In this article we will discuss about:- 1. Isomerism of Monosaccharides 2. Cyclic Structure of Monosaccharides 3. Types 4. Compounds Derived 5. Nomenclature 6. Chemical Properties.
The monosaccharides or simple sugars are molecules containing several alcohol groups as well as a reducing group, either aldehyde or ketone. Monosaccharides are classified according to the number of carbon atoms of their molecules (trioses, tetroses, pentoses, hexoses, heptoses, etc.) on the one hand, and the nature of the reducing function (aldoses and ketoses), on the other.
The simplest monosaccharides have three carbon atoms; they include an aldotriose – glyceraldehyde — and a ketotriose – dihydroxyacetone (see fig. 4-1).
Isomerism of Monosaccharides:
If we consider the projection of the three-dimensional structure of glyceraldehyde (see fig. 4-2) we find that there are 2 possibilities: in one case, the hydroxyl carried by the carbon next to the primary alcohol group (this carbon atom is called asymmetric because it carries 4 different substitutes, and it is indicated by an asterisk) is situated to the right of the plane formed by the carbon chain; this is the D-configuration; in the other case, the hydroxyl is situated to the left of this plane; this is the L-configuration.
These 2 forms are mirror images of each other; they represent a couple of optical isomers (or enantiomers), the physical and chemical properties of which are all practically identical.
The spatial structure of other monosaccharides having a larger number of carbon atoms derives from that of glyceraldehyde, and we will have aldoses of the D- or L-series depending on whether the hydroxyl carried by the asymmetric carbon next to the primary alcohol group is in a configuration identical to that of the D- or L-glyceraldehyde (i.e. depending on whether it is projected on the right or on the left).
In the case of ketoses which possess a primary alcohol group at each end, this definition may lead to confusion. For the definition to be more general, it may be stated that it is the configuration of the secondary alcoholic hydroxyl carried by the asymmetric carbon farthest from the reducing group (aldehyde or ketone) which determines whether the monosaccharide belongs to the D- or L- series (again by analogy with the D- or L-glyceraldehyde).
Let us examine the case of aldotetroses (aldoses with 4 carbon atoms). We can apply the rule we have just enunciated, but the situation is somewhat complicated by the fact that there are two asymmetric carbon atoms. We will have the 2 configurations D and L of erythrose (E1 and E2) forming a couple of enantiomers because they are mirror images of each other, and we will also have the 2 configurations D and L of threose forming a couple of enantiomers (T1 and T2).
On the contrary, E1 and T1, E1 and T2, E2 and T1, E2 and T2 do not form couples of enantiomers; they are diastereo-isomers; their physical and chemical properties are distinctly different, so that it is easier to separate 2 diastereo-isomers than 2 enantiomers (see fig. 4-3).
Now considering aldopentoses, one finds 3 asymmetric carbon atoms, and therefore 8 possible stereo-isomers. Only the 4 D-forms are shown in figure 4-4 (to each one of them corresponds a L-form, i.e., its mirror image).
As regards aldohexoses, which have 4 asymmetric carbon atoms, there are 16 possible stereo-isomers (i.e. 8 couples of enantiomers). Figure 4-5 shows only the 3 isomers most frequently found in living organisms.
It is observed that these 3 isomers are all of the D-series. In fact, natural monosaccharides, whether aldoses or ketoses, are mostly of the D-series (the only notable exceptions are L-arabinose and L-fucose).
Regarding the D- or L-configuration of ketoses, the same rule — given earlier — applies. Figure 4-6 shows the structure of some ketoses which play an important role in carbohydrate metabolism. It will be observed that they all have the ketone group in position 2 and – excepting fructose – their names are appended with the suffix -ulose which is characteristic of ketoses.
It may be noted that the 2 ketopentoses represented, D-ribulose and D- xylulose differ only by the configuration of a single carbon atom (carbon 3), they are epimers. D-glucose and D-galactose (see fig. 4-5) are also epimers (they differ only by the configuration of carbon 4) and so also D- glucose and D -man- nose (the difference in configuration is exclusively on carbon 2); on the contrary, D-mannose and D-galactose axe not epimers.
Cyclic Structure of Monosaccharides:
We have, so far, written the formula of monosaccharides in the form of a Linear chain. But this representation is not satisfactory because it does not explain some observations.
1. Glucose and other aldoses, contrary to most aldehydes, do not restore the colour of fuchsine decolorized by SO2 (Schiff s fuchsine).
2. The rotatory power of a freshly prepared glucose solution changes when it is observed in the polarimeter (this has been called mutarotation). But like the melting point or boiling point, the rotatory power is a constant characteristic of a substance, and this change must reflect a structure modification.
Besides, two stereo-isomers (or anomers) of glucose were isolated: a-D- glucose having a specific rotatory power [α]D = +112°2 and β-D-glucose with a rotatory power = +18°7; but, once in solution, each of these 2 forms undergoes a conversion and the mixture of anomers α and β finally obtained at equilibrium has a rotatory power of + 52°7 at 20°C.
3. When an aldehyde is treated by methanol in acid medium, 2 molecules of methanol react with one molecule of aldehyde to form an acetal.
But with D-glucose, the monosaccharide combines with only one molecule of methanol and one obtains a mixture of α-D-methylglucoside (hydrolyzable by an enzyme called α-glucosidase with production of α-glucose) and β-D- methylglucoside (hydrolyzable by a β-glucosidase with formation of β-glucose).
It was therefore necessary to envisage the existence of an additional asymmetric carbon atom and Tollens proposed a structure where carbon 1 of glucose becomes asymmetric after the appearance of a cycle formed by the elimination of one molecule of water between the aldehyde group (reacting in the form of aldehyde hydrate) and the hydroxyl carried by carbon 5 (see fig. 4-7), thus forming an oxide bridge.
This cyclization between the aldehyde group and the alcoholic group of carbon 5 is easier than what is suggested by the linear representation of glucose; these two groups can readily react because they are in fact close to one another in space, as shown by the construction of molecular models (taking into considerations the atomic distances and valence angles). This cyclization may involve either carbon 5 or carbon 4 of glucose.
In the case of the oxide bridge 1-5, one has a hexagonal cycle containing 5 carbon atoms and one oxygen atom; it is a pyranose ring. In the case of the oxide bridge 1-4, the pentagonal cycle contains 4 carbon atoms and one oxygen atom; it is a furanose ring. In both cases the reducing group is in the hemiacetal (or pseudo-aldehyde) form.
The same cyclic forms (pyranose and furanose rings) exist for ketoses, particularly for fructose; in this case, one speaks of a pseudo-ketone group for the hemiacetal form. Carbon 2 (i.e. the ketone group) is involved here in the cyclization and is linked by an oxide bridge either to carbon 6 (pyranose ring), or to carbon 5 (furanose ring).
We therefore have a new asymmetric carbon (carbon 1 in the case of aldoses, carbon 2 in the case of ketoses) and depending on the position of the hydroxyl carried by this carbon we will have the α or β isomer. Using Tollens’ formula, the α isomer is represented by placing this hydroxyl on the same side as the hydroxyl which determines whether the monosaccharide is of the D- or L-series, i.e., on the same side as the oxide bridge.
For simplicity, since monosaccharides are generally of the D-series, it may be said that in this series, α isomers are those with the hydroxyl carried by carbon 1 (aldoses) or 2 (ketoses) situated to the right, while isomers β are represented with this hydroxyl to the left.
Figure 4-8 shows the structures of α and β isomers of D-glucose and D-fructose, in pyranose form and furanose form. In fact, in an aqueous solution of D-glucose for example, there is an equilibrium where coexist not only the 4 isomers represented in figure 4-8 (with a very large predominance of the 2 isomers in the pyranose form), but also traces of D-glucose in free aldehyde form (see fig. 4-7) which explains certain reactions of the monosaccharides which are characteristic of aldehydes.
Monosaccharides in solution in water mainly adopt the pyran form. On the contrary in numerous cases where they are combined, they are found in the furan form (see for example, the formulae of sucrose and nucleotides, figs. 4-17 and 6-6).
Let us note that the α and β forms (of D-glucopyranose for example) are optical isomers, but not enantiomers, because they are not mirror images of each other. They have been named anomers, because they differ only by the configuration of substituents on the hemiacetal asymmetric carbon atom. The α anomer is defined as the most dextrorotatory compound.
The representation proposed by Haworth is increasingly used at present: the ring is perpendicular to the plane of the paper; the linkages in thin lines are behind the plane of the paper, those in thick lines are in front of this plane, i.e. nearer the reader.
The following rules permit the passage from Tollens’ representation to that of Haworth:
1. The hydroxyl groups figuring on the right of the carbon chain of Tollens’ formula, are represented downwards, i.e. below the plane of the cycle of Haworth’s formula. Inversely, those represented on the left of the chain of Tollens’ formula are shown upwards, i.e. above the plane of the cycle in Haworth’s representation.
2. When the number of carbon atoms of the monosaccharide is greater than the number of carbon atoms of the cycle (pyranose or furanose), the excess carbon atoms are represented upwards (above the plane of the cycle in Haworth’s formula) if, in Tollens’ representation, the oxide bridge is on the right of the carbon chain (which is the most frequent case, see fig. 4-8).
Inversely, if the oxide bridge is on the left of the chain, the excess carbon atoms are represented downwards. In the case of fructofuranose, this rule is respected with regard to carbon 6; but carbon 1 is attached to carbon 2, which also carries the hydroxyl determining the α or β configuration of the ketose; in this case, the first rule holds: the hydroxyl of carbon 2 is placed according to the α or β configuration of the monosaccharide (upwards for the β-isomer, downwards for the α-isomer) and carbon 1 is then represented in the position that remained vacant.
These two rules arc illustrated by some examples (see fig. 4-9). In the first example (α-D-glucopyranose) we have represented Haworth’s formula twice: in the first case we have shown the plane of the cycle and indicated the carbon atoms of the cycle; this is not indispensable; the simplified representation (shown on the right) is most frequently used.
Lastly, let us mention that in some works, the representation is further simplified by leaving out the linkages between the carbon atoms of the cycle and the hydrogen atoms; only the positions of hydroxyls are indicated (from which one can naturally deduce the positions of hydrogen atoms); an example of this diagrammatic representation is given for α-D-ribofuranose.
In reality the hexagonal cycle is not plane: owing to the valence angles of the carbon atom, the pyran cycle takes a boat conformation or a chair conformation:
Since the chair is the more stable form, it is now admitted that monosaccharides adopt this configuration which can take two forms denoted C1 and 1C, by Reeves.
We are giving below as examples, the axial or equatorial positions taken by the groups of substituents in the case of α and β glucoses of configuration C1.
The Different Types of Monosaccharides:
Monosaccharides are divided into four categories: “neutral” monosaccharides, osamines, uronic acids and sialic acids (or neuraminic acids).
1. “Neutral” Monosaccharides:
The “neutral” monosaccharides include carbohydrates which possess only alcoholic groups in addition to the aldehyde or ketone group: D-glucose, D-galactose, D-mannose, D-xylose, etc. may be cited as examples.
This group also comprises the deoxyoses, which are monosaccharides having lost 1 or 2 oxygen atoms. Among them, can be mentioned the 6-deoxyhexoses which may be considered, either as aldohexoses, the terminal — CH2OH of which is replaced by a — CH3, or as aldopentoses in which one hydrogen of carbon 5 is replaced by a methyl (examples: L-rhammose or 6-deoxy-L-man- nose, L-fucose or 6-deoxy-L-galactose).
The most important is a pentose, the 2-deoxy-D-ribose, which is the monosaccharide found in deoxyribonucleic acids and derives from D-ribose (see fig. 4-9) by simple replacement of the hydroxyl of carbon 2, by a hydrogen.
They derive from the neutral monosaccharides by replacement of a hydroxyl (generally the one carried by carbon 2) by an amine group. They are often found in polysaccharides which are described in the following. The amino group is frequently acetylated. Figure 4-10 shows the structure of the 4 most common hexosamines (the structures of glucosamine and muramic acid are represented in the N-acetylated form).
3. Uronic Acids:
Uronic acids derive from aldoses by oxidation of the primary- alcohol group into a carboxylic group (and therefore maintain the aldehyde group). D-glycuronic (also called “glucuronic”) acid is one of the most widely distributed uronic acids; it is found in various polysaccharides; furthermore, it participates in detoxification processes: some compounds are eliminated by the higher organisms in the form of heterosides called glucuronides (or glucorono- conjugates). Its structure is shown in figure 4-11.
4. Sialic Acids:
Sialic (or neuraminic) acids are derivatives (generally acetylated) of neuraminic acid which itself consists of a molecule of pyruvic acid (carbons 1, 2,3) condensed with a molecule of D-mannosamine (carbons 4 to 9). N-acetyl- neuraminic acid (see fig. 4-11) is obtained if the amino group of this osamine is acetylated.
The other acetylations, leading to various sialic acids, occur on hydroxyls (especially in positions 4 and 7). Sialic acids are constituents of various glycoproteins and glycolipids. There are also N-glycolyl-neuraminic acids (the OH of which can also be acetylated).
Compounds Derived from Monosaccharides:
1. L-Ascorbic Acid (Vitamin C):
A study of its structure (see fig. 4-11) reveals that it is the γ-lactone of an hexonic acid (which itself derives from an aldohexose by oxidation of the aldehyde group to acid). It is further characterised by a double bond between 2 carbon atoms, each carrying a hydroxyl (ene-diol). This substance readily oxidises to dehydroascorbic acid (reversible reaction), which enables its participation in cellular oxidation-reduction processes.
2. Polyalcohols (or Polyols):
Polyalcohols are obtained by reduction of the aldehyde or ketone group to alcohol group. For example, by reduction, D-glucose gives D-glucitol (usually known as sorbitol), D-galactose gives D-galactitol (usually known as dulcitol), D-mannose gives mannitol, D-ribose gives ribitol (found in the molecule of riboflavin, see fig. 2-17).
The compound with 3 carbon atoms, glycerol, which may be considered as the reduction product of glyceraldehyde or dihydroxyacetone (and which in fact, derives from the latter) is a trialcohol which has a considerable metabolic importance.
Lastly, let us mention the existence of cyclic polyalcohols, called cyclitols. The representative of this group most frequently found in nature is myo-inositol (see fig. 4-12); it is present either in the free state, or hexa-esterified by phosphoric acid (phytic acid, which exists in the form of a complex salt of Ca2+ and Mg2+ — called phytin — in the envelope of cereal grains), or as constituent of certain phospholipids, the phosphatidyl-inositols (see fig. 5-3).
Nomenclature of Monosaccharides:
The nomenclature of monosaccharides is at present regulated by international rules. Generally, the common name of the carbohydrate is used together with indications relative to the nature of the anomerism, form of the cycle, D-series or L-series and the rotatory power: for example, α-D( + )-gluco- pyranose. Sometimes, the terminology is complicated as in the case of D- glucosamine which becomes 2-amino-2-deoxy-D( + )-glucopyranose.
Lastly, initials have been adopted in order to facilitate the writing; the following are the most common: Glc: glucose; Gal: galactose; Man: mannose; Fuc: fucose; Xyl: xylose; Ara: arabinose; Rha: rhamnose; GlcN: glucosamine; GlcNAc: N- acetyl-glucosamine; Mur NAc: N-acetylmuramic acid; Glc AU: glucuronic acid; NeuAc: N-acetylneuraminic acid. The nature of the cycle and of the D- or L-series are also indicated: for example, D-glucopyranose becomes D-Glcp.
Chemical Properties of Monosaccharides:
As mentioned above, monosaccharides are polyhydroxyaldehydes or poly- hydroxyketones: they will generally give reactions characteristic of alcoholic hydroxyls and of carbonyl groups. Of these numerous possibilities we will consider only some important reactions either from the view point of carbohydrate metabolism, or because they enable the characterisation of monosaccharides.
1. Formation of Esters:
As will be seen in the following, phosphoric esters of monosaccharides are of very great importance in the metabolism of carbohydrates. In most cases the primary alcohol group is esterified, giving for example, glucose-6-phosphate, fructose-1-phosphate, fructose-6-phosphate, fructose- 1,6-bisphosphate, ribose-5-phosphate, ribulose-5-phosphate, glyceraldehyde-3-phosphate, dihydroxyacetone-phosphate, etc.
The hemiacetal group can also be esterified (example: glucose-1-phosphate) and in some cases the monosaccharide is esterified both on its hemiacetal group and its primary alcohol group (example: 5-phosphoribosyl- 1-pyrophosphate, see fig. 6-18).
In presence of alkaline agents (sodium hydroxide, silver oxide, dimethyl-for- mamide) and methyl sulphate or iodide, the free hydroxyls of monosaccharides are replaced by methoxy groups (OCH3).
Alkylation does not take place on the blocked OH, like the one involved in the oxide bridge or those engaged in a glycoside linkage, in oligo- or polysaccharide molecules. This property is utilized in the determination of the modes of linkage between the molecules of monosaccharides in polysaccharides.
3. Oxidation of Monosaccharides:
The aldehyde or ketone group of monosaccharides can be oxidized; aldoses and ketoses will therefore behave like reductants and in particular, they will be able to reduce metal salts (in alkaline solution) up to the metal stage or up to a lower degree of oxidation.
One of the reagents most frequently used for detecting the presence of reducing sugars for titrating them is based on a cupric salt (Cu2+) maintained in solution by a double tartrate of sodium and potassium which forms a complex (Fehling’s liquor);
The principle of the reaction is as follows:
Since the medium is alkaline, we obtain:
which is less soluble and gives a brick-red precipitate.
This reaction will be produced by all molecules of aldoses and ketoses which have, if not a free aldehyde or ketone group, at least a pseudo-aldehyde or pseudo-ketone group capable of yielding a free group as the equilibrium existing in the solution is displaced by the reaction.
On the contrary, the molecules whose pseudo-aldehyde or pseudo ketone group is involved in an oside linkage will not have any reducing character (except if this linkage is hydrolyzed). Examples will be given in the following while referring to heterosaccharides, disaccharides and polysaccharides.
4. Action of Concentrated Acids:
Under the effect of a concentrated acid and in heat, aldoses and ketoses give furfural (in the case of pentoses), a hydroxymethylated derivative of furfural (in the case of hexoses), or furoic acid (in the case of uronic acids). In the case of glucose the reaction is as follows (see fig. 4-13).
Furfural and its derivatives can condense with various phenols (naphtol, orcinol, etc.), and give colorations enabling either the characterization or the titration of monosaccharides, excepting osamines and sialic acids.
5. Action of Phenylhydrazine:
In a first step, a molecule of phenylhydrazine reacts with a molecule of aldose or ketose to form a hydrazone. Then, an osazone is obtained in presence of an excess of phenylhydrazine. Osazones are crystallized products whose characteristics (form of crystals, melting point) can allow the identification of monosaccharides.
However, it should be borne in mind that in all cases, carbons 1 and 2 participate in the formation of osazones, so that the same osazone will be given by:
1. Two epimer aldoses which differ only by the configuration of the hydroxyl carried by carbon 2; this is the case of glucose and mannose (see fig. 4-5).
2. An aldose and a ketose isomers having the same configuration of the carbon atoms carrying secondary alcohol groups; this is the case of glucose and fructose (see fig. 4-14).
6. Action of Alcohols:
Monosaccharides mostly exist in a hemiacetal cyclic form. The pseudo-aldehyde or pseudo-ketone hydroxyl of monosaccharide can also react with an alcoholic hydroxyl to form an acetal. Depending on whether this alcoholic hydroxyl does or does not belong to another molecule of a monosaccharide, a disaccharide or a heterosaccharide will be obtained; this leads us to the study of oligo-saccharides.