomers because they would have other differences. So anomers can only
differ in the configuration of the anomeric carbon. And by the way, the
anomeric carbon will always be the carbon that had
the double bonded oxygen. I’ll repeat that. The anomeric carbon
will always be the carbon that had the double
bonded oxygen. That’s true whether
it’s an aldose, or whether it’s a ketose. So we have a glucopyranose here, we have a glucopyranose here. Alpha vs. beta. Yes, Shannon? Student: So is an
anomer also an epimer? Ahern: Is an anomer
also an epimer? Technically it is, but we don’t
tend to use that term for that. We use epimers for other
than the anomeric carbon. all right, when we have a ketose
like fructose, what happens? Well, looky here. Here is our anomeric carbon. There is a double bonded oxygen. Here is carbon number 5. We see this same sort
of intermediate structure forming here and voila. We have in this case
alpha-D-fructofuranose. Alpha meaning the
hydroxyl is down. Notice it’s the hydroxyl
that determines the position of alpha or beta, not
the carbon that’s there. Can we have a
beta-D-fructofuranose? Yes, we can. They just have, your book has gotten
lazy and they haven’t drawn it. If we had the beta, we would
have the same structures we have the hydroxyl of and
we would have the CH2OH down. Now, notice this is
a 5-membered ring. It has 6 carbons. Carbon #1, 2, 4, 5, 6. If you want to spare
yourself grief on the exam, always number your carbons. You’ll always bail yourself out. Don’t forget to
number your carbons because the most
common things I’ll say, “what’s the structure
of fructose?” A five-membered ring, 1,
2, 3,4, 5, I’ve got it. Well you know that
fructose is a 6-membered, has a 6 carbon molecule. It’s a hexose, right? So don’t forget to
number your carbons. That will always bail you out. An important thing
about these structures is that they are reversible. They are reversible. In solution, which is the most
common way that we have glucose, these molecules can
go back and forth from one structure to the
other structure quite readily. They can go from one structure
to the other structure quite readily and
it turns out that there’s a little bit of steric
hindrance for the beta form. I’ll show you that
in just a little bit. And so we tend not to
see as many of these in the beta form as we
see in the alpha form. But nonetheless, we do
see some in the beta form. In solution it’s going
back here, over here. Back here, over here. One of the criteria for the
reverse ability of this process. Okay, is the ability of these guys
to go back to the straight chain. If they can’t go back to the
straight chain, they can’t flip. These guys can flip. Well what stops it from going
back to the straight chain? If I modify the hydroxyl. If I modify the hydroxyl,
that process is not reversible and it will be stuck
in that configuration. It will stay. So let’s say I put a
methyl group in place of that hydrogen right there. If I put a methyl group
right there, it can’t go back. It will stay stuck in the alpha
configuration in this case. Let’s say I put a
nitrate right there. Same problem. It’s not going to go
back, it’s going to stay in this case in the
beta configuration. So if I do anything to
that anomeric hydroxyl, and notice it’s the
anomeric hydroxyl, I will lock it in whatever
configuration it happens to be in. Student: So they switch
between alpha and beta, they don’t switch between
straight and ring… Ahern: Well they can
make straight, yes. They can make straight, yeah. They have to be able to go back
to straight and back to here. Don’t waste your
time on this slide. [laughing] Since I’ve shown
it, I’ll tell you. I’m going to show it to you,
you’re not responsible for it. This is to be
showing you that yes, these guys can make
6 membered rings just like glucose can
make 6 membered rings. It’s not the most common
form we find fructose in and I think it
just adds another level of memorization that
you don’t really need. So we’re not going to worry about the 6-membered rings
of fructose, okay? These are the ring
structures of sugars that we find very commonly. Yes, you’re
responsible for ribose, yes you’re responsible
for glucose, yes you’re responsible
for fructose, and yes you’re responsible for
galactose, alphas and betas. And again, these are very,
very similar to each other, but don’t forget to number
your carbons or you’ll get lost. Look at fructose. “Whoa, those aren’t
identical!” Yes they are. There’s carbon 1, 2, 3. There’s carbon 1, 2, 3. Hydroxyl up on 3,
hydroxyl up on 3. If you don’t number your
carbons, you will get lost. Yes? Student: So the ribose
ring doesn’t have an alpha or beta indication
which [inaudible]. Ahern: It actually
should have that. If I were to say, “what
configuration would that be?” What would you say? Student: Alpha. Ahern: That’s beta, that’s beta. They do have alpha and beta. What we see in nucleotides
is it’s always in the beta. I think that’s why
they haven’t drawn it or given that designation
but you’re right, it should have that
designation on there. So this would be the
beta-D-ribose right here. Good, you guys have
good eyes today. Let’s say a word
about steric hindrance, I had mentioned it. We talked about steric
hindrance earlier in the term and steric
hindrance relates to nuclei or electron clouds that
get too close to each other. And we saw that there’s a
tremendous amount of energy that opposed putting
things too close together. This is a schematic way
of looking at a sugar that has a couple of
groups that are kinda butting heads with each other. And we can imagine
that if there was a way for the sugar to
avoid butting heads, it probably would do that. And in the case of
an animatic carbon, it’s actually fairly
readily able to change that. This shows glucose in
the beta configuration. The beta configuration,
we can see that this guy over here has a hydroxyl
that is sort of interacting with this CH20H
in carbon number 6. They’re too close to each other. We describe the structure
this guy has as a boat. Because if we trace
the path of the carbons, the carbons look like this. There and then down and
then across like this. It looks like a boat, all right? The same beta, this is beta, this is beta, they’re both betas, can twist bonds
and rearrange itself so that that interaction
does not occur. This is a beta form
like this is a beta form, but this is a beta that
has a different confirmation and it’s flipped
itself so that hydroxyl which was in the way up here
is flipped down over here. And it should say
down equatorially instead of being flipped up. Now that configuration
is called the chair because it has a sort of
configuration of a chaise lounge. There’s the back,
there’s the butt end part, and there’s where
you put your feet. You have a question? Student: Yeah, over here,
that hydroxyl [inaudible]. Ahern: These two guys do
interact actually right here. There is interaction. There’s much more interaction
here than there is here. And so this is favored
of the two structures. The chair form is favored over
the boat form because of that. So if you compare this to this, this has much more
interaction than this one does. Yes, Connie? Student: When you say
the chair form is favored, do you mean in all
cases or just… Ahern: In this particular
case, but in general, when you can arrange
things away from each other, you’re going to be better off. I’m just illustrating
this as one example to show you how a
boat vs. a chair form might be favored for structure. Student: Will we need
to put these in chair or boat form on the exam? Ahern: Will we need to
draw a chair or boat form on the exam and get all
these axiology and so forth and the answer is no, I
think that’s kinda busy work. But I think you should certainly
know what a chair form is. And I think you should
know what a boat form and why one vs. the
other might be favored. Question back here? Student: So maybe I missed
it, but how do you determine whether it’s an alpha
or beta [inaudible]? Ahern: The alpha
has the hydroxyl down as we draw it and the
beta has the hydroxyl up. That’s a good place to
stop, I hear the rustling. I’ll see you guys on Friday. Captioning provided by
Disability Access Services at Oregon State University. [END]

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