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Bioquímica | Carbohidratos | Glucosaminoglucanos, Proteoglucanos y Glucoproteinas — Transcript

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0:03Hello, guys. Today we are going to talk
0:06about the topic of glycosaminoglycans.
0:08It is the subject of GAGs. Before we
0:10start with this, let's talk a little
0:13bit about complex carbohydrates and
0:23complex molecules in general. A complex
0:29carbohydrate is one that is formed by
0:33something other than just sugar units.
0:37For example, if you have glycogen which
0:40is formed by many glucoses, yes, it is
0:43a large structure, it is a structure
0:46with many units, but they are still
0:48just sugar. On the other hand, there
0:52are other carbohydrates that can be
0:54formed by sugar plus protein, or sugar
1:01plus amino acids, or there will also be
1:08sugar plus lipids. So when you have
1:17structures that are sugar and something
1:20else, you are already talking about a
1:22complex carbohydrate. Sugar plus
1:26protein or amino acids can be of
1:28different types. You can have a
1:31proteoglycan, a glycosaminoglycan, or a
1:44glycoprotein, and so you have to know
1:56that these obviously have carbohydrates
1:59. Obviously they will have protein, but
2:02you have to know what is abundant. And
2:05it is very simple because to know what
2:08it has, you look at the last word. For
2:13example, a glycosaminoglycan, what it
2:15contains most is glycans, these are
2:18sugar units. A proteoglycan is also a
2:23sugar that has a little bit of protein
2:26or a small protein with many sugars. In
2:30contrast, a glycoprotein tells you
2:33about a protein that is very large and
2:35has a few sugars. So the last word is
2:39what will tell you what your complex
2:41molecule has in abundance. For example,
2:46if I tell you about a glycolipid, you
3:00should already know that this
3:01glycolipid is formed by sugar, by
3:03lipids, but what abounds in this
3:05molecule are the fats, the lipids. Okay
3:09? So, I have the glycosaminoglycans,
3:11they are the first structure we are
3:13going to talk about. We are going to
3:16start with them. Let's start now with
3:20the GAGs, with the glycosaminoglycans.
3:24Glycosaminoglycans are said to be
3:27heteropolysaccharides with a negative
3:35charge. There is something important
3:42here. The difference between a
3:44heteropolysaccharide and a complex
3:46carbohydrate is this. Remember that I
3:49told you, a carbohydrate can be simple
3:52or complex depending on whether it has
3:54only sugars, regardless of the number,
3:56as long as they are pure sugars, or if
3:58it has sugars and also has lipids or
4:01proteins. Okay? When you mix two
4:04macromolecules that are not the same,
4:06you are already talking about a complex
4:09molecule. Now, with simple molecules
4:14you can have, okay, just carbohydrates,
4:17but it could be the case like glycogen,
4:20which is many glucoses, that would be a
4:23homopolysaccharide, many glucoses are
4:25the same thing. On the other hand, a
4:31heteropolysaccharide is as if you had a
4:33unit of glucoses and then galactoses
4:35and a fructose and a mannose and more
4:37glucoses again. It is many sugar units,
4:42but it is not the same unit. So, these
4:46GAGs, those are heteropolysaccharides.
4:49They are formed by many types of sugar
4:52and probably their most important
4:55characteristic is that they have a
4:58negative charge. This negative charge,
5:02exam question, helps them to attract
5:06large amounts of water. In fact, it is
5:21very common that on the exam they ask:
5:23which of the following characteristics
5:26of GAGs allows them to attract large
5:28amounts of water? And they give you, uh
5:32, things that are confusing, because
5:34they tell you: it is a very polar
5:37substance, it is a substance with many
5:39hydroxyls, it is a substance with many
5:42hydrogen bonds, and it kind of seems
5:44like what meets the characteristics of
5:47water. But in this case, in the
5:50specific case of GAGs, if they ask you:
5:52"Why does it bind large amounts of
5:54water?" it is because it has a strong
5:58negative charge. Underline this very
6:01well. So, as carbohydrates that attract
6:06large amounts of water, they will be
6:09located outside the cells. Imagine that
6:14, I am going to draw the GAGs in green
6:17for you. And by binding the amounts of
6:37water, what they are going to do is act
6:39as a gel. Okay. Like a gel or mucous
6:44matrix that will help the cell be in
6:48communication with the exterior, it
6:51will help things bind, okay? So here in
6:56this drawing we have the GAGs, we have
7:01the water that is binding to the GAG
7:06and this allows them to form the
7:09extracellular matrix. And we had said
7:19that it has a gel consistency or a
7:22mucous consistency that allows it to
7:27have lubricating properties, that will
7:32allow it to have adhesion properties,
7:35that will allow it to have
7:37shock-absorbing properties. among other
7:46things, okay? So, they will be located
7:49here on the exterior of the cells.
7:53Their function is that, at the cellular
7:55level, to act as adhesion to bind
7:58proteins, to bind carbohydrates to the
8:00exterior of the cell, okay? They will
8:05allow the binding of molecules at the
8:07tissue level. Also, they will serve as
8:12a support flexible, meaning they have a
8:18structural function, they regulate
8:24movement and I repeat, that of
8:33absorbing impacts. So there you have
8:36the functions of glycosaminoglycans.
8:41Note down here that these are the
8:43functions. Moving on. We are going to
9:04talk about the structure of these GAGs,
9:06that is, how they are formed because it
9:08says they have glucose, but they have
9:10amino groups. Here it goes. Write down
9:15here for your topic: structure of GAGs.
9:26The book tells you that this
9:28heteropolysaccharide is formed by
9:31repeating disaccharide units. Okay.
9:46That is, one disaccharide that will be
9:48joined many times to form the
9:50heteropolysaccharide. Remember that a
9:53polysaccharide is defined as the union
9:56of more than 10 carbohydrate units.
9:58Okay? So, five disaccharides already
10:01meet the term for a polysaccharide.
10:04Let's see how this disaccharide is
10:07formed. Imagine that each box I am
10:15drawing for you is one of the
10:16disaccharide units and there they are
10:24joined. Okay. One part of the
10:30disaccharide is formed by an acidic
10:32sugar. And the other unit to form the
10:46disaccharide is formed by a compound
10:49called an amino sugar. So, GAGs are
10:55heteropolysaccharides formed by
10:58disaccharides that repeat many times,
11:02and this disaccharide is formed by an
11:05acidic sugar and an amino sugar. Let's
11:10see examples of acidic sugars. I have
11:14glucuronic acid, I have iduronic acid,
11:26and I have uronic acid. Okay. So, any
11:34of these are the acidic sugars. And
11:39just to give you an idea of why they
11:41are called that, it's not really
11:42something you need to know, they are
11:50carbohydrates whose hydroxyl group was
11:54replaced by a carboxyl group COOH. The
12:02moment it acquires this characteristic
12:05or this acidic functional group, it
12:07becomes an acidic sugar, and then it
12:10can be glucuronic acid, iduronic acid,
12:13uronic acid, or even another one which
12:16is glucaric acid. Agreed? Now, the
12:24other unit, we said, was the amino
12:27sugar, and in this case, there are
12:29three possible amino sugars that will
12:32form this disaccharide that will make
12:34up the GAG. I have D-glucosamine, I
12:43have D-galactosamine, and I have a
12:50molecule called NANA. This is N-acetyl
12:57neuraminic acid. And there you have the
13:03example of an acidic sugar and the
13:05example of an amino sugar that will
13:08form the GAG. And then, once you have
13:14the disaccharides, imagine, there you
13:37have it. It's six disaccharides. I am
13:42joining them there with a red bond, and
13:46then all of this is now the
13:49glycosaminoglycan, agreed? All GAGs
13:54have this structure, except one. The
13:58only exception to this is a GAG called
14:05keratan sulfate. This is the only GAG
14:14that, instead of using an acidic sugar,
14:16uses a monosaccharide which is
14:18galactose. It uses a monosaccharide
14:39which is galactose. We will see it
14:42again in a moment. So if you wanted to
14:45draw the structure of keratan sulfate,
14:48you would have to show it is made of
14:50disaccharides that contain galactose
15:05and an amino sugar. All right? It is
15:13the only one that will not have an
15:15acidic sugar. And now we are going to
15:19talk about the types of GAGs that exist
15:21in the body. Write down a subtopic here
15:26called classification of GAGs. There
15:41are six main classes of GAGs. I will
15:55list them. The first is chondroitin
15:59sulfate. The second is keratan sulfate.
16:17The third is hyaluronic acid. The
16:27fourth is dermatan sulfate. The fifth
16:37is heparin and the sixth is heparan
16:44sulfate. The order in which you learn
16:49them doesn't matter. And so we are
16:54going to start looking at special
16:56characteristics of each type of GAG.
17:05For starters, if you notice, almost all
17:08GAGs have sulfate. In fact, heparin
17:12doesn't say it in its name, but heparin
17:15also has sulfate. This means that the
17:19only GAG that is not sulfated is
17:21hyaluronic acid. Remember that
17:25exceptions are always very likely to be
17:27on a test. So, hyaluronic acid, its
17:31first characteristic is that it is the
17:33only GAG that is not sulfated.
17:45Chondroitin sulfate, the most important
17:48characteristic it has is that it is the
17:51most abundant GAG in the body. This is
17:56also an exam question. So, please, I
18:08ask that you underline that chondroitin
18:11sulfate is the most abundant and
18:13hyaluronic acid is the only one not
18:16sulfated. And now we are going to talk
18:23a little bit about what the functions
18:25are or what organs and tissues these
18:28GAGs are found in. Chondroitin sulfate
18:32is practically everywhere. It is in
18:35cartilage, tendons, ligaments, in
18:47large-caliber blood vessels like the
18:49aorta. And it is generally in all
18:53arteries; it's not the main one, but it
18:56is in all arteries. For keratan sulfate
19:00, we had already noted its
19:02characteristic. Here it is. It is the
19:05only GAG that does not have an acidic
19:07sugar, but instead has galactose. We
19:12are going to note that. And again, this
19:18is likely to be an exam question. What
19:21is the only GAG that has galactose in
19:23its structure? I am going to ask you to
19:35underline that. Hyaluronic acid.
19:44Hyaluronic acid is the only GAG that is
19:46not sulfated, that does not have a
19:48sulfate group in its structure. It has
19:51the characteristics of being a
19:53lubricant. It has the characteristics
19:58of being, for example, in synovial
20:00capsules, in the synovial membrane. It
20:05absorbs impacts, it is in joints, it's
20:18in a fluid of the eye called the
20:20vitreous humor and it also has a use
20:25that isn't so recent, but it's a use
20:28that is currently very trendy, which is
20:31its use in aesthetic medicine. What is
20:40the rationale for using hyaluronic acid
20:42in aesthetic medicine? Imagine you have
20:48a patient who has wrinkles and, for
20:51example, we see these wrinkles in
20:53profile, they are like skin depressions
20:56, you inject the hyaluronic acid and
21:02since it is a GAG quantities of water,
21:07it will hydrate and obviously it will
21:10even out the skin and the wrinkle will
21:12disappear. Okay. Obviously, these
21:17effects tend to be lost the moment the
21:20GAG dehydrates. So, if they ask you
21:23which glycosaminoglycan has a use in
21:26aesthetic medicine, it is hyaluronic
21:29acid. I have dermatan sulfate. This is
21:35found in skin, blood vessels and in
21:43heart valves. Heparin has a very
21:52important use as an anticoagulant. That
21:59has a medical use; it is used as an
22:02anticoagulant and it is also located in
22:05arteries, specifically or mainly
22:10arteries of the liver and lungs, okay?
22:16Arteries of the liver and lungs are the
22:18ones that most commonly contain heparin
22:21. That is what is relevant about it.
22:26And now I have heparan sulfate; there
22:29is nothing to say about it. So, there
22:33are the six types of GAGs, their
22:36locations, and some key things you need
22:39to know about each of them. Let's
22:44continue. We are now going to talk
22:51about the synthesis of these
22:52glycosaminoglycans. How are they
22:57created and where are they created?
23:02Synthesis occurs in the Golgi apparatus
23:05. You will see that in this topic the
23:10Golgi apparatus takes on importance
23:12because it is the organelle in charge
23:15of joining macromolecules and making
23:17post-translational modifications,
23:19attaching sulfates, attaching glucoses,
23:22making bonds. So, molecules of this
23:26nature that are already more
23:28specialized are synthesized in the
23:31Golgi apparatus. And here, the
23:37following is important. Everyone needs
23:40the disaccharides to be joined. So,
23:44everyone uses glycosyltransferases as
23:49the main enzymes. The
23:58glycosyltransferase enzymes are in
24:01charge of joining the disaccharides and
24:05all, except hyaluronic acid, will also
24:09use enzymes called sulfotransferases.
24:18Those, what will they do? Well, they
24:20are going to attach the sulfate groups.
24:31So you have that in the Golgi apparatus
24:38they are going to be joined as a first
24:40step by the glycosyltransferases, the
24:46sugars of the disaccharide And in a
25:06second step, once having the
25:08disaccharide already formed, the
25:21sulfate groups will be added. Okay? And
25:27in this second step, the one that adds
25:30the sulfate group will be the
25:32sulfotransferase. And if you wanted to
25:49go a little deeper into this, we can
25:53say that these sulfate groups come from
25:56a molecule called PAPS. PAPS is the
26:01main sulfate group donor in the
26:04organism. And later on, we will see
26:07where it comes from. So, for now, we'll
26:11stick with the fact that the synthesis
26:14of these glycosaminoglycans occurs in
26:16the Golgi apparatus. In the first step,
26:21the disaccharide is made, the amino
26:23sugar and acidic sugar are linked by
26:26glycosyltransferase, and in the second
26:28step, sulfate groups are added to the
26:31formed disaccharide by the enzyme
26:33sulfotransferase. Where do these
26:37sulfate groups come from? They come
26:40from a molecule called PAPS, which is
26:43the body's main donor of sulfate groups
26:46. Alright? So, let's talk about the
26:52first type of diseases. Errors in
27:10sulfation, errors in the binding or
27:13degradation of these sulfate groups. I
27:30have two diseases that result from
27:33errors involving sulfate groups. I have
27:37chondrodystrophies and I have Austin
27:47disease. Let's see what each one is
27:57about right now. These two diseases are
28:00therefore caused by errors involving
28:03the sulfate groups. Alright? In
28:09chondrodystrophies, there is an error
28:13in sulfation, that is, at the time of
28:20adding the sulfate groups. On the other
28:27hand, Austin disease is due to an error
28:33in de sulfation. That is, an error in
28:41removing the sulfates. The damaged
28:50enzyme, because these are genetic
28:52diseases caused by an enzyme deficiency
28:56. Let's note it down. The enzyme that
29:01is damaged in chondrodystrophies is the
29:04one we saw that was responsible for
29:06attaching the sulfate group. It is the
29:10sulfotransferase enzyme. The enzyme
29:21that is damaged in Austin disease is
29:24the sulfatase enzyme responsible for
29:27removing sulfate groups when you want
29:30to eliminate any of these
29:32glycosaminoglycans. Okay? What will I
29:37find in the clinical presentation? The
29:45clinical presentation of
29:47chondrodystrophies, as the name
29:50suggests, are skeletal or cartilage
30:01alterations. They can have
30:07musculoskeletal alterations, they can
30:10have short stature, they can have axial
30:12skeleton abnormalities, and so on. And
30:18in Austin disease, we will see later
30:20that since these GAGs are eliminated in
30:22the lysosome, if you cannot remove the
30:25sulfate group, they will get trapped
30:27there, so there will be accumulation in
30:34the lysosome. Alright? And these are
30:41the two most common diseases caused by
30:44errors involving the sulfate groups of
30:47GAGs. And obviously, the accumulated or
30:52altered GAG in any of these diseases
30:55can be any GAG except hyaluronic acid,
30:58because it is the only one that does
31:00not have a sulfate group. We finished
31:04with the synthesis. Now we are going to
31:08talk about the degradation of the GAGs.
31:20The degradation of GAGs takes place in
31:27the lysosome. This is very important,
31:34by a group of enzymes called acid
31:39hydrolases. They are called acid
31:49because they work at a pH lower than
31:54five. Okay? So, that is why they are
31:58called acid, because they work at an
31:59acidic pH. Therefore, each GAG will be
32:04degraded by a specific type of acid
32:06hydrolase. When there is a defect in
32:13the degradation, when there are defects
32:22in the degradation it means it is an
32:25absence of some enzyme, an absence of
32:30one of the acid hydrolases. And so, if
32:36there is no degradation, the GAGs will
32:39accumulate. There will be an
32:41accumulation of GAGs in the lysosome
32:54and these genetic diseases where an
32:57acid hydrolase is missing and thus the
33:00GAGs, instead of degrading, will
33:02accumulate in the lysosome, are all
33:05known by the name of mucopoly--
33:10saccharidosis, "muco" for these
33:22characteristics of attracting water
33:24that the GAGs had, like gels. So,
33:28sometimes the exam question—this
33:30topic is a bit complex, it's extensive,
33:33but the questions tend to be the same,
33:35I have been pointing them out to you.
33:38And this is another one of the most
33:40common questions on the topic, and it
33:42asks you, what is a
33:44mucopolysaccharidosis? and they list
33:47accumulation of GAGs, accumulation of
33:49mucopolysaccharides, accumulation of
33:52oligosaccharides, accumulation of X
33:54thing. Just learn that in
33:57mucopolysaccharidoses, what will
34:00accumulate are the GAGs, okay? So we
34:03are going to start looking at each one
34:05of these. These are, then, the second
34:13group of diseases that we are going to
34:19talk about. Remember that the first
34:21ones were the diseases that were caused
34:24by errors in the sulfate groups. So, we
34:30had agreed on mucopolysaccharidoses. I
34:34am going to write down again what is
34:35above. It is very important. They are
34:38diseases in which there will be an
34:40accumulation of GAGs at the lysosome
34:46level. They are genetic diseases caused
34:57by a deficiency of acid hydrolases.
35:07These were the enzymes that are in the
35:10lysosome that are in charge of
35:12degrading the GAGs. That is to say,
35:14there is an error in the degradation.
35:24They will accumulate in the lysosome,
35:26giving me different symptoms that will
35:28vary in severity. Uh, another important
35:32fact that they all share is that there
35:35will come a time when these GAGs will
35:38start to leak out when cells are
35:40destroyed and will end up in the urine.
35:43So, there will be GAGs in the urine.
35:48This is an important fact you are
35:50taught in genetics class. It is
35:53practically the key fact for diagnosing
35:56these diseases. The gold standard for
35:59diagnosing mucopolysaccharidosis is
36:01determining the presence of GAGs in the
36:04urine. And in fact, depending on the
36:07GAG that has accumulated in the urine,
36:09that is the type of
36:10mucopolysaccharidosis present. So,
36:14let’s continue. They all follow an
36:17inheritance pattern that is autosomal
36:22recessive, except for Hunter syndrome.
36:46Hunter syndrome is an X-linked disorder
36:50. And this, again, is one of the most
36:56frequent exam questions. In fact, uh, I
37:01think it is repeated on every exam.
37:04What is the only mucopolysaccharidosis
37:07that is X-linked? Hunter syndrome.
37:11Let’s start looking at each one of
37:14them. We will start with Hurler
37:21syndrome. Hurler syndrome is
37:26mucopolysaccharidosis. MPS is type 1
37:32mucopolysaccharidosis. It is
37:37characterized by a deficiency of the
37:43enzyme alpha-L-iduronidase. An
37:50important fact is that this is the most
37:53severe mucopolysaccharidosis. In fact,
37:56it is another frequent exam question.
37:59Which is the most severe
38:01mucopolysaccharidosis? And the answer
38:04is Hurler syndrome. Do not confuse it
38:08with Hunter. What do they present
38:11clinically? Besides the presence of
38:13GAGs in the urine, which is what will
38:15give you the diagnosis. Clinically,
38:18they may present with corneal clouding.
38:26Severe intellectual disability,
38:34dwarfism. Usually, these patients die
38:45at a very young age, either from
38:52coronary artery occlusion, a heart
38:56attack, or from airway obstruction. And
39:22remember that it is the most severe
39:24form and, very importantly, they
39:26present with facial dysmorphism. Facial
39:35dysmorphism is basically alterations in
39:38the structure of the face. And these
39:42facial features, which are so common in
39:46patients who have Hurler syndrome, led
39:49to it being known as gargoylism.
39:55Colloquially, they used to say these
39:57patients looked like gargoyles. So I am
40:01going to put a photo here of a patient
40:04with Hurler syndrome so that you can
40:11see how they all share certain common
40:13facial features. So, I have an image
40:27there so you remember that Hurler
40:30syndrome also presents with gargoylism,
40:32which is the presence of facial
40:34dysmorphism. Okay, let’s go to the
40:39next mucopolysaccharidosis, which is
40:42Hunter syndrome. This is type 2
40:51mucopolysaccharidosis. It is not as
40:56severe as Hurler’s, and the most
41:00important thing is that it is the only
41:05X-linked mucopolysaccharidosis. The
41:11rest are autosomal recessive. In Hurler
41:18syndrome, the deficient enzyme is the
41:25enzyme iduronate sulfatase. they
41:35present data similar to Hurler disease,
41:39but of lower severity. And even mental
41:50retardation is usually mild; it can
41:57vary in severity, but this is usually
41:59mild. The next mucopolysaccharidosis is
42:05Sanfilippo disease. This is
42:15mucopolysaccharidosis type three.
42:21Sanfilippo disease. There are many
42:25types. There are four types. A, B, C,
42:34and D. Each of them caused by an enzyme
42:37deficiency, obviously you don't have to
42:40know them. In fact, the enzymes are
42:44rarely asked about here; the important
42:46characteristics of each disease are
42:49more likely to be asked, and these
42:51patients almost always present with
42:53central nervous system delay. The last
42:58mucopolysaccharidosis we are going to
43:01talk about is Sly syndrome or disease.
43:11And this is mucopolysaccharidosis type
43:14four. In these patients, again, you
43:18don't have to know the enzyme
43:22clinically. They present with
43:24hepatomegaly. deformity, short stature
43:37and developmental defects. And these
43:48are the four mucopolysaccharidoses,
43:50which remember are lysosomal storage
43:53diseases. there will be an accumulation
43:57of GAGs in the lysosome because one of
44:00the acid hydrolase enzymes is missing,
44:02and you already saw that these acid
44:04hydrolases can have different names
44:06depending on the GAG they are going to
44:09destroy, okay? They are all autosomal
44:13recessive, except for Hurler disease,
44:16which is the mucopolysaccharidosis
44:19linked to...sorry, Hunter disease,
44:21which is the mucopolysaccharidosis
44:24linked to the X chromosome. Okay? And
44:30finally we are going to talk about what
44:34happens to GAGs when they bind to
44:36another molecule. The next topic or
44:39subtopic is proteoglycans. We are done
44:53with GAGs. Let's talk about
44:56proteoglycans now. Proteoglycans are a
45:04protein, a protein that has many GAGs
45:10attached. Your book says it normally
45:15has between 100 to 200 GAG units. Okay.
45:20These are synthesized in different
45:26places. Okay? The protein is
45:35synthesized in the rough endoplasmic
45:37reticulum and we had agreed that GAGs
45:43were synthesized at the Golgi apparatus
45:45level. So the protein leaves the rough
45:55endoplasmic reticulum, goes to the
45:57Golgi apparatus, and there they join to
46:00form proteoglycans. And the structure
46:03of the proteoglycan is very simple. In
46:13red, I put the core protein. And then
46:29these core proteins will bind GAGs in
46:38this way. Each of those little lines is
46:42a different type of GAG. They are many,
46:58many repeating units of
47:00glycosaminoglycans. Okay. In fact, when
47:10you take histology, they will tell you
47:13that this seen under a microscope looks
47:15like a brush or a swab, because you
47:18have the core protein and you have on
47:20the sides all the GAGs that will be
47:22repeated. The functions of these
47:26proteoglycans is to be components of
47:34the extracellular matrix. And examples
47:46of proteoglycans include aggrecan or
47:49versican. I'll see if I can find an
47:53image right now, a microscopy, so you
47:56can see how under the microscope it
47:58does look like a bottle brush or a
48:01broom. There aren't any microscopies,
48:38but here is a drawing so you can see
48:41the structure I told you about; you
48:43have the protein in the center and then
48:46you have the GAGs attached, giving the
48:49appearance of a little brush or a
48:51cleaning brush. This is all you need to
48:55know about proteoglycans. And now we
48:58are going to talk about another type of
49:00molecule. We already talked about GAGs,
49:02we already talked about proteoglycans,
49:04and finally, we are going to talk about
49:06glycoproteins. Glycoproteins are
49:11proteins that have oligosaccharides
49:16attached, okay? There are many proteins
49:25that have a few oligosaccharides;
49:27because it’s called a glycoprotein,
49:29it is mostly protein. These proteins
49:35and oligosaccharides will be joined by
49:37a bond, either O-glycosidic or
49:51N-glycosidic, depending on the site
49:54where it occurs. So, it is not relevant
50:00to know the structure exactly, but
50:03rather that they can be joined by two
50:06types of bonds, N-glycosidic or
50:08O-glycosidic. And obviously, they are
50:12formed by glycosylation. We already
50:20talked about glycosylation in the first
50:22exam; it is a type of modification,
50:28post-translational, carried out by
50:39enzymes called glycosylases.
50:47Glycosyltransferases, sorry,
50:49glycosyltransferases. Remember that
50:56sometimes there are proteins in the
50:58blood or proteins in the cell, and a
51:01few carbohydrates can be added to these
51:03proteins. It is a glycosylation process
51:07. We saw it in the hemoglobin example,
51:11we saw it in the collagen example. Okay
51:14? The functions of glycoproteins are
51:20numerous. Some glycoproteins can act as
51:27hormones, or rather, some hormones are
51:32glycoproteins. The ones you already
51:36know are FSH and LH. Luteinizing
51:41hormone and follicle-stimulating
51:43hormone, both gonadotropins, are a type
51:46of glycoprotein that have a hormonal
51:48function. They also function as
51:52receptors on the cell surface. Many
52:02viruses bind to glycoproteins that are
52:06on the cell surface. Okay? And in fact,
52:09if you want, you can read articles
52:11about the two receptors that have been
52:14found, to which COVID-19 binds, which
52:16is the disease that is trendy right now
52:18. So, it also binds to cell surface
52:22receptors that have a chemical nature
52:25of being glycoproteins, okay? They also
52:30function as antigens, they are
52:32recognized by the immune system. And
52:37this is not only in eukaryotic cells,
52:40human cells, but prokaryotic cells,
52:42bacterial cells, also have
52:44glycoproteins that are antigens, which
52:47are recognized by our immune system so
52:50they can be attacked. I'm going to give
52:54you an example. You get infected by a
52:58certain microorganism. Your immune
53:02system recognizes its antigens, it
53:04recognizes its glycoproteins, and then
53:06it prepares so that next time you get
53:08infected, you won't have such a severe
53:11infection. It's you, that is, you start
53:14to build resistance or create
53:16immunological memory. It is a mechanism
53:19used by vaccines, for example. It also
53:23works, uh, for the system, the
53:26system for characterizing blood types
53:30—group A, group B, and group O, which
53:33is actually not O, but zero. You'll see
53:37why in a moment. They function as
53:40components of the extracellular matrix.
53:48They have a lubricant function. There
53:55are many globular proteins that are
54:01glycoproteins. Uh, in fact, for example
54:06, the hemoglobin itself that we
54:08mentioned, hemoglobin could bind
54:11glucose, becoming glycosylated
54:14hemoglobin. Well, glycosylated
54:16hemoglobin is a glycoprotein, okay? And
54:20they have an immune function.
54:23Antibodies are also types of
54:26glycoproteins. It is said that the
54:30structure is a protein with only about
54:3310%glucose, reiterating then that what
54:36they contain most is their protein unit
54:39. Let's talk now about the synthesis of
54:47these glycoproteins. The synthesis of
55:00these glycoproteins. Okay. These
55:04glycoproteins, we had agreed that they
55:06are mostly protein. All proteins in the
55:10body are synthesized in the ribosomes.
55:14So, in the ribosome, the proteins will
55:21be made. These ribosomes can be in two
55:25places in the cell.
55:27There can be free ribosomes
55:30in the cytoplasm
55:35or they can be ribosomes attached to
55:39the rough endoplasmic reticulum. So,
55:44these proteins can come from either of
55:47these two places, whether they are free
55:50or attached to the rough endoplasmic
55:52reticulum. Free ribosomes in the
55:57cytoplasm are in charge of making
55:59proteins that will remain there, free
56:02in the cytoplasm. On the other hand,
56:05ribosomes that are attached to the
56:07endoplasmic reticulum will be in charge
56:09of making proteins that will be
56:11exported to the cell's exterior. How
56:14can you learn this? Imagine that the
56:19ribosomes are workers in a country, and
56:22you have workers in a factory who make
56:25products for export, for instance,
56:28imagine they make bags to export abroad
56:31,
56:37and on the other hand, you have free or
56:40freelance workers who make local
56:42products that stay inside where they
56:44live. So, these stay in the interior of
56:49the cell. The thing is, before they can
56:55reach the interior of the cell or the
56:57exterior, they have to pass through the
57:00Golgi apparatus. Okay. And the Golgi
57:07apparatus is the place where they are
57:10packaged. And here it goes. We had said
57:13that the ribosome would only create the
57:16protein, but for the protein to become
57:23a glycoprotein, it is missing
57:31the addition of the carbohydrate, and
57:37this carbohydrate binds in the Golgi
57:40apparatus. That is where glycosylation
57:43takes place. Once the Golgi apparatus
57:47takes the protein that came from either
57:49the cytoplasm ribosome or the
57:51endoplasmic reticulum ribosome, it
57:53attaches the carbohydrate and decides
57:56whether to send it outside or keep it
57:58inside the cell. Well, a few of the
58:03internal proteins will go to the
58:06lysosome, and it's worth talking about
58:12what happens with lysosomal proteins,
58:14okay? Lysosomal proteins or enzymes.
58:29How does it work so that they don't?
58:50Here it goes. Imagine you are inside
58:55the cell, okay? And let's separate the
58:59three important locations for
59:02glycoprotein synthesis here. On one
59:10hand, I have the rough endoplasmic
59:12reticulum. On the other hand, I have,
59:19if you want, let's draw it a bit more
59:22accurately, the rough endoplasmic
59:24reticulum has the ribosomes attached
59:26there, which are the ones that will
59:29make proteins. Or I have the few
59:36ribosomes that are just free and
59:39scattered. I have the Golgi apparatus
59:51here now, which is the one that,
1:00:00depending on where the proteins arrive,
1:00:02will send them either outside the cell
1:00:04or keep them inside. So, let's imagine
1:00:08that since these proteins have the
1:00:11function of reaching the lysosome, well
1:00:20, they are proteins that will be made
1:00:22from free ribosomes. So, the free
1:00:26ribosome synthesizes the protein. The
1:00:30protein has to travel to the Golgi
1:00:35apparatus. In the Golgi apparatus,
1:00:43sugars will be attached to it. Imagine
1:00:58that glucose units are attached to it,
1:01:05and usually the glycoprotein synthesis
1:01:08would end there, but this extra step
1:01:12happens only for the lysosome, and that
1:01:15is that a phosphate is attached. When
1:01:25you have this structure, it means it
1:01:31can travel from the Golgi apparatus to
1:01:34the lysosome. Agreed? This structure is
1:01:39specifically known as mannose 6-
1:01:48phosphate or as the mannose 6-phosphate
1:01:51receptor. So, everything that has this
1:01:55phosphate will be able to interact with
1:01:57the receptor and will be able to travel
1:01:59to the lysosome. The enzyme that
1:02:04attaches this is called
1:02:06phosphotransferase.
1:02:13Agreed? So, to write it down here below
1:02:16with numbers, step number one, protein
1:02:22synthesis
1:02:27in a free ribosome. Step number two,
1:02:40protein in the Golgi apparatus. It is
1:02:52glycosylated, meaning glucose is
1:02:54attached to it. Here we have it. Step
1:02:58number three, attachment of the
1:03:03phosphate. To be able to create what
1:03:10will be recognized by mannose. Six
1:03:14phosphate. Remember that this binding
1:03:18is thanks to the enzyme
1:03:23phosphotransferase. And step number
1:03:34four is just for it to migrate and go
1:03:38to the lysosome. Glycoprotein is
1:03:47transported to the lysosome. All right.
1:03:58One last time to repeat everything. I
1:04:02have
1:04:05that glycoproteins are proteins that
1:04:08have glucose attached. They are
1:04:11synthesized in the ribosome, which can
1:04:13be free in case you want to leave it
1:04:15inside the cell, or it can be attached
1:04:18to the endoplasmic reticulum, to the
1:04:20RER, in case you want to export it. The
1:04:23ones that stay inside the cell often
1:04:25have to go to the lysosome. To go to
1:04:28the lysosome, they need to have mannose
1:04:31-6-phosphate attached to the receptor.
1:04:34All right? So, uh, the protein is made
1:04:38in the free ribosome, and goes to the
1:04:41Golgi apparatus. In the Golgi apparatus
1:04:44, the glucose is attached and the
1:04:46phosphate is attached. What is
1:04:48important here? That if it is going to
1:04:51the lysosome, the phosphotransferase
1:04:54has to attach the phosphate group, and
1:04:56once it is attached, it can go to the
1:04:59lysosome, and that is how lysosomal
1:05:01proteins reach this site. Okay? Why did
1:05:06I put so much emphasis on lysosomal
1:05:09protein synthesis? Well, because there
1:05:12is something called I-cell disease, and
1:05:17this is an error in the synthesis of
1:05:27lysosomal proteins. So, the error in
1:05:50the synthesis of lysosomal proteins is
1:05:53known as the disease. I-cell and the
1:06:03name comes from the inclusion bodies
1:06:08that are formed. We will talk about
1:06:12them now. This I-cell disease is known
1:06:17as a mucolipidosis, okay? caused by a
1:06:24deficiency of the enzyme
1:06:27phosphotransferase. The enzyme
1:06:39phosphotransferase served to send the
1:06:41proteins, already with the phosphate,
1:06:42to the lysosome, remember? So, if I do
1:06:46not have this enzyme, there is an error
1:06:52in the transport of proteins that were
1:07:03going to the lysosome. And if they do
1:07:11not go to the lysosome, there will be
1:07:14lysosomal proteins or enzymes, free in
1:07:22blood and urine. All right? So, I have
1:07:33these lysosomal proteins and enzymes
1:07:36free in the blood and urine. This is
1:07:39one of the most important facts. And
1:07:42obviously, if you remember, well,
1:07:44lysosomal enzymes serve to degrade
1:07:46things in the lysosome. If I do not
1:07:49have these enzymes, there will be an
1:07:51accumulation of products that will not
1:07:57be degraded there. And that is where
1:08:13the inclusion bodies come from. When
1:08:16you look under the microscope, you see
1:08:18that the lysosome has things in there,
1:08:20and those things are nothing more than
1:08:23the products that could not be degraded
1:08:25because you did not have the enzymes to
1:08:27degrade them. That is why it is I-cell
1:08:31disease. And What will be seen
1:08:36clinically besides free lysosomal
1:08:38enzymes in the blood and urine, which
1:08:40is one of the main exam questions. They
1:08:44present a patient with lysosomal
1:08:46enzymes in blood and urine, they have
1:08:49I-cell disease, and what enzyme is
1:08:51missing? The answer is
1:08:53phosphotransferase. The clinical
1:08:56presentation can also have dysmorphic
1:08:59features, they can have skeletal
1:09:07abnormalities, they can have
1:09:16psychomotor deterioration And they can
1:09:25also have death in infancy, death at a
1:09:28very early age, mainly due to pulmonary
1:09:35complications. This is just to complete
1:09:43the clinical picture, but believe me,
1:09:45knowing that I-cell disease is an
1:09:47alteration of phosphotransferase is
1:09:49enough. There are free lysosomal
1:09:52enzymes. It is an error in the
1:09:54transport of these enzymes. That is
1:09:57more than enough. We continue talking
1:10:00about glycoproteins. Right now, this
1:10:02was only to talk about the
1:10:03glycoproteins that go to the lysosome.
1:10:06The last thing we need to know, if we
1:10:09already saw the synthesis, is the
1:10:11degradation of these enzymes—these
1:10:14glycoproteins, sorry. Their degradation
1:10:23is also at the lysosomal level by the
1:10:29enzymes, acid hydrolases. these
1:10:45diseases. Uh, sorry, uh, when I don't
1:10:49have these acid hydrolases and then
1:11:02there is an accumulation of
1:11:09glycoproteins. In the lysosome a group
1:11:21of diseases appear known as
1:11:23oligosaccharidoses. This is the last
1:11:29thing we are going to see and it is the
1:11:31last super common exam question, and
1:11:34they just ask you. In
1:11:36oligosaccharidosis, what compound do
1:11:38you expect to find free in urine or
1:11:40expect to find accumulated? And they
1:11:44give you options. What compound is
1:11:47accumulated or free in urine?
1:11:50Oligosaccharides, GAGs, proteoglycans
1:12:03or glycoproteins. And you must remember
1:12:09then that in the case of
1:12:24oligosaccharidoses, what accumulated
1:12:33were the glycoproteins. In the case of
1:12:37mucopolysaccharidoses, this is to
1:12:40repeat,
1:12:47they are the GAGs, the
1:12:49glycosaminoglycans. So, just to finish,
1:12:53it is very important that this is clear
1:12:56. You have two diseases in which you
1:12:59lack acid hydrolases, two diseases in
1:13:01which something is going to accumulate
1:13:03in the lysosome, something is going to
1:13:05be free in the urine. Okay? If what is
1:13:09free in the urine are glycoproteins,
1:13:11that disease is an oligosaccharidosis.
1:13:15If what is free in the urine or
1:13:17accumulated in the lysosome are GAGs,
1:13:20that disease is a mucopolysaccharidosis
1:13:22. If what is free in the urine are
1:13:27lysosomal enzymes.
1:13:41In this case, the disease was I-cell
1:13:44disease. Okay. So, I just ask you to
1:13:53pay close attention to this and, uh,
1:13:55remember, you can let me know if you
1:13:57have any questions. The last thing I
1:14:02want to do is check an article with you
1:14:04that I found so you can see an example
1:14:07of a mucopolysaccharidosis, but you
1:14:09really have to focus, as always, more
1:14:12than on the structures, uh, on knowing
1:14:14which part of the cell it happens in,
1:14:17which enzymes are important, and above
1:14:19all, the diseases. Starting with what's
1:14:23in the image, you need to know, number
1:14:26one, what is accumulating, okay? So,
1:14:30we're just going to quickly review this
1:14:32. You have a 10-year-old male patient.
1:14:43Okay. The first thing he presented with
1:14:47was kyphosis. Okay. This means he had
1:14:53an excessive curvature of the cervical
1:14:57spine, okay? Uh, he had respiratory
1:15:02infections, he had nasal congestion and
1:15:08this presented at 2 years of age. Okay?
1:15:12Afterward, the following signs were
1:15:15added. Macrocephaly, a very large head,
1:15:20coarse facies, flat nasal bridge,
1:15:36psychomotor retardation, language
1:15:39development alterations, corneal
1:15:41opacity; and if you notice, the
1:15:44clinical picture I told you about for
1:15:47mucopolysaccharidosis is being
1:15:49fulfilled, specifically type one,
1:15:52because we said corneal opacity, facial
1:15:55dysmorphism, mental retardation, and
1:15:58musculoskeletal alterations. Okay? A
1:16:03urine sample is sent and reports
1:16:06urinary GAGs. Remember that urinary
1:16:11GAGs are what define the diagnosis of
1:16:14mucopolysaccharidosis. To this was
1:16:19added a case of a heart murmur and
1:16:22that's when they decided to look for
1:16:25which enzyme was affected, okay? and
1:16:30they realized he had a deficiency of
1:16:32the alpha-iduronidase enzyme. With this
1:16:36, you know the diagnosis is
1:16:39mucopolysaccharidosis type one, also
1:16:44known as the syndrome or disease of
1:16:51Hurler. And here are the images of the
1:16:58patient and if you notice, well, he
1:17:00presents the characteristic facial
1:17:05features. You guys ask me a lot, hey,
1:17:08what is the cure? Remember that most of
1:17:11these genetic diseases have no cure.
1:17:14And I've told you, there is something
1:17:16called enzyme replacement therapy,
1:17:19meaning, you give them the missing
1:17:21enzyme. Not all therapies are, uh,
1:17:25successful, they are very expensive,
1:17:27but in this case, this patient started
1:17:30enzyme replacement therapy, giving him
1:17:33the enzyme he was missing, and he
1:17:35showed improvement, at least he showed
1:17:38improvement in his respiratory symptoms
1:17:41. And that is what I wanted you to take
1:17:46away from the case. So,
1:17:48mucopolysaccharidosis, the clinical
1:17:50picture, the diagnosis with urinary
1:17:52GAGs, the phenotype, that is, what
1:17:55these patients look like, and finally,
1:17:57that in this case, an enzyme
1:17:59replacement therapy could be provided,
1:18:01which in this case was successful.
1:18:04Alright, and with that, we finish the
1:18:07topic of GAX. Any questions, you
1:18:10already know you can tell me on social
1:18:13media or you can write to the
1:18:15institute's phones or to mine, okay?
1:18:18Goodbye.

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