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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 electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs, and the stable balance of attractive and repulsive forces between atoms, when they s ...
that joins a
carbohydrate A carbohydrate () is a biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a ...
(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 have 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 In , alcohol is an that carries at least one (−OH) bound to a ...

hemiacetal
or
hemiketal of a hemiacetal Image:Hemiketal-2D-skeletal.png, 150px, Hemiketal A hemiacetal or a hemiketal is a compound that results from the addition of an alcohol File:Alcohol general.svg, upright=0.8, The bond angle between a hydroxyl group (-OH) and ...

hemiketal
group of a
saccharide A carbohydrate () is a biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a ...
(or a molecule derived from a saccharide) and the
hydroxyl group A hydroxy or hydroxyl group is a functional group with the chemical formula -OH and composed of one oxygen Oxygen is the chemical element Image:Simple Periodic Table Chart-blocks.svg, 400px, Periodic table, The periodic table of the ...

hydroxyl group
of some compound such as an
alcohol In chemistry, alcohol is an organic compound that carries at least one hydroxyl functional group (−OH) bound to a Saturated and unsaturated compounds, saturated carbon atom. The term alcohol originally referred to the primary alcohol ethan ...

alcohol
. A substance containing a glycosidic bond is a
glycoside In chemistry Chemistry is the science, scientific study of the properties and behavior of matter. It is a natural science that covers the Chemical element, elements that make up matter to the chemical compound, compounds composed of atoms ...

glycoside
. 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 Image:Simple Periodic Table Chart-blocks.svg, 400px, Periodic table, The periodic table of the chemical elements In chemistry, an element is a pure substance consisting only of atoms that all have the same ...

oxygen
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 (in nontechnical British English: sulphur) is a chemical element In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: th ...

sulfur
atom. In the same way, N-glycosidic bonds, have the glycosidic bond oxygen replaced with
nitrogen Nitrogen is the chemical element upright=1.0, 500px, The chemical elements ordered by link=Periodic table In chemistry Chemistry is the science, scientific study of the properties and behavior of matter. It is a natural science ...

nitrogen
. Substances containing N-glycosidic bonds are also known as
glycosylamine 120px, Cyclic hemiaminal ether bond derived from an aldehyde Glycosylamines are a class of biochemical compounds consisting of a Glycosyl, glycosyl group attached to an amine, amino group, -NR2. They are also known as N-glycosides,. as they are a ty ...
s. C-glycosyl bonds have the glycosidic oxygen replaced by a
carbon Carbon (from la, carbo "coal") is a with the C and 6. It is lic and —making four s available to form s. It belongs to group 14 of the periodic table. Carbon makes up only about 0.025 percent of Earth's crust. Three occur naturally, ...

carbon
; 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 OrganizationsNational Adhering Organizations in chemistry are the organizations that work as the authoritative power over chemist ...
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#REDIRECT Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ελλάδα, , ), officially the Hellenic Republic, is a country located in Southeast Europe. Its population is a ...

glucuronic acid
via glycosidic bonds in order to increase their water
solubility In chemistry Chemistry is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts A fact is an occurrence i ...

solubility
; this is known as
glucuronidationGlucuronidation 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 glycosidic ...
. Many other
glycoside In chemistry Chemistry is the science, scientific study of the properties and behavior of matter. It is a natural science that covers the Chemical element, elements that make up matter to the chemical compound, compounds composed of atoms ...

glycoside
s have important physiological functions.


Chemical approaches

Nüchter ''et al.'' (2001) have shown a new approach to
Fischer glycosidationFischer glycosidation (or Fischer glycosylation) refers to the formation of a glycoside by the reaction of an aldoseAn aldose is a monosaccharide Monosaccharides (from Greek '' monos'': single, ''sacchar'': sugar), also called simple sugars, are t ...

Fischer glycosidation
. Employing a
microwave Microwave is a form of electromagnetic radiation In physics Physics is the natural science that studies matter, its Elementary particle, fundamental constituents, its Motion (physics), motion and behavior through Spacetime, space a ...

microwave
oven equipped with
refluxing apparatus
refluxing apparatus
in a rotor reactor with
pressure bomb 300px, A diagram showing the setup of a Pressure bomb A pressure bomb or pressure chamber or Scholander bomb is an instrument that can measure the approximate water potential of plant tissue (biology), tissues. A leaf and petiole (botany), petiole ...
s, 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 In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, b ...

lithium carbonate
which is less expensive and toxic than the conventional method of using
silver Silver is a chemical element In chemistry, an element is a pure Chemical substance, substance consisting only of atoms that all have the same numbers of protons in their atomic nucleus, nuclei. Unlike chemical compounds, chemical ele ...

silver
or
mercury Mercury usually refers to: * Mercury (planet) Mercury is the smallest planet in the Solar System and the closest to the Sun. Its orbit around the Sun takes 87.97 Earth days, the shortest of all the Sun's planets. It is named after the Roman g ...

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 A chemical compound is a chemical substance composed of many identical molecules (or molecular entity, molecular entities) composed of atoms from more than one chemical element, ...

acetic anhydride
in
acetic acid Acetic acid , systematically named ethanoic acid , is a colourless liquid organic compound with the chemical formula CH3COOH (also written as CH3CO2H, C2H4O2, or HC2H3O2). Vinegar is no less than 4% acetic acid by volume, making acetic acid ...

acetic acid
, and then addition of
hydrogen bromide Hydrogen bromide is the inorganic compound In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, ...
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 1HNY, a glycoside hydrolase Glycoside hydrolases (also called glycosidases or glycosyl hydrolases) catalysis, catalyze the hydrolysis of glycosidic bonds in polysaccharide, complex sugars. They are extremely common enzymes with roles in nature incl ...
(or glycosidases), are
enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates in ...

enzyme
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 In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanis ...
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 (chemistry), salt, functional group or ester derived from a phosphoric acids and phosphates, phosphoric acid. It most commonly means orthophosphate, a derivative of phosphoric acid, orthophosphoric a ...

phosphate
group of a
nucleotide Nucleotides are organic molecules , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, ...

nucleotide
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 Functional group, group, the pentose sugar ribose, and the nucleobase uracil. ...

uridine diphosphate
(UDP),
guanosine diphosphate Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate 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 ribonucl ...
(GDP), thymidine diphosphate (TDP), or
cytidine monophosphate Cytidine monophosphate, also known as 5'-cytidylic acid or simply cytidylate, and abbreviated CMP, is a nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid p ...
(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 Dolichol refers to any of a group of long-chain mostly unsaturated organic compounds that are made up of varying numbers of isoprene units terminating in an α-saturated isoprenoid group, containing an alcohol File:Alcohol general.svg, uprigh ...

dolichol
. These activated donors are then substrates for enzymes known as
glycosyltransferase Most glycosyltransferase enzymes form one of two folds: GT-A or GT-B Glycosyltransferases (GTFs, Gtfs) are enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules ...
s, which transfer the sugar unit from the activated donor to an accepting
nucleophile In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and the changes they undergo during a ...

nucleophile
(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 An anomer is a type of geometric variation found at certain atoms in carbohydrate is a disaccharide found in animal milk. It consists of a molecule of D-galactose and a molecule of D-glucose bonded by beta-1-4 glycosidic linkage. A carbohy ...
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 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 Biochemistry or biological chemistry, is the study of es within and relating to living s. A sub-discipline of both and , biochemistry may be divided ...
(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 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 OrganizationsNational Adhering Organizations in chemistry are the organizations that work as the authoritative power over chemist ...
Compendium of Chemical Terminology, the "
Gold Book The International Union of Pure and Applied Chemistry The International Union of Pure and Applied Chemistry (IUPAC ) is an international federation of National Adhering Organizations that represents chemists in individual countries. It is a m ...
" * Varki A ''et al.'
''Essentials of Glycobiology.''
Cold Spring Harbor Laboratory Press; 1999. Searchable online {{DEFAULTSORT:Glycosidic Bond Glycosides Carbohydrates Carbohydrate chemistry Chemical bonding