BIOCHEMISTRY DISCUSSION 4

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All right - so now we’re going to talk about carbohydrates, which are a critical class of molecules that are responsible for energy storage and signaling and also structural reasons.

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Biochemistry: A Short Course Fourth Edition

CHAPTER 10 Carbohydrates

Tymoczko • Berg • Gatto • Stryer

We’ll start with monosaccharides, which are the simplest form, and then we will talk about how they get linked together to form complex carbohydrates. These carbohydrates can be attached to proteins and they can also be used to recognize certain cells using a type of protein called lectin.

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Chapter 10: Outline

10.1 Monosaccharides Are the Simplest Carbohydrates

10.2 Monosaccharides Are Linked to Form Complex Carbohydrates

10.3 Carbohydrates Are Attached to Proteins to Form Glycoproteins

10.4 Lectins Are Specific Carbohydrate-Binding Proteins

Carbohydrates are all of a very similar formula, which is CH2O - the C is for the “carbo-”, H2O for “-hydrate” {water} - so it’s hydrated carbon. And most of them you’ll find actually have that empirical formula {notable exceptions include deoxyribose in DNA}. Monosaccharides, which are the elements that all carbohydrates are built out of, are either aldehydes or ketones that contain two or more alcohol groups. A ketone and aldehyde are similar because they have a carbonyl group. So there is usually one double-bonded carbon and oxygen, and then two or more alcohol groups, or hydroxyl groups, sticking off of these … carbohydrates.

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Section 10.1 Monosaccharides Are the Simplest Carbohydrates

Learning objective 1: Differentiate between monosaccharides and polysaccharides in regard to structure and function.

• Monosaccharides are aldehydes or ketones that contain two or more alcohol groups.

• The smallest monosaccharides are composed of three carbons.

And yet, they are still quite complex

General Empirical Formula = (CH2O)n “carbo” “hydrate”

Figure 10.1 Isomeric forms of carbohydrates.

You can have a lot of different “isomeric forms” of carbohydrates, and “isomeric forms” mean that the empirical formula for them is exactly the same, but their shape is different. The most common one you’ll see, up on the left, is the constitutional isomers. If you’ll look at those two molecules we’ll see that the glyceraldehyde and dihydroxyacetone have exactly the same formula, C3H6O3, but they have a different location of the double bond of oxygen and so that makes them behave differently in cells. Another type of isomer is called the stereoisomer, which is where we have enantiomers on the left, which are nonsuperimposable mirror images of each other, and diastereomers, which are not mirror images of each other. They do have exactly the same formula, but all of these differences make them behave differently in the body. You’ll see epimers on the top right - they differ at one of several asymmetric carbon atoms. Anomers, at the bottom right, isomers that are different at a new asymmetric carbon atom, which is formed on ring closure. Now let’s focus on the anomers briefly, because those are going to become important. We have alpha-D- Glucose and beta-D-Glucose. So they’re almost identical, except for the one hydroxyl group on the left is pointing down, and on the right it’s pointing up - and that actually has a very important consequence for the activity of these glucoses.

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Diagram of Isomeric Forms of Carbohydrates

QUESTIONS ABOUT SPECIFIC TYPES OF ISOMERS WILL NOT BE ON THE TEST, BUT YOU WILL BE EXPECTED TO KNOW IF TWO MOLECULES ARE THE SAME OR DIFFERENT

Figure 10.2 Common monosaccharides. Aldoses contain an aldehyde (shown in blue), whereas ketoses, such as fructose, contain a ketone (shown in blue). The asymmetric carbon atom farthest from the aldehyde or ketone (shown in red) designates the structures as being in the D configuration. The numbers are the standard designations for the positions of the carbon atoms. For example, the number 2 identifies the carbon atom in the second position.

So as I’ve mentioned, we have monosaccharides that have either an aldehyde group or a ketone group. And ones with the aldehyde group are called aldoses. And, you can see, most of these here are aldoses - that CHO in blue, at the top of these structures, is an aldehyde group. That would be the C double-bonded to the oxygen and single- bonded to a hydrogen. The fructose on the right is a ketose where the double bond is actually on the second carbon. Now, another important part of all of these is the asymmetric carbon, which is furthest from the aldehyde or ketone, and that’s shown in red. That is a configuration that designates these as either D- or L-carbohydrates {enantiomers!}. Most of the carbohydrates we’re going to encounter are D- carbohydrates. Another important thing to mention about this, is that the top two structures have 5 carbons in them, and the bottom four have 6 carbons. The bottom four have exactly the same chemical formula of C6H12O6.

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Common Monosaccharides

Figure 10.3 Pyranose formation. The open-chain form of glucose cyclizes when the C- 5 hydroxyl group attacks carbon atom C-1 of the aldehyde group to form an intramolecular hemiacetal. Two anomeric forms, designated α and β, can result.

So looking at D-glucose, and we’re going to look a lot at D-glucose, that is the archetypal carbohydrate - it’s the most common that we are going to find and so we will study that in depth - but D-glucose can exist in two different forms. There is the open chain form on the left and then there is the closed form, which you see on the right. And depending on how that closure occurs, you can produce either alpha glucose or beta glucose and that only differs in the orientation of the alcohol group on the far right, there. The carbon that is “making the decision” as to whether or not this is an alpha glucose or a beta glucose is called the anomeric carbon, because those two structures are anomers of one another. If you were to take a solution of glucose you would find them, actually, the glucose molecules, shifting and changing between these various forms. They spontaneously will switch from alpha glucopyranose to open chain form and then to beta glucopyranose {and back again}. If you were to measure the amounts, then there would be about ⅓ of the alpha glucose, ⅔ of the beta glucose, and about 1% of the open chain. That indicates that the beta glucose is actually the most stable out of all of them, and the open chain is not too stable. It is much more likely to find it in the circular form.

Figure 10.4 Furanose formation. The open-chain form of fructose cyclizes to a five- membered ring when the C-5 hydroxyl group attacks carbon C-2 of the ketone to form an intramolecular hemiketal.

Fructose, which has a keto group rather than an aldehyde group, is able to form a 5- membered ring, and we call that a furanose. And, similarly to glucose, it can exist in either the alpha or beta anomeric form.

Figure 10.6 Chair and boat forms of β-D-glucopyranose. The chair form is more stable owing to less steric hindrance because the axial positions are occupied by hydrogen atoms. Abbreviations: a, axial; e, equatorial.

Now, six membered rings are not static - they, like any molecule, move a lot and they find themselves in many configurations. Two of the configurations that are most common to find them in, because they are the most stable, are called the “boat” and the “chair” conformation. You can see, on the bottom, the chair form on the left, kind of looks like a chair - with the back of the chair on the left, and then the seat in the middle, and the place for your legs on the right (sorry if you’re not able to see that too clearly). The other conformation would be the boat form, where, on the right we see the two prows of the boat on either end of the molecule. And the molecules are always flipping around between these different conformations {and others}. Now, there are two {substituents} attached to each of the carbon atoms on these, and those {substituents} either point up along the axis of the ring {the axial atoms}, or they point out, and those would be the equatorial atoms (equatorial we can think about as the equator, they kind of point out toward the middle). What’s axial and what’s equatorial is depending on the conformation - so you can see, in the chair form, in the center of this slide, there are, on the right-hand side, there is an equatorial group that when you shift into the boat form, it becomes an axial group.

Now axial and equatorial configurations are important because you will see that when the groups are larger they tend to be equatorial, because when they’re axial they’re too close together and they have steric hindrance {bang into each other}. So when we’re looking at these carbohydrates, we’re generally looking at hydrogen and hydroxide that are sticking off of these carbons, and the hydroxides prefer to be in the equatorial form. So what you see there on the right, in the boat form, would not be a favored conformation for this molecule. We would expect to find it much more in the chair form - and that is in fact the case when this is studied. This is a molecule of beta-D-glucopyranose, and that is usually found in the chair conformation. One of the reasons that you find the beta-glucopyranose more often than the alpha is that the alpha has the anomeric form which will force one of the hydroxyl groups to be in the axial position, which is slightly less stable.

It’s important to note here that the anomeric carbon in monosaccharides is the one that has the double bonded oxygen and is therefore the most reactive - so if you’re going to attach anything to that molecule you’ll probably attach it at that anomeric carbon. And when that occurs, the product is called a glycoside. You can form these anomeric bonds usuallywith an amine group or a hydroxyl group. If they are with a hydroxyl group we call it an O-glycosidic bond, because it’s an oxygen making the connection, and if it’s an amine we call it an N-glycosidic bond because it’s a nitrogen. Carbohydrates can also form ester linkages to phosphates as you can see in the lower right hand corner.

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Monosaccharides Are Joined to Alcohols and Amines Through Glycosidic Bonds

• A bond formed between the anomeric carbon atom of glucose and a hydroxyl group of another molecule is called an O- glycosidic bond, and the product is called a glycoside.

• A bond formed between the anomeric carbon atom of glucose and an amine is called an N-glycosidic bond.

• Carbohydrates also form ester linkages to phosphates.

Figure 10.7 Modified monosaccharides. Carbohydrates can be modified by the addition of substituents (shown in red) other than hydroxyl groups. Such modified carbohydrates are often expressed on cell surfaces.

Carbohydrates can be modified by the addition of things other than hydroxyl groups. This is very common and you can see on the top left there’s a methyl group that has been added. The next one shows an acetylgalactosamine which is actually quite common, then there’s acetylglucosamine, which is the same modification, but being made to glucose rather than galactose. And once again what’s the difference between glucose and galactose? Well, they’re isomers of each other. They’re almost identical except for the one hydroxyl group in galactose is pointing up and in glucose is pointing down. Sialic acid has multiple attachments and phosphate can be attached to these molecules as well as shown on the lower right. The attachment of a phosphate is one of the more important things that occurs in digestion and glycolysis.

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Structure of Modified Monosaccharides Carbohydrates can be modified by the addition of substituents (shown in red) other than hydroxyl groups. Such modified carbohydrates are often expressed on cell surfaces.

FIGURE 10.8 Maltose, a disaccharide. Two molecules of glucose are linked by an α- 1,4-glycosidic bond to form the disaccharide maltose. The angles in the bonds to the central oxygen atom do not denote carbon atoms. The angles are added only for ease of illustration.

So, for example, we have here two molecules of glucose that are linked by what we call an alpha-1,4 glycosidic bond. It’s called that because the anomeric carbon on the left hand side of this diagram is in the alpha configuration and not the beta configuration. And that is the number 1 carbon. When you’re looking at the carbons, we number them, and that’s the first one, the anomeric carbon. It’s connected to a similar alpha glucose on the right but connected at the fourth carbon, there. These two glucoses attached in this way create what’s called maltose, a disaccharide and an important molecule.

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Section 10.2 Monosaccharides Are Linked to Form Complex Carbohydrates

• Oligosaccharides contain two or more monosaccharides linked by O-glycosidic bonds.

So the addition of these oligosaccharides is conducted by a large class of enzymes called glycosyltransferases.

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Specific Enzymes Are Responsible for Oligosaccharide Assembly

• A large class of enzymes, glycosyltransferases, catalyze the formation of glycosidic bonds.

Figure 10.10 Common disaccharides. Sucrose, lactose, and maltose are common dietary components. The angles in the bonds to the central oxygen atoms do not denote carbon atoms.

The three most common disaccharides are sucrose, lactose, and maltose. Sucrose obviously is sugar that you would eat, and lactose is the sugar that you find in milk, and they are different primarily in their connectivity. I believe they all actually have the same formula but sucrose is connected with an alpha-1 carbon to the beta-2 carbon of fructofuranose, whereas the lactose is a beta-1,4 linkage and maltose is an alpha-1,4 linkage. Now I wanted to include some pictures on the lower right to show you what these molecules actually look like, because I think these diagrams can sometimes be misleading. So at the top there, you see a sort of diagrammatic representation of lactose, and then there’s the ball-and-stick model, and finally a space filling model of lactose. And with the space filling model we can get a little bit more sense of what these molecules would look like when floating around in the cell, what their surface landscape, their shape would be - and remember that shape is important for recognition by enzymes and other molecules.

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Sucrose, Lactose, and Maltose Are the Common Disaccharides

lactose

So we’ve seen how you can put together two monosaccharides - well you can actually string them together and make very long polysaccharides. Two of the most common polysaccharides that you’ll come across are glycogen and starch, and those are storage forms of glucose. Glucose, of course, is the most common fuel for all life on the planet (basically) and it’s important to be able to store it. So glycogen is how glucose is stored in animal cells, and starch is how it’s stored in plant cells.

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Glycogen and Starch Are Storage Forms of Glucose

• Large polymeric oligosaccharides are called polysaccharides.

• The polysaccharide glycogen is the storage form of glucose in animal cells.

• Glycogen and starch have essentially the same structure, but glycogen is more highly branched

Figure 10.12 Branch point in glycogen. Two chains of glucose molecules joined by α- 1,4-glycosidic bonds are linked by an α-1,6-glycosidic bond to create a branch point. Such an α-1,6-glycosidic bond forms at approximately every 10 glucose units, making glycogen a highly branched molecule.

So in glycogen we have what we normally see with the alpha-1,4 linkage between glucoses and then occasionally there is a branch where the alpha-1 anomeric carbon of a glucose will attach to a 6 carbon of another glucose, and that causes a branch point. A very similar thing occurs in starches.

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Diagram of Branch Point in Glycogen

Another very common complex carbohydrate, polysaccharide, is cellulose. In fact, it may in fact be one of the most common molecules on the planet. It’s also made out of glucose, but linked by a beta-1,4-glycosidic bond rather than an alpha-1,4- glycosidic bond. Now that’s actually a little more favorable to form cellulose because, if you recall, the beta form of the glucose is a little more prevalent. But the effect is very different. When you have a beta linkage between glucose molecules the chains tend to be straight and they can link together to form strong fibrils. Alpha linkages that you find in starch and glycogen are more helical. Sadly, we can not digest cellulose because we lack the enzyme to break the beta-1,4-glycosidic bond. But some insects can - and bacteria.

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Cellulose, a Structural Component of Plants, Is Made of Chains of Glucose

• Cellulose is a homopolymer of glucose units linked by β-1,4- glycocidic bonds.

• The β linkage yields a straight chain capable of interacting with other cellulose molecules to from strong fibrils.

• The α linkages of starch and glycogen form compact hollow cylinders suitable for accessible storage.

• Mammals cannot digest cellulose because we lack the enzyme to dissolve the β-1,4-glycosidic bond.

Figure 10.14 Glycosidic bonds determine polysaccharide structure. The β-1,4 linkages favor straight chains, which are optimal for structural purposes. The α-1,4 linkages favor bent structures, which are more suitable for storage.

But its stability and strength make cellulose an excellent material for building the elements of plants out of.

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Polysaccharide Structures

Starch and glycogen, on the other hand, have the alpha-1,4 linkages and do not form straight sheets, they form sort of curved helical formations. We will discuss this in more detail later in the course, but essentially the helical configuration of starch and glycogen allow them to be reached by enzymes and broken apart easily.

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Polysaccharide Structures

Carbohydrates can be attached to proteins, and ARE frequently attached to proteins, and we call those glycoproteins. So there’s three main kinds. Glycoproteins {mostly protein, but decorated with carbohydrates} are very important for cell signaling and recognition of proteins. Proteoglycans are much larger structures and those are containing a polysaccharide called glycosaminoglycan. Mucins are the third category and they are attached to the carbohydrate with an N-acetylgalactosamine.

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Section 10.3 Carbohydrates Are Attached to Proteins to Form Glycoproteins

Learning objective 2: Differentiate among the structures and functions of glycoproteins. Proteins with carbohydrates attached are called glycoproteins. There are three main classes of glycoproteins: 1. Glycoproteins: The protein is the largest component by weight.

Glycoproteins play a variety of roles, including as membrane proteins. 2. Proteoglycans: The protein is attached to a particular type of

polysaccharide called a glycosaminoglycan. By weight, proteoglycans are mainly carbohydrate. Proteoglycans play structural roles or act as lubricants.

3. Mucins or mucoproteins: Like proteoglycans, mucins are predominantly carbohydrate. The protein is characteristically attached to the carbohydrate by N-acetylgalactosamine. Mucins are often lubricants.

So carbohydrates can be linked to proteins usually through an asparagine, serine, or threonine residue. Once again - the asparagine is called an N-linkage, and the threonine and serine are called O-linkages.

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Carbohydrates May Be Linked to Asparagine, Serine, or Threonine Residues

of Proteins

• In all classes of glycoproteins, carbohydrates are attached to the nitrogen atom in the side chain of asparagine (N- linkage) or to the oxygen atom of the side chain of serine or threonine (O-linkage).

(Also arginine, tyrosine, and others, to a lesser extent)

Figure 10.15 Glycosidic bonds between proteins and carbohydrates. A glycosidic bond links a carbohydrate to the side chain of asparagine (N-linked) or to the side chain of serine or threonine (O-linked). The glycosidic bonds are shown in red. Abbreviations: GlcNAc, N-acetylglucosamine; GalNAc, N-acetylgalactosamine.

Here we have two examples of linkage of carbohydrates to proteins. On the left it’s linked to an asparagine residue {N-linked}, and on the right it’s linked to a serine residue (which is O linked). The linkage occurs at the anomeric carbon, as usual, because that’s where the double bonded oxygen is.

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Diagram of Glycosidic Bonds Between Proteins and Carbohydrates

A glycosidic bond links a carbohydrate to the side chain of asparagine (N-linked) or to the side chain of serine or threonine (O-linked).

One thing that glucose reacts with is hemoglobin. And hemoglobin with glucose attached to it, is called A1c, and it’s a fully functional protein and that’s a good way of measuring what the blood glucose level is in diabetics. If the blood glucose level is too high then you’ll see a great deal more of this hemoglobin A1c than you would in a normal person. But it is also possible that the glycosylation of proteins can inhibit their function, and we will discuss that in more detail later.

Figure 10.16 N-linked oligosaccharides. A pentasaccharide core (shaded gray) is common to all N-linked oligosaccharides and serves as the foundation for a wide variety of N-linked oligosaccharides, two of which are illustrated: (A) high-mannose type; (B) complex type. Detailed chemical formulas and schematic structures are shown for each type (for the key to the scheme, see Figure 10.17). Abbreviations for sugars: Fuc, fucose; Gal, galactose; GalNAc, N-acetylgalactosamine; GlcNAc, N- acetylglucosamine; Man, mannose; Sia, sialic acid.

Now all N-linked polysaccharides have a common pentasaccharide core. And you can see that in these diagrams - there are two N-acetylglucosamine units {I incorrectly say “N-acetylgalactosamine” in the audio} attached to the asparagine residue, and then attached to those two are three mannoses. And you can build off of that core structure to create a wide variety of different polysaccharides.

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Diagram of N-linked oligosaccharides • All N-linked polysaccharides consist of a common pentasaccharide core

consisting of three mannoses, a six-carbon sugar, and two N- acetylgalactosamine units.

• Additional monosaccharides may be attached to the core.

Another example of a glycosylated protein is erythropoietin, which is also known as EPO, and glycosylation stabilizes erythropoietin so that it will stick around longer, which makes it useful to athletes.

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Clinical Insight: The Hormone Erythropoietin Is a Glycoprotein

CLINICAL INSIGHT The Hormone Erythropoietin Is a Glycoprotein

• Erythropoietin is a glycoprotein secreted by the kidney into the blood that stimulates the production of red blood cells.

• Glycosylation of erythropoietin enhances the stability of the protein in the blood.

Figure 10.17 Oligosaccharides attached to erythropoietin. Erythropoietin has oligosaccharides linked to three asparagine residues and one serine residue. The structures shown are approximately to scale. The carbohydrate structures represented in the amino acid residues are depicted symbolically by employing a scheme (shown in the key, which also applies to Figures 10.16, 10.23, and 10.24) that is becoming widely used. [Drawn from 1BUY.pdf.]

Erythropoietin is glycosylated in four different places - three of them are N-linked glycosylations, and one of them is an O-linked glycosylation, and I think you can tell by looking at the diagram which is which. Remember, all N-linked glycosylations have that five monosaccharide core.

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Diagram of Oligosaccharides Attached to Erythropoietin

Proteoglycans are composed of polysaccharides and protein - but they are mostly glycosaminoglycans, which is a form of disaccharide, and these proteoglycans are used a lot in extracellular matrix and also as lubricants in the cells.

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Proteoglycans, Composed of Polysaccharides and Protein, Have

Important Structural Roles • Proteoglycans are proteins attached to

glycosaminoglycans, which make up 95% of the proteoglycan by weight.

• Glycosaminoglycans are composed of repeating units of a disaccharide, one of which is a derivative of an amino sugar and one of which carries a negative charge, either as a carboxylate or sulfate.

• Proteoglycans are key components of the extracellular matrix and serve as lubricants.

Figure 10.18 Repeating units in glycosaminoglycans. Structural formulas for five repeating units of important glycosaminoglycans illustrate the variety of modifications and linkages that are possible. Amino groups are shown in blue and negatively charged groups in red. Hydrogen atoms have been omitted for clarity. The right-hand structure is a glucosamine derivative in each case. The parent amino sugars, β-D-glucosamine and β-D-galactosamine, are shown for reference.

There are various repeating units in glycosaminoglycans, but you can see the common theme is that there is an amino group attached to at least one of these repeating units. You’ll probably recognize several of these. Glucosamine, at the top, is considered a dietary supplement that some people use. Chondroitin sulfate also. And there are several other groups that can be attached along the sides of these, such as the carboxylic acid group or a sulfate group, as shown in this diagram.

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Diagram of Repeating Units of Glycosaminoglycans

One of the most important roles of proteoglycans are as components of cartilage. And it’s important to note that these carbohydrates are very water soluble, they’re very hydrophilic, because they are basically coated in electronegative groups such as alcohols or nitrogens, and, therefore, the water sticks to them quite a bit.

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Clinical Insight: Proteoglycans Are Important Components of Cartilage

CLINICAL INSIGHT Proteoglycans Are Important Components of Cartilage

• Cartilage is composed, in part, of the proteoglycan aggrecan and collagen. The glycosaminoglycan component of aggrecan cushions joints by releasing water on impact and then rebinding water.

Figure 10.20 Cartilage acts as a shock absorber. The cartilage of a runner’s foot cushions the impact of each step that she takes. [Untitled x-ray/ Nick Veasey/Getty Images.]

Water, then, will make up a large portion of these {proteoglycan complexes – water is not part of the proteoglycans, per se, but is associated with them}, and then when pressure is put on them, the water can be squeezed out {slowly}, creating a cushion.

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X-ray of a Shoe and Foot

Figure 10.21 The structure of proteoglycan from cartilage. (A) Electron micrograph of a proteoglycan from cartilage (with color added). Proteoglycan monomers emerge laterally at regular intervals from opposite sides of a central filament of hyaluronanate. (B) Schematic representation in which G stands for globular domain. [(A) Courtesy of Dr. Lawrence Rosenberg. From J. A. Buckwalter and L. Rosenberg. Collagen Relat. Res. 3:489–504, 1983.]

Here we see a proteoglycan in cartilage (color has been added, of course). This is an electron micrograph, and you can clearly see the proteoglycans emerging at regular intervals from opposite sides of the central filament of hyaluronan which is in the middle. So in all of those little cracks - that’s where the water would be and that’s where the resilience of the cartilage comes from.

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The Structure of Proteoglycan from Cartilage (1/2)

Figure 10.21 (B) Schematic representation in which G stands for globular domain.

Here’s a schematic of that cartilage fragment and you can see the central hyaluronan filament, and then, the aggrecans extending out from the central filament. And there is keratan sulfate and chondroitin sulfate, and globular domains labeled G1, G2, and G3.

{NOTE – there are reasons why cartilage is organized this way, but we’re not going into them. It’s just too much. What I want you to be aware of is that there ARE structures for all of these things, all of these crazy carbohydrates, and you can look them up if you ever need to.}

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The Structure of Proteoglycan from Cartilage (2/2)

Figure 10.22 Chitin, a glycosaminoglycan, is present in insect wings and the exoskeleton. Glycosaminoglycans are components of the exoskeletons of insects, crustaceans, and arachnids. [FLPA/Alamy.]

Chitin, which is a glycosaminoglycan and very closely related to cellulose, is found in the exoskeleton of insects - and insects are everywhere, making this one of the most abundant carbohydrates in the world (in fact it is a glycosaminoglycan).

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Image of an Insect • Chitin, a glycosaminoglycan found in the exoskeleton of

insects, is one of the most abundant carbohydrates in the world.

http://nzetc.victoria.ac.nz/tm/scholarly/Bio14Tuat01-fig-Bio14Tuat01_038a.html

Mucins are glycoprotein components of mucus and they also absorb a lot of water, which makes them big and slippery, and so they are very good as lubricants.

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Clinical Insight: Mucins Are Glycoprotein Components of Mucus

CLINICAL INSIGHT Mucins Are Glycoprotein Components of Mucus

• In mucins, the protein component is extensively glycosylated to serine and threonine residues beginning with N-acetylgalactosamine.

• A region of the protein backbone rich in serines and threonines, called variable number of tandem repeats (VNTR), is the site of glycosylation.

• Mucins serve as lubricants.

Figure 10.23 Mucin structure. (A) A schematic representation of a mucoprotein. The VNTR region is highly glycosylated, forcing the molecule into an extended conformation. The Cys-rich domains and the D domain facilitate the polymerization of many such molecules. (B) An example of an oligosaccharide that is bound to the VNTR region of the protein. [After A. Varki, R. D. Cummings, J. D. Esko, H. H. Freeze, G. W. Hart, and M. E. Etzler, Essentials of Glycobiology, 2d ed. (Cold Spring Harbor Press, 2009), (Part A) p. 117, Fig. 9.1; (Part B) p. 118, Fig. 9.2.]

In a mucin we have a D-domain, which facilitates polymerization, along with the cysteine rich domains. And then the VNTR, also called the “variable number of tandem repeats” region, is where the glycosylation takes place. And at the bottom we have an example of an oligosaccharide that would be bound to that G-VNTR region.

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Mucin Structure

Blood groups are based on glycosylation patterns. If you are familiar with the Type A blood, Type B blood, Type O blood - well, the thing that makes them Type A and B and O are the glycosylation patterns which is mediated by the glycosyltransferases.

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Biological Insight: Blood Groups Are Based on Protein Glycosylation Patterns

BIOLOGICAL INSIGHT Blood Groups Are Based on Protein Glycosylation Patterns

• The human ABO blood groups reflect the specificity of glycosyltransferases.

• All of the blood groups share the oligosaccharide foundation called O.

• In A, N-acetylgalactosamine is added to the O by a specific glycosyltransferase.

• In B, galactose is added by another transferase. • The blood type O produces no active glycosyltransferase.

Figure 10.24 Structures of A, B, and O oligosaccharide antigens. The carbohydrate structures represented in the upper part of this illustration are depicted symbolically (refer to the key in Figure 10.17).

If you have no functional glycosyltransferases then you will be Type O which you see on the left. Type A and B are the result of different glycosyltransferases that exist.

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Structures of A, B, and O oligosaccharide antigens

Glycosylation is very important for recognition of proteins, and directing them to the proper locations in the cell. For example, in I-cell disease, there is an enzyme that gets improperly glycosylated - and as a result, it gets secreted into the blood instead of being directed into the lysosome.

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Clinical Insight: Lack of Glycosylation Can Result in Pathological Conditions

CLINICAL INSIGHT Lack of Glycosylation Can Result in Pathological Conditions

• In I-cell disease, lysosomal enzymes are secreted into the blood rather than directed to the lysosome.

• The defect results from a mutation that disrupts the oligosaccharide signal on the enzymes that normally directs the enzymes to the lysosome.

Another example of how glycosylation affects signaling is on the surface of cells. The surfaces of cells are covered with oligosaccharides, and different cells have different kinds of oligosaccharides, and that's how cells recognize each other, using proteins called lectins that are specific for one or a different kind of oligosaccharide.

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Beginning of section 10.4 Lectins Are Specific Carbohydrate-Binding Proteins

• Glycan-binding proteins bind to specific oligosaccharides on the cell surface.

• Lectins are a particular class of glycan-binding protein.

Figure 10.26 Selectins mediate cell–cell interactions. The scanning electron micrograph shows lymphocytes adhering to the endothelial lining of a lymph node. The L selectins on the lymphocyte surface bind specifically to carbohydrates on the lining of the lymph-node vessels. [Courtesy of Dr. Eugene Butcher.]

The lectins on one cell will bind to certain carbohydrates on another cell and that will bring the cells in close proximity to each other for cell-cell interaction.

Created by Brett Barbaro

Lectins Promote Interactions Between Cells • The lectins on one cell recognize and bind to

carbohydrates on another cell with multiple weak interactions. Such binding facilitates cell–cell interaction.