Fundamentals of Biochemistry - A. A. Anisimov 1986

Carbohydrates
Monosaccharides

6.2.1. Classification, Nomenclature, and Molecular Structure. There are several principles for classifying Monosaccharides: they are divided into aldoses and ketoses depending on whether they contain an aldehyde or a ketone group; they can also be classified by the number of carbon atoms in the molecule (trioses, tetroses, pentoses, hexoses, heptoses, octoses, etc.).

Sugars containing more than seven carbon atoms are referred to as higher sugars. Chemically, all monosaccharides are categorized into neutral (containing only carbonyl and alcohol groups), acidic (which also contain carboxyl groups), and aminosugars, which feature an amino group In addition to carbonyl and alcohol groups, conferring basic properties upon these compounds. Polyfunctional sugars, containing carboxyl and amino groups alongside carbonyl and hydroxyl groups, are also known—neuraminic acid being a prime example.

The names of various monosaccharides are predominantly based on the trivial names of neutral sugars (xylose, ribose, glucose, fructose). These serve as the ROOT for naming aminosugars (glucosamine, galactosamine) and carboxyl-containing sugars (glucuronic acid, mannuronic acid, galactaric acid). Trivial names of monosaccharides typically consist of two parts: a root denoting a specific property or Water/144.html">Origin of the sugar, and the suffix "-ose," indicating its carbohydrate nature. For instance, the name "fructose" reflects the presence of this monosaccharide in fruits.

The suffix "-ulose" is used for ketoses; for example, a C₄ ketose is termed a tetrulose, and a C₅ ketose is a pentulose. Monosaccharide nomenclature frequently combines two principles, indicating both the presence of an aldehyde or ketone group and the carbon atom count: aldopentose, ketohexose.

To designate various Monosaccharide Derivatives, the carbon atoms are numbered starting from the aldehyde group or from the end closer to the keto group. The positions of substituents are indicated by numerals, along with the specific atom to which the substituent is attached, provided it is not directly linked to carbon. For example: 2-deoxy-2-amino-3,4-di-O-methylglucose.

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Stereoisomerism is characteristic of all monosaccharides starting from trioses, existing in two enantiomeric forms: D and L. Whether a monosaccharide belongs to the D- or L-series is determined by the configuration of the OH group at the highest-numbered chiral carbon atom (counting from the aldehyde or keto group). If this group is on the right side of the carbon chain, the molecule is assigned to the D-series; if on the left, to the L-series. The designations D and L do not indicate the direction of optical rotation. Some D-series monosaccharides are levorotatory, whereas many L-series representatives are dextrorotatory. To specify both the D- or L-configuration and the direction of optical rotation, the symbols (+) or (—), denoting dextrorotation or levorotation respectively, are placed in parentheses before the sugar name following the D or L prefix.

In living organisms, monosaccharides occur overwhelmingly in the D-configuration. Exceptions include L-arabinose, relatively rare L-monosaccharides found in Bacteria, and plant-derived L-rhamnose and L-sorbose.

Since the number of stereoisomers for aldohexoses with four chiral centers equals 2⁴ (i.e., sixteen), they can be grouped into eight pairs of enantiomers. The D- and L-isomers of each of the eight aldohexose enantiomeric pairs share identical chemical and physical properties, differing only in the direction of plane-polarized light rotation.

An equimolar mixture of enantiomers (D- and L-forms) is termed a racemic mixture or racemate and exhibits no optical activity. When comparing non-enantiomeric stereoisomers of monosaccharides, structural differences are sufficient to result in distinct chemical properties, melting and boiling points, solubility, and so forth. Such pairs of stereoisomers are called diastereomers. For instance, D-mannose is an enantiomer to L-mannose and a diastereomer to 14 other hexoses (the D- and L-forms of galactose, glucose, gulose, idose, etc.).

Diastereomers that differ in configuration at only one of several chiral centers are known as epimers. Particularly common epimers in nature include glucose and galactose (differing in configuration solely at C-4), and glucose and mannose (differing at C-2). Fructose is frequently grouped with the latter pair of epimers, although this is incorrect, as the differences between fructose and glucose are structural. The conversion of one epimer into another is referred to as epimerization.

The straight-chain sugar formulas proposed by E. Fischer are convenient for representing isomeric forms and demonstrating the General Properties of monosaccharides. However, they do not account for all The properties of these compounds. Furthermore, they fail to explain The phenomenon of mutarotation, which involves A change in the specific rotation value when monosaccharides are dissolved in water.

In 1870, Moscow professor M. A. Colley first suggested that carbohydrate molecules possess a cyclic structure to explain the phenomenon of mutarotation. This hypothesis was subsequently confirmed by the research of the German chemist B. Tollens.

It is now well established that in nature only a small fraction of pentose and hexose molecules exist in an open-chain form, with the majority occurring as cyclic structures. The formation of these rings becomes understandable when we recall that the four covalent bonds of carbon form a tetrahedron; consequently, the carbon chain is not truly straight but significantly bent, which facilitates interaction between the carbonyl and hydroxyl groups to form a ring. Such a reaction is characteristic of all monosaccharides containing more than four carbon atoms. When a monosaccharide molecule cyclizes, an intramolecular reaction takes place, resulting in the formation of a hemiacetal or hemiketal.

Formation of cyclic structures

Depending on which carbon atom's hydroxyl group takes part in the Formation of the hemiacetal or hemiketal, five-membered rings (consisting of four C atoms and one O atom) or six-membered rings (consisting of five C atoms and one O atom) can be formed. These structures are referred to as furanose or pyranose forms, respectively, by analogy with the well-known Organic compounds furan and pyran.

Pentose monosaccharides typically feature a furanose ring, whereas most hexoses exist in the pyranose form. The formation of seven-membered rings in hexoses is rarely observed due to significant ring strain.

During the formation of the intramolecular hemiacetal or hemiketal, an additional chiral center and a new pair of isomers (the a- and ß-forms), known as anomers, appear in the pentose and hexose molecules (derived from the Greek ano, meaning upper, since carbonyl groups are positioned at the top in monosaccharide formulas).

Anomeric pairs differ in the spatial arrangement of substituents only at the anomeric carbon atom, and thus they can be regarded as a special case of epimers. The a- and ß-anomeric forms are distinguished by the relative positions of the hemiacetal (or hemiketal) hydroxyl and the hydroxyl group of the last chiral carbon. If they are located on the same side of the carbon chain (cis-position), it is designated as the a-anomer; if these hydroxyl groups are on opposite sides of the carbon chain (trans-position), it is the ß-anomer. The carbon atom involved in the formation of the hemiacetal (hemiketal) is called the hemiacetal (hemiketal) or anomeric carbon, and the resulting hydroxyl group is referred to as the hemiacetal (hemiketal) or glycosidic hydroxyl.

Fig. 6.1. Interconversion of Various Forms of glucose in aqueous solution

Each hexose forms four cyclic structures (a- and ß-furanose, as well as a- and ß-pyranose) that exist in dynamic equilibrium in solution with the acyclic form. Thus, in an aqueous glucose solution, all of its forms are present simultaneously (four cyclic and one acyclic, aldehyde form). Meanwhile, the proportion of the acyclic form is less than 1%. All these forms are capable of interconverting via the oxo form (i.e., the acyclic form) of glucose (Fig. 6.1).

In ketohexoses, the formation of the hemiketal involves the carbonyl group and the hydroxyl at C-5 or C-6, which likewise yields furanose or pyranose forms of the sugar. The pyranose forms of hexoses and pentoses are significantly more stable than the furanose forms, meaning the former always substantially predominate in solution. However, within oligo- and Polysaccharides, hexoses may also occur in the furanosyl form (for example, fructofuranose in the sucrose molecule). The inherent tendency of hexoses and pentoses to cyclize enables the formation of stable polymers from highly reactive, unstable monomers.

The formation of cyclic structures by monosaccharides explains the "anomalies" in their behavior as aldehydes or ketones.

1. In their cyclic form, sugars lack a free carbonyl group; consequently, they fail to give certain color reactions typical of aldehydes.

2. Unlike other hydroxyls in the sugar molecule, hemiacetal and hemiketal hydroxyls readily react with alcohols to form easily hydrolyzable ethers.

3. The D- and L-forms of each monosaccharide exist as a- and ß-isomers, which results in 4 series of derivatives rather than 2.

4. The a- and ß-forms of monosaccharides, which exhibit different optical rotation values, mutually transform into one another upon dissolution in water; hence, their specific rotation changes until equilibrium is established. As a result, immediately after dissolution, a multitude of specific rotation values can be observed—hence the phenomenon known as mutarotation or multirotation (from the Latin multirotatio meaning many rotations). For instance, when a-D-glucose ([a]²⁰_D = +112.2°) and ß-D-glucose ([a]²⁰_D = +18.7°) are dissolved in water, their specific rotation shifts until equilibrium is reached (36% a-form, 64% ß-form, and traces of the acyclic form), at which point it settles at a value of +52.7°.

A more sophisticated method for depicting the cyclic forms of monosaccharides as projection formulas was proposed by W. Haworth in 1927. An example of a Haworth projection formula is structure II, shown below. In this representation, the carbon Skeleton of the molecule, along with the ethereal oxygen, is assumed to lie in a single plane. Bonds extending closer to the observer are indicated by bolder lines. The carbon atoms within the ring are omitted, and hydrogen atoms are sometimes omitted as well. To denote the configuration of substituent groups, they are positioned either above or below the plane of the ring.

When converting from Fischer formulas (structure I) to Haworth projection formulas (structure II), the following rules are applied: 1) substituents located to the right of the molecular carbon skeleton in its linear representation are placed below the ring plane when depicting the molecule in its cyclic form, whereas substituents on the left occupy positions above the ring plane; 2) the reverse rule applies solely to the carbon atom whose OH group participates in forming the cyclic hemiacetal. This exception arises because linear formulas of type I fail to provide an accurate representation of the structure. The structural identity of the linear and cyclic formulas becomes clearer if the linear formula is drawn as shown in structure III. Various Methods for depicting a-D-glucopyranose molecules are presented below.

In such a formula, the arrangement of substituents at C-5 follows the rule established for all other carbon atoms. However, Haworth projection formulas are also merely approximate, since the actual Bond Angles between carbon valencies are 120°. These formulas fail to reflect the spatial arrangement of atoms within sugar molecules. In nature, the pyranose ring is not flat; due to puckering of its plane, A large number of Conformations can arise, of which eight are stable: six in the boat conformation (designated by the letter B, from the English "boat") and two in the chair conformation (C, from the English "chair") (Fig. 6.2).

Various substituents on carbon atoms can occupy either equatorial or axial planes, imparting distinct properties to the compound. The equatorial OH groups of pyranosides—those occupying positions close to the molecular plane—undergo Esterification much more readily than axial ones, which occupy positions nearly perpendicular to the molecular plane.

The "chair" conformation is more rigid and stable, whereas the "boat" form is more flexible, existing in several variations. Furanose conformations have been less thoroughly investigated. It is believed that the furanose ring may exist either in an "envelope" conformation (with four atoms in one plane and one protruding from it) or in a "twist" form, where three atoms lie in one plane and two project from it.

Fig. 6.2. Conformations of the pyranose ring:

a — axial bond, e — equatorial bond

6.2.2. Physical and Chemical Properties. Monosaccharides are solid, colorless, crystalline substances that are highly soluble in water and poorly soluble (or even completely insoluble) in organic Solvents (alcohol, ether). They all share a sweet taste, although the sweetness varies among sugars. If the sweetness of sucrose is taken as 100%, that of fructose is 173%, glucose 74%, xylose 40%, and lactose 16%. Monosaccharide solutions exhibit a neutral reaction.

Action of Acids and Bases on Monosaccharides. Monosaccharides are stable in hot, dilute solutions of inorganic acids, allowing them to be quantitatively isolated unchanged during polysaccharide Hydrolysis. Under the action of concentrated acids, monosaccharides undergo dehydration to yield cyclic aldehydes known as furfurals. Specifically, hexoses yield hydroxymethylfurfural, whereas pentoses yield furfural.

The resulting furfurals can undergo Condensation reactions with phenols or their derivatives, producing colored products. This property forms The basis of several color tests for sugars. Ketoses form hydroxymethylfurfural at a faster rate than aldohexoses, a principle underlying Seliwanoff's test for ketohexoses.

Dilute aqueous solutions of bases at room Temperature induce rearrangement around the anomeric carbon atom and its adjacent carbon, leaving substituent groups at other carbon atoms unaffected—in other words, epimerization takes place. This transition proceeds via an enol form that is identical for all three sugars. Solutions of Ba(OH)₂ or Ca(OH)₂ are typically employed to carry out this reaction.

Upon heating with dilute alkalis or at high alkali concentrations, free monosaccharides undergo intramolecular rearrangements, fragmentation, and condensation. Sugar condensation yields colored products (ranging from yellow to dark brown), with the color intensity depending on the carbohydrate concentration. This property is utilized in Althausen's quantitative METHOD FOR DETERMINING sugars in urine.

Oxidation of Sugars. The oxidation of aldoses in an acidic medium yields three classes of sugar acids: aldonic, aldaric, and uronic acids.

In the presence of mild oxidizing agents (such as sodium hypoiodide or bromine water) or under the action of specific Enzymes, the aldehyde group of aldoses is oxidized to form aldonic acids (for example, glucose yields gluconic acid, and mannose yields mannuronic acid). Gluconic acid is used in medicine in the form of calcium salts. Its phosphorylated derivative plays a crucial role as an intermediate in Carbohydrate METABOLISM (see Section 6.9.3).

Under more forceful oxidation (using nitric acid), both the aldehyde group and the primary alcohol group at the terminal carbon atom are oxidized, yielding dicarboxylic, or aldaric, acids. The oxidation product of D-glucose is called D-glucaric (or saccharic) acid, while that of D-galactose is known as D-galactaric (or mucic) acid. Acids of this class are of little biological significance.

In contrast, the third class of acids—alduronic acids—is of paramount importance. They are formed by the oxidation of only the primary alcohol group at C-6. Uronic acids serve as components of numerous polysaccharides.

When aldoses are oxidized in an alkaline medium, aldonic acids are formed initially, followed by the Cleavage of the carbon skeleton. This process generates a series of products with strong reducing properties, allowing monosaccharides to easily reduce mild oxidizing agents, such as silver(I) oxide and copper(II) hydroxide, to metallic silver and copper(I) oxide, respectively. The reactions of simple sugars with Ag₂О, Cu(OH)₂, and Fehling's solution (an alkaline solution of copper(II) oxide and potassium sodium tartrate) are widely utilized for the qualitative detection and Quantitative determination of monosaccharides. Ketoses undergo oxidation with the cleavage of the carbon chain in both acidic and alkaline environments.

Reduction of monosaccharides. The carbonyl group of a monosaccharide can be reduced with hydrogen gas or sodium amalgam in water to yield the corresponding polyhydric alcohols (often referred to as sugar alcohols). D-Glucose yields the alcohol sorbitol, whereas D-mannose produces mannitol.

6.2.3. Derivatives of Monosaccharides. Glycosides are formed analogously to ethers through the reaction of a hemiacetal or hemiketal (glycosidic) hydroxyl group with the hydroxyl group of another compound. For instance, D-glucose reacts with methanol to form methyl-α-D-glucoside and methyl-β-D-glucoside. The "non-sugar" moiety of a glycoside is termed the aglycone.

Oligosaccharides and polysaccharides can also be considered specialized types of glycosides, formed by the interaction between the hemiacetal or hemiketal hydroxyls of certain monosaccharides and the hydroxyls of others. However, the term "glycosides" is conventionally used to denote specifically the condensation products of sugars with alcohol aglycones.

A wide variety of glycosides occur in nature. Many of them possess a distinct (often bitter) taste or a specific aroma (such as sinigrin in mustard and glucovanillin), thereby playing a significant role in the food industry. Others find application in medicine, such as the cardiac glycosides found in plants of the genera Strophanthus and Digitalis.

O-Methyl derivatives. While the OH group at the anomeric carbon readily reacts with methanol in an acidic medium to yield methyl glycosides, the methylation of the remaining OH groups in monosaccharides requires more drastic conditions. Under these circumstances, methyl ethers are formed instead of methyl acetials; unlike methyl glycosides, these ethers do not undergo hydrolysis upon boiling with acid. The methylation of all free hydroxyl groups in a carbohydrate is referred to as exhaustive methylation.

This technique is employed to determine the positions of substituents that lack free OH groups (such as amino groups). Because glycosides of methylated sugars exhibit high volatility under high vacuum, they are utilized in Gas-Liquid Chromatography and mass spectrometry of CARBOHYDRATES.

O-Acyl derivatives. The replacement of hydrogen atoms in the hydroxyl groups of carbohydrates with acid residues yields ester-like compounds.

Many mono- and diphosphate esters of monosaccharides are of paramount importance in the metabolism of every Cell and tissue, acting as intermediates in Respiration, Fermentation, Biosynthesis, and carbohydrate interconversion. The formation of phosphate esters dramatically enhances the reactivity and biochemical activity of monosaccharides.

Amino sugars. The substitution of the hydroxyl group at C-2 by an amino group leads to the formation of amino sugars. Two amino sugars—D-glucosamine and D-galactosamine—are widely distributed in nature.

Amino sugars are constituents of numerous Glycoproteins and Glycolipids, most commonly occurring as N-acetyl derivatives.

Muramic and neuraminic acids. These sugar derivatives play a leading role as Building Blocks of structural polysaccharides that comprise bacterial cell walls (N-acetylmuramic acid) and animal Plasma Membranes (N-acetylneuraminic acid). In the N-acetylmuramic acid molecule, the acetylated D-glucosamine is linked via an ether bond to lactic acid. N-Acetylneuraminic acid contains residues of acetylated D-mannosamine and pyruvic acid. All O- and N-acyl derivatives of neuraminic acid are collectively known as sialic acids.

Neuraminic and sialic acids are vitally important primarily as Structural components of Nervous Tissue membranes. However, sialic acid-containing glycolipids have also been identified in other tissues. They perform mechanical, immunochemical, and other Functions, can restore the electrical excitability of Brain tissue, and specifically bind or neutralize certain Bacterial toxins.

6.2.4. Selected Monosaccharides. Trioses (C₃H₆O₃). The primary representatives are glyceraldehyde and dihydroxyacetone, which generally do not occur in the free state.

Triose phosphate esters are synthesized in animal, plant, and bacterial organisms as intermediates in the transformation of more complex monosaccharides, as well as during plant Photosynthesis and bacterial Chemosynthesis.

Tetroses (C₄H₈O₄). Within this group of monosaccharides, D-erythrose deserves mention; it is formed as an intermediate during photosynthesis and within the Pentose Phosphate Pathway of Carbohydrate Oxidation in the form of its 4-phosphate ester. The reduction product of erythrose, the alcohol erythritol, has been discovered in Algae and Lichens.

Pentoses (C₅H₁₀O₅). Pentoses are exceedingly rare in the free state (found in urine and the leaves of certain plants); more commonly, they are incorporated into more complex carbohydrates and other organic compounds, and they also arise as intermediates during carbohydrate metabolism.

L-Arabinose is widely distributed in nature as a component of hemicelluloses, pectic substances, plant mucilages, and Gums. It can be detected in free form in the urine following the consumption of large amounts of fruits or fruit juices (alimentary pentosuria). D-Arabinose is found in the polysaccharides of various bacteria and serves as a component of certain plant glycosides.

D-Xylose (wood sugar) is found in plants in a free state, but in significantly larger amounts as part of hemicelluloses and plant mucilages. High concentrations of xylose are present in straw, bran, wood, and cotton seed husks, and it is particularly abundant (up to 12%) in corn cobs, from which it is extracted for the confectionery industry. Xylitol, the alcohol derived from xylose, is used as a sucrose substitute in the diets of patients with diabetes and obesity. In humans, animals, and microorganisms, xylose is a constituent of glycoproteins.

D-Ribose and D-2-deoxyribose are integral Components of nucleic acids and free NUCLEOTIDES. The reduction product of ribose, the alcohol ribitol, serves as an essential building block for certain Vitamins and coenzyme prosthetic groups.

Ketopentoses—specifically D-ribulose and L-xylulose—have been identified in green plants, microorganisms, and animal tissues. The phosphate esters of these sugars play a crucial role as metabolic intermediates in The Calvin Cycle and The pentose phosphate pathway of carbohydrate oxidation.

Hexoses (С₆Н₁₂О₆). Many representatives of this group of monosaccharides occur naturally in a free state and play a vital role in the metabolism of all organisms.

D-Glucose (grape sugar, dextrose) is present in a free state in the green parts of plants, seeds, various fruits and berries, honey, and in Human and Animal Blood. Healthy individuals have a blood glucose concentration ranging from 0.07 to 0.11%. Additionally, it is a building block for a vast number of polysaccharides and numerous glycosides.

D-Fructose (fruit sugar, levulose) is found in a free state in the green parts of plants, floral nectar, fruits, and honey.

D-Galactose is a structural component of the Disaccharides lactose and melibiose, the trisaccharide raffinose, the oligosaccharides stachyose and verbascose, as well as a wide range of secondary polysaccharides of both PLANT AND ANIMAL origin.

D-Mannose occurs in plants as part of high-molecular-weight polysaccharides, such as mucilages and hemicelluloses. In animals and humans, mannose has been identified in glycoproteins and the carbohydrate chains of Proteoglycans. Mannose is also found in microorganisms, notably as a constituent of certain capsular polysaccharides and O-antigenic determinants in Gram-negative bacteria.

Monodeoxyhexoses and their derivatives are well known as structural components of cardiac glycosides. Several 6-deoxy sugars have been discovered in bacterial glycolipids and certain Antibiotics. The most widely distributed are L-fucose, L-rhamnose, and their methyl mono- and diesters. For instance, L-fucose serves as a structural component of human milk oligosaccharides, blood group-specific polysaccharides, and bacterial cell walls.

Dideoxyhexoses and their derivatives frequently occur in cardiac glycosides (e.g., D-digitoxose). Certain antibiotics have also been found to contain 2,6- and 2,4-dideoxy sugars. 3,6-Dideoxy sugars have been isolated from microbial sources (such as abequose and colitose); they form part of the specific polysaccharides of Gram-negative bacteria, accounting for an average of 10–15% of bacterial polysaccharides. Their biological significance is profound, as these sugars occupy terminal positions in polysaccharide chains, thereby determining antigenic Specificity. Another notable sugar is the 2,3,6-trideoxyhexose amicetose, which has been isolated from antibiotics.

Heptoses (С₇Н₁₄О₇) and other higher sugars are found in nature in various forms. For example, D-sedoheptulose and D-mannoheptulose, among others, have been isolated from plants. Sedoheptulose is formed in the form of its phosphate ester as an intermediate during photosynthesis, as well as within the pentose phosphate cycle. Furthermore, D-glycero-D-mannoheptose, D-glycero-D-glucoheptose, and other higher sugars have been isolated from bacteria.