Why are carbohydrates becoming increasingly important?
Carbohydrates were traditionally regarded mainly as energy sources or structural materials—components that make up plant cell walls or animal shells. They weren't considered particularly important in relation to biological activity. Molecular biology has focused largely on DNA, RNA, and proteins, but it has become increasingly clear that these alone are insufficient to fully explain biological phenomena. At the same time, sugars have come into the spotlight for their significant roles in cell signaling, immune responses, and the regulation of protein structures.
Unlike proteins, which are directly encoded by genes, sugars are synthesized by a variety of enzymes, allowing for much more complex and diverse regulation. Even small changes in sugar patterns can lead to different functions. In nature, all cells and macromolecules are covalently linked to sugar chains (glycans) such as monosaccharides or oligosaccharides. These glycans, found on cell surfaces and in the extracellular matrix, are directly involved in fundamental interactions essential for the survival of multicellular organisms.
As the critical biological functions of carbohydrates became more recognized, the field of glycobiology emerged in the late 1980s as a branch of molecular biology. The study of sugar modifications for disease diagnosis and the development of biologics targeting these sugars—especially in diseases like cancer—has made glycobiology a key area of research in modern medicine.
A hot potato for me.
Personally, I think of carbohydrates as one of the hottest issues of the 21st century. They're at the center of endless debates—there are even popular diets that eliminate carbs entirely. While opinions on carbohydrates vary widely (except for the generally accepted truth that "too much sugar is bad"), I began to ask myself: How much do I really understand about carbohydrates?
I have my own stance on carbs, but before making any claims, I felt I should take a deeper dive into the subject. This time, I want to organize my thoughts clearly. Carbohydrates cover an incredibly broad range, so let's start from the very basics.
A misleading name by chance
The term "carbohydrate" refers to substances that plants create by using sunlight to convert carbon dioxide (CO₂) from the air and water (H₂O) from their roots into glucose, while also producing oxygen (O₂). Carbohydrates are composed of three elements: carbon, hydrogen, and oxygen. Because carbohydrates vary so widely, it’s hard to define them by a single molecular formula. Initially, they were expressed as Cn(H₂O)n, which led to the mistaken idea that they were hydrates (compounds containing water), thus the name "carbohydrate"—a combination of carbon and "hydrate.".
Speaking of names, it is true that when studying carbohydrates, countless terms emerge, making our heads spin. So, it would be helpful to grasp the concepts of the frequently encountered terms and organize them first. Just like a man can be called "father," "son," "uncle," or "manager" depending on context, the same carbohydrate can be referred to differently depending on how it's classified. But due to the vast diversity of carbohydrates, this isn’t simple either. So let’s begin by understanding how carbohydrates are classified.
Carbohydrates with Chirality
In the previous articles, we explored concepts like carbon’s hybridization(sp³, sp², sp), chirality, and the enantiomers formed at chiral centers in detail. In fact, all these concepts are closely related to monosaccharides and form the foundational basis for understanding them. This is because all monosaccharides have one or more chiral centers, meaning all monosaccharides have enantiomers. This leads us to intuit that monosaccharides are neither simple nor easy substances to understand.
Chirality 1: handedness and non-superimposable mirror image
Fisher Projection
Let's start by examining the structure of monosaccharides. Monosaccharides exist in both an open chain structure and a cyclic ring structure. In fact, most monosaccharides exist in a cyclic form in aqueous environments like the human body. However, we will first look at the simpler open-chain structure and address the cyclic form later for easier understanding. Since our body is in an aqueous environment, it is said that glucose exists in a cyclic form almost 99% of the time in the body. This is because the cyclic structure has a lower energy level and is much more stable than the chain structure. The conversion of the chain form to the cyclic form is a very important topic that will be discussed in detail later.
Monosaccharides have a carbon skeleton with carbon atoms connected in a long chain at the center. The Fischer projection method attempts to represent the stereochemical arrangement that arises from the chirality of a linear chain of hydrocarbons that is not branched. In expressing the chirality created by four different atoms or substituents connected to a central carbon, the Fischer projection uses vertical and horizontal lines. The vertical lines above and below the central carbon represent atoms that are positioned away from the observer, while the horizontal line indicates the direction toward the observer, which can be imagined as if the horizontal line is like two arms extending forward. The illustration below explains how to transfer a 3D model of glucose into a skeletal representation using the Fischer projection method. Although the Fischer projection appears flat when drawn on paper, it actually resembles a three-dimensional structure, like a pill bug or a yoga mat that is rolled up (as shown in the second illustration). The rolled structure can be represented by vertical lines as it appears to roll back from the observer, while the arms extending forward can be represented by horizontal lines. The wedge shape indicates the side closer to the observer, while the dashed line represents the side farther away. In contrast to the open-chain structure represented by the Fischer projection, the Haworth projection expresses the cyclic structure of monosaccharides in a three dimensional perspective on a plane. In other words, the open linear skeletal structure is represented using the Fischer projection, while the cyclic closed ring structure is depicted using the Haworth projection.
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If the number of chiral centers is denoted as n, the number of stereoisomers that a single molecule can have is calculated as 2ⁿ. If there is one chiral center, two enantiomers can be formed, and if there are two chiral centers, four stereoisomers can be formed. Taking glucose as an example, which consists of six carbon atoms, glucose has four chiral carbons, resulting in a total of 16 stereoisomers, half of which are enantiomers of each other (half are L-forms and half are D-forms). The Fisher projection method transforms the three-dimensional molecular structure of monosaccharides into a two-dimensional plane to show the skeleton, and a consistent and standardized way to represent the stereochemical arrangement was likely needed to facilitate the comparison among the numerous isomers. For example, all Fisher projections position the aldehyde group at the top. To understand carbohydrates well, it is essential to have a clear understanding of aldehydes; otherwise, it will continue to be a pebble in the shoe. 😆
Aldehyde and Ketone groups containing Carbonyl Groups
Monosaccharides are organic compounds made up of carbon, hydrogen, and oxygen, with a central carbon skeleton. This skeleton consists of carbons that are connected to one carbonyl group (C=O) and two or more hydroxyl groups (-OH). The carbonyl group is a chemical unit where oxygen and carbon are double-bonded, represented as C=O. As can be seen in the table below, this functional group is part of various organic compounds. If at least one hydrogen is bonded to the carbon of the carbonyl group (R−CHO), it is called an aldehyde; if two carbons are bonded to the carbon of the carbonyl group (C−CO−C), it is called a ketone. Understanding the carbonyl group, aldehyde group, and ketone group first will make it easier to examine the chemical structure of carbohydrates.
A functional group can be defined as a specific arrangement of atoms that possess unique chemical properties, determining the chemical characteristics and reaction patterns of a molecule. When more than 20 million organic compounds have similar functional groups, they tend to undergo similar reactions. Atoms that confer similar chemical properties and reactivity whenever they appear in such diverse compounds are referred to as functional groups. Therefore, even if other molecules present within a compound change, functional groups tend to react in a consistent manner.
When separating functional groups for easier identification, the rest of the molecule, excluding these groups, is represented as R (for "Rest of the molecule"). There are specific names for compounds that contain certain functional groups, so it is important to use these terms carefully to avoid confusion. For example, a compound that contains the hydroxyl group ‘-OH’ is called an alcohol, and it is denoted as R-OH to distinguish it from other compounds.
Classification based on the position of the Carbonyl Group
We have learned that compounds such as aldehydes and ketones commonly include a carbonyl (C=O) functional group. The reason we must examine this is that in all monosaccharides, the location of this carbonyl group within the skeletal structure is fundamentally important. When the carbonyl group is bonded to a hydrogen, forming an aldehyde group, it is located at the outermost end of the molecule, making it highly reactive and prone to oxidation due to its easy interaction with surrounding atoms or molecules. In a Fischer projection, the aldehyde group is always placed at the top, and the carbon of the aldehyde becomes the first carbon of the monosaccharide.
The ketone group, which bonds to two carbon atoms, is always located in the middle of the molecule and is usually placed just below the aldehyde group, making it the second carbon. Monosaccharides are sometimes classified based on this difference between aldehyde and ketone groups. I’ve seen an analogy likening the aldehyde group to “a main gate” and the ketone group to “an entrance door to a house.” The aldehyde group is more reactive than the ketone group, and this metaphor effectively illustrates the differences in accessibility and reactivity arising from their positions.
These two functional groups are the very sites where reactions necessary for forming ring structures occur, and furthermore, they serve as the core points for synthesizing disaccharides and polysaccharides, making them extremely important. We will cover the details of this later, but for now, let's understand that the position of the carbonyl group is closely related to the reactivity of carbohydrates.
Aldose and Ketose
These are names based on the position of the carbonyl functional group within the structure of a monosaccharide. By attaching the suffix “-ose,” which means sugar, a monosaccharide with an aldehyde group at the top is called an “aldose,” while a monosaccharide with a ketone group located somewhere in the middle of the skeleton is called a “ketose.” In short, if the carbonyl group is at the first carbon, it is an aldose; if it is at the second carbon, it is a ketose.
Classification based on the number of carbons
Monosaccharides are also classified based on the number of carbon atoms in their skeletons. Although a monosaccharide consists of one carbonyl group and multiple hydroxyl (-OH) groups, the central focus in organic chemistry is carbon, so we distinguish them using the number of carbon atoms as the standard, such as triose (3 carbons), tetrose (4), pentose (5), hexose (6), and heptose (7). The number of carbon atoms is expressed using prefixes like tri-, tetr-, pent-, hex-, etc., and the suffix “-ose” indicates that it is a sugar. Among monosaccharides, pentoses and hexoses are the most well-known, especially ribose, which is a component of RNA, and deoxyribose, which is derived from ribose by the literal removal (de-oxy) of the oxygen atom at the 2nd carbon, leaving only hydrogen. Deoxyribose is a key component of DNA and an essential sugar for the human body.
A few representative aldoses and ketoses among the pentoses and hexoses are illustrated below. These are classified by combining both the number of carbon atoms and the position of the carbonyl group. For example, a sugar composed of five carbon atoms (pentose) with the carbonyl group at the top is an aldo-pentose, while if the carbonyl is located in the middle, it is a keto-pentose. Note that in these illustrations, only the first and second carbons are labeled for explanation, as the other carbons in the backbone are generally omitted.
Classification of D/L based on mirror image isomers
You will notice that both of the diagrams above begin with the letter D. This denotes the mirror image isomer. As explained in a previous article, this nomenclature is based on chirality. Although the internationally standardized R/S system is most commonly used to distinguish mirror image isomers arising from chiral centers, the D/L system is still traditionally used for some compounds, especially carbohydrates. This system determines whether the OH group attached to the chiral carbon farthest from the carbonyl group — that is, the one with the highest number — is on the right or left. If the OH group is on the right, it is designated as D-form; if on the left, it is L-form. When there is one chiral carbon, there are two possible stereoisomers. When there are two chiral carbons, four stereoisomers exist. Half of these will be D-forms, and the other half will be L-forms.
The table below classifies all possible stereoisomers according to the number of chiral carbons, the total number of carbon atoms, and the position of the carbonyl group. Due to space limitations, only the D-forms are shown. Keep in mind that the L-forms are the mirror images of these D-forms, and can be obtained by switching the positions of the H and OH groups at each chiral center to the opposite side.
Isomers are compounds that have the same number of atoms and identical chemical formulas but differ in molecular structure or arrangement, resulting in different physical and chemical properties. Isomers are broadly divided into structural isomers and stereoisomers. Structural isomers differ in the connectivity of atoms. For example, glucose and fructose are both monosaccharides with the same formula, C₆H₁₂O₆, but differ in the arrangement of their atoms. Glucose contains an aldehyde group, while fructose contains a ketone group. Although composed of the same components, the difference in position of the functional group makes them structural isomers.
In contrast, stereoisomers arise due to chiral carbons and have identical chemical and structural formulas, yet differ in their three-dimensional arrangement, resulting in mirror image isomers. Monosaccharides with multiple chiral carbons can give rise to a large number of stereoisomers, significantly contributing to the diversity of monosaccharides. Glucose, for instance, has four chiral carbons, resulting in 16 possible stereoisomers, half of which are mirror images of the others. This is why monosaccharides exhibit such great diversity. The table below shows the 16 stereoisomers of aldohexoses, divided into D- and L-forms, and further classified by the R/S system and optical activity.
Enantiomers Vs. Epimers Vs. Diastereomers
Among stereoisomers, those that are non-superimposable mirror images of each other, with opposite configurations at all chiral centers, are called enantiomers. If two isomers differ at only one chiral center while all others remain the same, they are called epimers. When two isomers differ at more than one (but not all) chiral centers, they are called diastereomers. Referring to the table above, D-glucose has the configuration (R, S, R, R), and its L-form has (S, R, S, S), with all four chiral centers being opposite, making them enantiomers. D-glucose and D-mannose differ only at the second carbon (C2), making them epimers. Similarly, D-glucose and D-allose (different at C3), and D-glucose and D-galactose (different at C4), are epimers as well. These relationships also apply to the corresponding L-forms.
Furthermore, since D-mannose (S, S, R, R) and D-galactose (R, S, S, R) differ at two chiral centers, they are diastereomers. Epimers are a subtype of diastereomers, so all stereoisomers that are not enantiomers can be classified as diastereomers.
Monosaccharides, Disaccharides, and Polysaccharides
Just as amino acids are the basic units that make up proteins, monosaccharides are the basic units of carbohydrates. Monosaccharides, which cannot be hydrolyzed further, combine in twos to form disaccharides. Chains of approximately 10 monosaccharides form oligosaccharides, and much longer chains form polymers called polysaccharides. These polysaccharides may be composed of identical monosaccharides (homopolysaccharides) or a mixture of different ones (heteropolysaccharides). Familiar examples of polysaccharides include plant starch and animal glycogen.
When we think of monosaccharides, we typically think of glucose, fructose, galactose, ribose, and deoxyribose. In fact, there are many more types of monosaccharides. Some derivatives arise from substituting certain OH groups in the skeletal structure with other groups, and there are also isomers, making the variety even greater. A representative example of a monosaccharide derivative is an amino sugar, such as glucosamine or galactosamine, in which an OH group is replaced by an amino group (NH₂).
We have explored the classification of monosaccharides, the minimum unit of carbohydrates, based on various criteria and the different names that arise from these classifications. In the next article, let’s take a closer look at how monosaccharides transition from an open-chain structure to a cyclic structure. The formation of a cyclic structure is a crucial first step, as it enables monosaccharides to grow into more complex structures, including disaccharides.
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