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A glycosidic bond or glycosidic linkage is a type of
covalent bond A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between ato ...
that joins a
carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may o ...
(sugar) molecule to another group, which may or may not be another carbohydrate. A glycosidic bond is formed between the
hemiacetal A hemiacetal or a hemiketal has the general formula R1R2C(OH)OR, where R1 or R2 is hydrogen or an organic substituent. They generally result from the addition of an alcohol to an aldehyde or a ketone, although the latter are sometimes called hemi ...
or
hemiketal A hemiacetal or a hemiketal has the general formula R1R2C(OH)OR, where R1 or R2 is hydrogen or an organic substituent. They generally result from the addition of an alcohol to an aldehyde or a ketone, although the latter are sometimes called hemike ...
group of a
saccharide In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or ma ...
(or a molecule derived from a saccharide) and the
hydroxyl group In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
of some compound such as an
alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...
. A substance containing a glycosidic bond is a
glycoside In chemistry, a glycoside is a molecule in which a sugar is bound to another functional group via a glycosidic bond. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. ...
. The term 'glycoside' is now extended to also cover compounds with bonds formed between hemiacetal (or hemiketal) groups of sugars and several chemical groups other than hydroxyls, such as -SR (thioglycosides), -SeR (selenoglycosides), -NR1R2 (N-glycosides), or even -CR1R2R3 (C-glycosides). Particularly in naturally occurring glycosides, the compound ROH from which the carbohydrate residue has been removed is often termed the aglycone, and the carbohydrate residue itself is sometimes referred to as the 'glycone'.


S-, N-, C-, and O-glycosidic bonds

Glycosidic bonds of the form discussed above are known as O-glycosidic bonds, in reference to the glycosidic
oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements ...
that links the glycoside to the aglycone or reducing end sugar. In analogy, one also considers S-glycosidic bonds (which form thioglycosides), where the oxygen of the glycosidic bond is replaced with a
sulfur Sulfur (or sulphur in British English) is a chemical element with the symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms form cyclic octatomic molecules with a chemical formul ...
atom. In the same way, N-glycosidic bonds, have the glycosidic bond oxygen replaced with
nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...
. Substances containing N-glycosidic bonds are also known as glycosylamines. C-glycosyl bonds have the glycosidic oxygen replaced by a
carbon Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent—its atom making four electrons available to form covalent chemical bonds. It belongs to group 14 of the periodic table. Carbon ma ...
; the term "C-glycoside" is considered a misnomer by
IUPAC The International Union of Pure and Applied Chemistry (IUPAC ) is an international federation of National Adhering Organizations working for the advancement of the chemical sciences, especially by developing nomenclature and terminology. It is ...
and is discouraged. All of these modified glycosidic bonds have different susceptibility to hydrolysis, and in the case of C-glycosyl structures, they are typically more resistant to hydrolysis.


Numbering, and α/β distinction of glycosidic bonds

When an anomeric center is involved in a glycosidic bond (as is common in nature) then one can distinguish between α- and β-glycosidic bonds by the relative stereochemistry of the anomeric position and the stereocenter furthest from C1 in the saccharide. Pharmacologists often join substances to
glucuronic acid Glucuronic acid (from Greek γλεῦκος "''wine, must''" and οὖρον "''urine''") is a uronic acid that was first isolated from urine (hence the name). It is found in many gums such as gum arabic (c. 18%), xanthan, and kombucha tea ...
via glycosidic bonds in order to increase their water
solubility In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solubi ...
; this is known as
glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gl ...
. Many other
glycoside In chemistry, a glycoside is a molecule in which a sugar is bound to another functional group via a glycosidic bond. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. ...
s have important physiological functions.


Chemical approaches

Nüchter ''et al.'' (2001) have shown a new approach to Fischer glycosidation. Employing a
microwave Microwave is a form of electromagnetic radiation with wavelengths ranging from about one meter to one millimeter corresponding to frequencies between 300 MHz and 300 GHz respectively. Different sources define different frequency ra ...
oven equipped with refluxing apparatus in a rotor reactor with pressure bombs, Nüchter ''et al.'' (2001) were able to achieve 100% yield of α- and β-D-glucosides. This method can be performed on a multi-kilogram scale. ;Vishal Y Joshi's method Joshi ''et al.'' (2006) propose the Koenigs-Knorr method in the stereoselective synthesis of alkyl D-glucopyranosides via glycosylation, with the exception of using
lithium carbonate Lithium carbonate is an inorganic compound, the lithium salt of carbonate with the formula . This white salt is widely used in the processing of metal oxides. It is listed on the World Health Organization's List of Essential Medicines because it c ...
which is less expensive and toxic than the conventional method of using
silver Silver is a chemical element with the symbol Ag (from the Latin ', derived from the Proto-Indo-European ''h₂erǵ'': "shiny" or "white") and atomic number 47. A soft, white, lustrous transition metal, it exhibits the highest electrical ...
or mercury salts. D-glucose is first protected by forming the peracetate by addition of
acetic anhydride Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula (CH3CO)2O. Commonly abbreviated Ac2O, it is the simplest isolable anhydride of a carboxylic acid and is widely used as a reagent in organic synthesis. It is a co ...
in
acetic acid Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main componen ...
, and then addition of
hydrogen bromide Hydrogen bromide is the inorganic compound with the formula . It is a hydrogen halide consisting of hydrogen and bromine. A colorless gas, it dissolves in water, forming hydrobromic acid, which is saturated at 68.85% HBr by weight at room tem ...
which brominates at the 5-position. On addition of the alcohol ROH and lithium carbonate, the OR replaces the bromine and on deprotecting the acetylated hydroxyls the product is synthesized in relatively high purity. It was suggested by Joshi ''et al.'' (2001) that lithium acts as the nucleophile that attacks the carbon at the 5-position and through a transition state the alcohol is substituted for the bromine group. Advantages of this method as well as its stereoselectivity and low cost of the lithium salt include that it can be done at room temperature and its yield compares relatively well with the conventional Koenigs-Knorr method.


Glycoside hydrolases

Glycoside hydrolases (or glycosidases), are
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s that break glycosidic bonds. Glycoside hydrolases typically can act either on α- or on β-glycosidic bonds, but not on both. This specificity allows researchers to obtain glycosides in high epimeric excess, one example being Wen-Ya Lu's conversion of D-Glucose to Ethyl β-D-glucopyranoside using naturally-derived glucosidase. It is worth noting that Wen-Ya Lu utilized glucosidase in a reverse manner opposite to the enzyme's biological functionality:


Glycosyltransferases

Before monosaccharide units are incorporated into glycoproteins, polysaccharides, or
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids in ...
s in living organisms, they are typically first "activated" by being joined via a glycosidic bond to the
phosphate In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid . The phosphate or orthophosphate ion is derived from phosph ...
group of a
nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecu ...
such as
uridine diphosphate Uridine diphosphate, abbreviated UDP, is a nucleotide diphosphate. It is an ester of pyrophosphoric acid with the nucleoside uridine. UDP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase uracil. UDP is an im ...
(UDP), guanosine diphosphate (GDP), thymidine diphosphate (TDP), or cytidine monophosphate (CMP). These activated biochemical intermediates are known as sugar nucleotides or sugar donors. Many biosynthetic pathways use mono- or oligosaccharides activated by a diphosphate linkage to lipids, such as dolichol. These activated donors are then substrates for enzymes known as glycosyltransferases, which transfer the sugar unit from the activated donor to an accepting
nucleophile In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they ar ...
(the acceptor substrate).


Disaccharide phosphorylases

Different biocatalytic approaches have been developed toward the synthesis of glycosides in the past decades, which using “glycosyltransferases” and “glycoside hydrolases” are among the most common catalysis. The former often needs expensive materials and the later often shows low yields, De Winter et al. investigated use of cellobiose phosphorylase (CP) toward synthesis of alpha-glycosides in ionic liquids. The best condition for use of CP was found to be in the presence of IL AMMOENG 101 and ethyl acetate.


Directed glycosylations

Multiple chemical approaches exist to encourage selectivity of α- and β-glycosidic bonds. The highly substrate specific nature of the selectivity and the overall activity of the pyranoside can provide major synthetic difficulties. The overall specificity of the glycosylation can be improved by utilizing approaches which take into account the relative transition states that the anomeric carbon can undergo during a typical glycosylation. Most notably, recognition and incorporation of Felkin-Ahn-Eisenstein models into rationale chemical design can generally provide reliable results provided the transformation can undergo this type of conformational control in the transition state. Fluorine directed glycosylations represent an encouraging handle for both B selectivity and introduction of a non-natural biomimetic C2 functionality on the carbohydrate. One innovative example provided by Bucher et al. provides a way to utilize a fluoro oxonium ion and the trichloroacetimidate to encourage B stereoselectivity through the gauche effect. This reasonable stereoselectivity is clear through visualization of the Felkin-Ahn models of the possible chair forms. This method represents an encouraging way to selectivity incorporate B-ethyl, isopropyl and other glycosides with typical trichloroacetimidate chemistry.


O-linked glycopeptides; pharmaceutical uses of O-glycosylated peptides

O-linked glycopeptides recently have been shown to exhibit excellent CNS permeability and efficacy in multiple animal models with disease states. In addition one of the most intriguing aspects thereof is the capability of O-glycosylation to extend half life, decrease clearance, and improve PK/PD thereof the active peptide beyond increasing CNS penetration. The innate utilization of sugars as solubilizing moieties in Phase II and III metabolism (glucuronic acids) has remarkably allowed an evolutionary advantage in that mammalian enzymes are not directly evolved to degrade O glycosylated products on larger moieties. The peculiar nature of O-linked glycopeptides is that there are numerous examples which are CNS penetrant. The fundamental basis of this effect is thought to involve "membrane hopping" or "hop diffusion". The non-brownian motion driven "hop diffusion" process is thought to occur due to discontinuity of the plasma membrane. "Hop diffusion" notably combines free diffusion and intercomparmental transitions. Recent examples notably include high permeability of met-enkephalin analogs amongst other peptides. The full mOR agonist pentapeptide DAMGO is also CNS penetrant upon introduction of glycosylation.


N-Glycosidic bonds in DNA

DNA molecules contain 5-membered carbon rings called riboses that are directly attached to two phosphate groups and a nucleobase that contains amino groups. The nitrogen atoms from the amino group in the nucleotides are covalently linked to the
anomeric In carbohydrate chemistry, a pair of anomers () is a pair of near-identical stereoisomers that differ at only the anomeric carbon, the carbon that bears the aldehyde or ketone functional group in the sugar's open-chain form. However, in order fo ...
carbon of the ribose sugar structure through an N-glycosidic bond. Occasionally, the nucleobases attached to the ribose undergo deamination, alkylation, or oxidation which results in cytotoxic lesions along the DNA backbone. These modifications severely threaten the cohesiveness of the DNA molecule, leading to the development of diseases such as cancer.
DNA glycosylases DNA glycosylases are a family of enzymes involved in base excision repair, classified under EC number EC 3.2.2. Base excision repair is the mechanism by which damaged bases in DNA are removed and replaced. DNA glycosylases catalyze the first st ...
are enzymes that catalyze the hydrolysis the N-glycosidic bond to free the damaged or modified nucleobase from the DNA, by cleaving the carbon-nitrogen glycosidic bond at the 2' carbon, subsequently initiating the
base excision repair Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from ...
(BER) pathway. Monofunctional glycosylases catalyze the hydrolysis of the N-glycosidic bond via either a stepwise, SN1 like mechanism, or a concerted, SN2 like mechanism. The stepwise function, the nucleobase acts as a leaving group before the anomeric carbon gets attacked by the water molecule, producing a short-lived unstable oxacarbenium ion intermediate. This intermediate rapidly reacts with the nearby water molecule to substitute the N-glycosidic bond of the ribose and the nucleobase with an O-glycosidic bond with a hydroxy group. The concerted mechanism, the water acts as a nucleophile and attacks at the anomeric carbon before the nucelobase gets to act like a leaving group. The intermediate produced is a similar oxacarbenium ion where both the hydroxy groups and the nucleobase are still attached to the anomeric carbon. Both mechanisms theoretically yield the same product. Most ribonucleotides are hydrolyzed via the concerted SN2 like mechanism, while most deoxyribonucleotides proceed through the stepwise like mechanism. These reactions are practically irreversible. Due to the fact that the cleavage of the N-glycosidic bond from the DNA backbone can lead to detrimental mutagenic and cytotoxic responses in an organism, have the ability to also catalyze the synthesis of N-glycosidic bonds by way of an abasic DNA site and a specific nucleobase.


References

* Marco Brito-Arias, "Synthesis and Characterization of Glycosides", second edition, Editorial Springer 2016.


External links


Definition of glycosides
from the
IUPAC The International Union of Pure and Applied Chemistry (IUPAC ) is an international federation of National Adhering Organizations working for the advancement of the chemical sciences, especially by developing nomenclature and terminology. It is ...
Compendium of Chemical Terminology, the " Gold Book" * Varki A ''et al.'
''Essentials of Glycobiology.''
Cold Spring Harbor Laboratory Press; 1999. Searchable online {{DEFAULTSORT:Glycosidic Bond Glycosides Carbohydrates Carbohydrate chemistry Chemical bonding