Carbohydrate 5: Glycosidic bonds forming disaccharides (with maltose, lactose, sucrose)

In this article, we will examine how disaccharides are formed through glycosidic bonds between two monosaccharide units, using three representative disaccharides—maltose, lactose, and sucrose—as examples.

Glycosidic linkage (glycosidic bond): C-O-C link

When we first began our discussion on carbohydrates, we explored the carbonyl group (C=O) and how its position within a monosaccharide determines whether the sugar is an aldose or a ketose. The aldehyde group (or ketone group) in a monosaccharide plays a crucial role throughout the entire lifecycle of a carbohydrate. The aldehyde group reacts with an alcohol (-OH) to form a hemiacetal, while the ketone group reacts to form a hemiketal. The carbon involved in forming this hemiacetal or hemiketal becomes the anomeric carbon, which is the very point at which monosaccharides link to form disaccharides and ultimately polysaccharides. Furthermore, the aldehyde group can also react with other molecules by donating electrons and getting oxidized to a carboxylic acid (-COOH), thereby reducing the other molecule—this property defines a reducing sugar. Glucose, for example, acts as a reducing sugar that donates electrons in the metabolic pathways that convert glucose into energy.

From hemiacetal to acetal: formation of the glycosidic bond

Now let’s take a closer look at how two anomers formed from hemiacetals or hemiketals attach to form larger and more complex carbohydrates. After ring formation, the first carbon(C1) becomes the anomeric carbon. When this anomeric carbon bonds with the hydroxyl group (-OH) of another monosaccharide, the result is a glycosidic bond. In this way, a monosaccharide, which has many OH groups, initially reacts internally to form a hemiacetal, but under favorable conditions, it can undergo a second reaction with an external OH group from another monosaccharide to form a full acetal. This linkage is known as a glycosidic bond. If the bond is made through the α-anomeric carbon, it is called an α-glycosidic bond; if made through the β-anomer, it is a β-glycosidic bond. The α-glycosidic bond can be observed in maltose, whereas the β-glycosidic bond appears in cellulose. 

Glycosidic bonds are relatively strong covalent bonds and are not easily broken under normal biochemical conditions. Breaking down polysaccharides linked by such bonds is, essentially, what we call digestion. The formation of glycosidic bonds is a dehydration condensation reaction, where a water molecule is removed. To break this bond and return to the original state, hydrolysis—adding water—is required.

Enzyme that breaks glycosidic bonds = digestive enzyme

Fortunately, the human body possesses a variety of hydrolytic enzymes capable of breaking glycosidic bonds between monosaccharides. Enzymes like amylase, maltase, lactase, and sucrase have high specificity, recognizing and cleaving only certain glycosidic bonds. These enzymes efficiently break down complex carbohydrates. However, the human body lacks the enzyme cellulase, which is needed to break down cellulose. Additionally, some individuals lose the enzyme lactase as they grow older, leading to lactose intolerance. 

Beyond digestion, glycosidic bonds play a broader role in forming polysaccharides like starch and glycogen, which store energy in plants and animals, respectively. In plants, cellulose forms a strong structural component of the cell wall, while in animals, chitin forms a robust exoskeleton in crustaceans, providing a powerful defense.

Glycosidic bonds in glycoproteins and glycolipids  

It is important to note that glycosidic bonds are not just tools for connecting monosaccharides into large carbohydrates. Molecules linked via glycosidic bonds are collectively known as glycosides, and this category includes not only energy-storage and structural carbohydrates but also glycoproteins and glycolipids—biomolecules essential for cellular recognition and signal transmission.

O-linked glycosylation and N-linked glycosylation

Glycosides can be further classified by the atom that the anomeric carbon bonds to. If it binds to a hydroxyl group (-OH), it forms an O-glycoside; if it binds to an amino group (-NH₂), it forms an N-glycoside. Rarely, it may bind to a thiol group (-SH), forming an S-glycoside, but these are seldom found in biological systems. These names originate from the atom involved—oxygen, nitrogen, or sulfur.

In glycoproteins, the anomeric carbon of a monosaccharide can form bonds with the hydroxyl group (-OH) of amino acids such as serine or threonine, or with the amino group (NH₂) of asparagine. If the bond is with a hydroxyl group (i.e., through oxygen), it's called O-linked glycosylation. If the bond is with an amino group (through nitrogen), it's known as N-linked glycosylation. Glycolipids are typically formed through O-glycosides, with the sugar attaching to the hydroxyl group of a lipid molecule.

Glycoproteins, which are commonly found on the cell surface, are essential for signal transmission between the inside and outside of the cell. They play roles in intercellular communication, protein stability, and the cell’s response to environmental stimuli. In my article about the complement system, we saw examples such as mannose-binding lectin (MBL), which recognizes pathogens, and selectins, which guide white blood cells to infection sites—both of which are glycoproteins.

Glycolipids are also major structural components of the cell membrane. They help maintain membrane stability and are involved in cell recognition and signaling. In particular, gangliosides, a type of glycolipid abundant in neuronal membranes, are crucial for intercellular signal transmission and for maintaining neural connectivity.

Thus, glycosidic bonds are responsible for forming essential biomolecules that play key roles in biochemical processes and support the maintenance and regulation of life itself. 

Glycosidic bond formation process 

Among the broad range of molecules created via glycosidic bonds, let’s examine the formation of the smallest unit: disaccharides. The synthesis of disaccharides gives us a clear view of how glycosidic bonds work. The "three musketeers" of disaccharides—maltose (glucose + glucose), lactose (glucose + galactose), and sucrose (glucose + fructose)—all share the same chemical formula: C₁₂H₂₂O₁₁, making them structural isomers. A single monosaccharide has the formula C₆H₁₂O₆, so combining two would theoretically give C₁₂H₂₄O₁₂, but since a water molecule (H₂O—two hydrogen atoms and one oxygen) is lost during the condensation reaction that forms the glycosidic bond, the resulting formula is C₁₂H₂₂O₁₁.

Despite sharing the same chemical formula, these disaccharides differ in their component monosaccharides and the types of glycosidic bonds they form. Let’s begin with maltose, which is composed of two glucose units.

1. Maltose 

Maltose is found in malt (germinated barley) and sprouted grains, and in the human body, it is produced during the digestive process. When we consume polysaccharides like starch—long chains of glucose—these large molecules must be broken down into smaller units to pass through cell membranes and enter cells. In this process, pairs of glucose units are cleaved off, forming maltose. In the small intestine, the enzyme maltase breaks maltose down into two glucose molecules, which are then absorbed through intestinal cells and used as an energy source.

Of the two glucose units in maltose, the first glucose is almost always in the α-anomeric form, where the OH group on the anomeric carbon (carbon 1) points downward in the axial direction. The second glucose, however, can exist in either the α- or β-anomeric form. This is due to the phenomenon of mutarotation, where, in aqueous solution, the anomeric carbon can open into a linear aldehyde form and then close again into a ring, freely interconverting between α and β anomers. Thus, depending on the anomeric form of the second glucose, maltose can exist as either α-maltose or β-maltose.

α(1→4) glycosidic bond

In maltose, the anomeric carbon (carbon 1) of the first glucose (in the α-form) bonds with the fourth carbon (C4) of the second glucose, forming an α(1→4) glycosidic bond. During this reaction, two hydroxyl groups (-OH) combine, releasing a water molecule (H₂O), and the remaining oxygen atom links the two glucose molecules. This process is called dehydration synthesis or a condensation reaction. Conversely, the reverse process—breaking the bond by adding water and reverting to two monosaccharides—is called hydrolysis. 

Maltose, a reducing sugar

Another important point is that the first glucose’s anomeric carbon (C1), having formed a glycosidic bond, can no longer react further. However, the anomeric carbon of the second glucose, not involved in the glycosidic bond, remains free in aqueous solution and can revert to its aldehyde form, enabling it to participate in oxidation-reduction reactions. Therefore, maltose is a reducing sugar, because this free aldehyde group can donate electrons (be oxidized) while reducing other molecules.

The full chemical name of maltose is α-D-glucopyranosyl-(1→4)-D-glucopyranose. While it may seem long and cumbersome, it is actually quite informative: the first part describes the first glucose, the middle indicates the carbons involved in the linkage, and the last part describes the second glucose. Since both glucose units form six-membered rings, the term pyranosyl is used. The anomeric form of the second glucose is not specified because it can freely convert between α and β forms in aqueous solution.

α(1→6) glycosidic bonds that create branches

There’s another form of glycosidic bond related to maltose. When forming polysaccharides, monosaccharides can connect linearly via α(1→4) glycosidic bonds. However, α(1→6) glycosidic bonds are responsible for forming branches off the linear chain. Maltose has the molecular formula C₁₂H₂₂O₁₁, and its isomer isomaltose—which also appears during digestion—shares the same formula but differs in bonding.

In maltose, the first glucose’s carbon 1 bonds with the carbon 4 of the second glucose to form an α(1→4) bond. In contrast, isomaltose features a bond between carbon 1 of the first glucose and carbon 6 of the second, forming an α(1→6) bond. This difference is significant when examining how polysaccharides like starch or glycogen are structured.

Amylose and Amylopectin

When glucose units are repeatedly joined as in maltose synthesis, the result is a mostly linear polysaccharide called amylose. If, at some point along this linear chain, branches form, the polysaccharide becomes amylopectin. Although the amylose is lined up sideways and looks flat and linear, it is actually more accurate to say that it is slightly rounded in a spiral rather than straight due to the three-dimensional structure of glucose. However, while it is simply linear with no extending branches, its structure changes when a bond is formed between carbon number 1 and carbon number 6 instead of number 4 in amylopectin.

This α(1→6) glycosidic bond creates the branch. Starch consists of 20–25% amylose and 75–80% amylopectin. Amylose is the main component responsible for resistant starch (RS). Amylopectin, due to its branched structure, is more exposed to enzymatic digestion, allowing for quicker digestion with easier accessibility. Additionally, its branches do not easily crystallize upon cooling, further contributing to its easy digestibility. Hence, foods high in resistant starch usually have a higher amylose content.

During the digestion of glucose chains, the branched segments are cleaved and found as isomaltose. While amylopectin features α(1→6) bonds approximately every 30 glucose units, animal glycogen has an even denser branching pattern, with α(1→6) bonds about every 8 glucose units. In summary, maltose arises from the breakdown of the linear component (amylose) of starch, whereas isomaltose results from the breakdown of branched components like amylopectin or glycogen.

 2. Lactose 

Lactose, also known as milk sugar, is a disaccharide found in the milk of all mammals. It consists of β-D-galactose and D-glucose connected by a β(1→4) glycosidic bond, and is expressed as β-D-Galactopyranosyl-(1→4)-D-Glucose.

Lactose is always formed from galactose in the β-anomeric form, while the glucose component can exist in both α and β anomeric forms because it can freely interconvert in aqueous solution. Structurally, galactose and glucose are epimers—they differ only in the spatial configuration around the fourth carbon atom (C4), specifically the orientation of the hydrogen and hydroxyl groups.

Because of this close similarity, galactose can be synthesized directly from glucose in the body through the action of an epimerase enzyme, which interconverts epimers by altering the position of functional groups at C4. Galactose produced in this way is then used for synthesizing glycoproteins and glycolipids. Conversely, galactose can also be converted back into glucose using the same type of reaction. While galactose can be synthesized internally, it is mainly obtained through the consumption of milk and dairy products.

Lactose is broken down in the small intestine by the enzyme lactase, which splits it into its two monosaccharide components: galactose and glucose. Like maltose, the anomeric carbon of the glucose in lactose is not involved in the glycosidic bond, so it remains free in aqueous solution. This means it can open up into its aldehyde form and participate in chemical reactions such as oxidation. Therefore, lactose is also classified as a reducing sugar.. 

3. Sucrose 

Sucrose, commonly known as table sugar, is a disaccharide made up of glucose (α-D-glucose) and fructose (β-D-fructose), joined by an α(1→2) glycosidic bond. Its chemical name is α-D-Glucopyranosyl-(1→2)-β-D-Fructofuranoside.

Unlike other disaccharides, sucrose is a non-reducing sugar. This is because the anomeric carbons of both glucose and fructose are involved in the glycosidic bond and thus are no longer free to participate in chemical reactions. That means neither sugar has a free aldehyde (in glucose) or ketone (in fructose) group to undergo oxidation or reduction. In sucrose, the bond connects C1 of glucose (the anomeric carbon) and C2 of fructose (also its anomeric carbon), making the glycosidic bond specifically α(1→2).

Sucrose is hydrolyzed in the small intestine by the enzyme sucrase, which breaks it down into glucose and fructose, allowing the body to absorb them for energy.

In the glycosidic bond of sucrose, the ring of fructose undergoes a three-dimensional twist to minimize steric hindrance and to achieve the optimal bonding angle between the two anomeric carbons. This structural change allows for a more stable configuration with the lowest possible energy state. As a result of this conformational adjustment, the OH group on fructose’s C2 appears to shift from the upper to the lower side, and the CH₂OH group on C6 also seems to move downward. This is why the β form of fructose in sucrose may appear visually similar to an α form, due to this structural adaptation during bonding. 

We’ve now explored disaccharides composed of two monosaccharide units. In the next article, we’ll dive into oligosaccharides, which are composed of a few more sugar units than disaccharides.