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Glycosyltransferases (GTFs, Gtfs) 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 ( EC 2.4) that establish natural glycosidic linkages. They
catalyze that utilizes a low-temperature oxidation catalyst to convert carbon monoxide to less toxic carbon dioxide Carbon dioxide (chemical formula ) is a colorless gas with a density about 53% higher than that of dry air. Carbon dioxide molecules ...

catalyze
the transfer of
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 ...
moieties from an activated nucleotide sugar (also known as the "
glycosyl donorA glycosyl donor is a carbohydrate mono- or oligosaccharide that will react with a suitable glycosyl acceptor to form a new glycosidic bond. By convention, the donor is the member of this pair that contains the resulting anomeric carbon of the new gl ...
") to a
nucleophilic 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 in the ...

nucleophilic
glycosyl acceptorA glycosyl acceptor is any suitable nucleophile In chemistry, a nucleophile is a chemical species that forms bonds with Electrophile, electrophiles by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi ...
molecule, the nucleophile of which can be
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
-
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
-,
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
-, or
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
-based. The result of glycosyl transfer can be 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 ...
,
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
,
oligosaccharide An oligosaccharide (/ˌɑlɪgoʊˈsækəˌɹaɪd/; from the Greek ὀλίγος ''olígos'', "a few", and σάκχαρ ''sácchar'', "sugar") is a saccharide is a disaccharide A disaccharide (also called a double sugar or ''biose'') is the sug ...
, or a
polysaccharide Polysaccharides (), or polycarbohydrates, are the most abundant 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 crystallograp ...
. Some glycosyltransferases catalyse transfer to
inorganic phosphate 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 durin ...

inorganic phosphate
or
water Water (chemical formula H2O) is an Inorganic compound, inorganic, transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known li ...

water
. Glycosyl transfer can also occur to
protein Proteins are large 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 No ...

protein
residues, usually to
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemi ...

tyrosine
,
serine Serine (symbol Ser or S) is an α-amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, ...

serine
, or
threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated ...

threonine
to give O-linked
glycoprotein Glycoproteins are protein Proteins are large s and s that comprise one or more long chains of . Proteins perform a vast array of functions within organisms, including , , , providing and , and from one location to another. Proteins dif ...
s, or to
asparagine Asparagine (symbol Asn or N), is an α-amino acid Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compound ...

asparagine
to give N-linked glycoproteins. Mannosyl groups may be transferred to
tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a non-polar Aromatic hydrocarbon, aromatic amino ...

tryptophan
to generate C-mannosyl tryptophan, which is relatively abundant in eukaryotes. Transferases may also use
lipids 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 ...

lipids
as an acceptor, forming
glycolipids Glycolipids are lipids with a carbohydrate attached by a glycosidic linkage, glycosidic (covalent) bond. Their role is to maintain the stability of the cell membrane and to facilitate Cell (biology), cellular recognition, which is crucial to th ...

glycolipids
, and even use lipid-linked sugar phosphate donors, 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
phosphates in eukaryotic organism, or
undecaprenyl phosphate Bactoprenol is a lipid first identified in certain species of Lactobacillus, lactobacili. It is a Hydrophobe, hydrophobic alcohol that plays a key role in the growth of cell walls (peptidoglycan) in Gram-positive bacteria. Occurrence Bactopreno ...

undecaprenyl phosphate
in bacteria. Glycosyltransferases that use sugar nucleotide donors are Leloir enzymes, after Luis F. Leloir, the scientist who discovered the first sugar nucleotide and who received the 1970
Nobel Prize in Chemistry ) , image = Nobel Prize.png , alt = A golden medallion with an embossed image of a bearded man facing left in profile. To the left of the man is the text "ALFR•" then "NOBEL", and on the right, the text (smaller) "NAT•" then "M ...
for his work on carbohydrate metabolism. Glycosyltransferases that use non-nucleotide donors 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
or
polyprenol
polyprenol
pyrophosphate In chemistry, pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a P–O–P linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate (Na2H2P2O7) and tetrasodium pyrophosphate (Na4P2O7), among others ...
are non-Leloir glycosyltransferases. Mammals use only 9 sugar nucleotide donors for glycosyltransferases:
UDP-glucose Uridine diphosphate glucose (uracil-diphosphate glucose, Uridine diphosphate, UDP-glucose) is a nucleotide sugar. It is involved in glycosyltransferase reactions in metabolism. Functions UDP-glucose is used in nucleotide sugars metabolism, nucleot ...

UDP-glucose
,
UDP-galactose Uridine diphosphate galactose (Uridine diphosphate, UDP-galactose) is an intermediate in the production of polysaccharides. It is important in nucleotide sugars metabolism, and is the substrate for the transferase B4GALT5. See also * Galactose * U ...
,
UDP-GlcNAc Uridine diphosphate ''N''-acetylglucosamine or UDP-GlcNAc is a nucleotide sugar and a coenzyme in metabolism. It is used by glycosyltransferases to transfer N-Acetylglucosamine, ''N''-acetylglucosamine residues to substrates. D-Glucosamine is made ...
, UDP-GalNAc, UDP-xylose,
UDP-glucuronic acid UDP glucuronic acid is a sugar used in the creation of polysaccharides and is an intermediate in the biosynthesis of ascorbic acid (except in primates and guinea pigs). It is made from UDP-glucose by UDP-glucose 6-dehydrogenase (EC 1.1.1.22) using ...
,
GDP-mannose
GDP-mannose
, GDP-fucose, and CMP-sialic acid. The phosphate(s) of these donor molecules are usually coordinated by divalent cations such as manganese, however metal independent enzymes exist. Many glycosyltransferases are
single-pass transmembrane protein Bitopic proteins (also known as single-pass or single-spanning proteins) are transmembrane proteins that span the lipid bilayer only one time. These proteins may constitute up to 50% of all transmembrane proteins, depending on the organism, and con ...
s, and they are usually anchored to membranes of
Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that stu ...

Golgi apparatus


Mechanism

Glycosyltransferases can be segregated into "retaining" or "inverting" enzymes according to whether the stereochemistry of the donor's anomeric bond is retained (α→α) or inverted (α→β) during the transfer. The inverting mechanism is straightforward, requiring a single nucleophilic attack from the accepting atom to invert stereochemistry. The retaining mechanism has been a matter of debate, but there exists strong evidence against a double displacement mechanism (which would cause two inversions about the anomeric carbon for a net retention of stereochemistry) or a dissociative mechanism (a prevalent variant of which was known as SNi). An "orthogonal associative" mechanism has been proposed which, akin to the inverting enzymes, requires only a single nucleophilic attack from an acceptor from a non-linear angle (as observed in many crystal structures) to achieve anomer retention.


Reaction reversibility

The recent discovery of the reversibility of many reactions catalyzed by inverting glycosyltransferases served as a paradigm shift in the field and raises questions regarding the designation of sugar nucleotides as 'activated' donors.


Classification by sequence

Sequence-based classification methods have proven to be a powerful way of generating hypotheses for protein function based on sequence alignment to related proteins. The carbohydrate-active enzyme database presents a sequence-based classification of glycosyltransferases into over 90 families. The same three-dimensional fold is expected to occur within each of the families.


Structure

In contrast to the diversity of 3D structures observed for
glycoside hydrolase Glycoside hydrolases (also called glycosidases or glycosyl hydrolases) catalyze that utilizes a low-temperature oxidation catalyst to convert carbon monoxide to less toxic carbon dioxide Carbon dioxide (chemical formula ) is a colorless ...
s, glycosyltransferase have a much smaller range of structures. In fact, according to the
Structural Classification of Proteins The Structural Classification of Proteins (SCOP) database is a largely manual classification of protein structural domain A protein domain is a region of the protein's Peptide, polypeptide chain that is self-stabilizing and that folds indepen ...
database, only three different folds have been observed for glycosyltransferases Very recently, a new glycosyltransferase fold was identified for the glycosyltransferases involved in the biosynthesis of the NAG-NAM polymer backbone of
peptidoglycan Peptidoglycan or murein is a polymer A polymer (; Greek ''poly- Poly, from the Greek :wikt:πολύς, πολύς meaning "many" or "much", may refer to: Businesses * China Poly Group Corporation, a Chinese business group, and its subsidia ...

peptidoglycan
.


Inhibitors

Many inhibitors of glycosyltransferases are known. Some of these are natural products, such as
moenomycin
moenomycin
, an inhibitor of peptidoglycan glycosyltransferases, the nikkomycins, inhibitors of chitin synthase, and the echinocandins, inhibitors of fungal β-1,3-glucan synthases. Some glycosyltransferase inhibitors are of use as drugs or antibiotics. Moenomycin is used in animal feed as a growth promoter.
Caspofungin Caspofungin (International nonproprietary name, INN) (brand name Cancidas) is a lipopeptide Antifungal medication, antifungal drug from Merck & Co., Merck & Co., Inc. discovered by James Balkovec, Regina Black and Frances A. Bouffard. It is a me ...

Caspofungin
has been developed from the echinocandins and is in use as an antifungal agent.
Ethambutol Ethambutol (EMB, E) is a medication primarily used to treat tuberculosis. It is usually given in combination with other Tuberculosis treatment, tuberculosis medications, such as isoniazid, rifampicin and pyrazinamide. It may also be used to treat ...

Ethambutol
is an inhibitor of mycobacterial arabinotransferases and is used for the treatment of tuberculosis.
Lufenuron Lufenuron is the active ingredient in the veterinary flea control medication program, and one of the two active ingredients in the flea, heartworm, ringworm and anthelmintic medicine milbemycin oxime/lufenuron (Sentinel). Lufenuron is stored ...

Lufenuron
is an inhibitor of insect chitin syntheses and is used to control fleas in animals. Imidazolium-based synthetic inhibitors of glycosyltransferases have been designed for use as antimicrobial and antiseptic agents.


Determinant of blood type

The
ABO blood group system The ABO blood group system is used to denote the presence of one, both, or neither of the A and B antigen In immunology Immunology is a branch of biology that covers the study of immune systems in all organisms. Immunology charts, meas ...
is determined by what type of glycosyltransferases are expressed in the body. The ABO gene locus expressing the glycosyltransferases has three main allelic forms: A, B, and O. The A allele encodes 1-3-N-acetylgalactosaminyltransferase that bonds α-
N-acetylgalactosamine #REDIRECT N-Acetylgalactosamine ''N''-Acetylgalactosamine (GalNAc), is an amino sugar derivative of galactose Galactose (, '' galacto-'' + ''wikt:-ose#Suffix 2, -ose'', "milk sugar") sometimes abbreviated Gal, is a monosaccharide Carbohydrat ...
to D-galactose end of H antigen, producing the A antigen. The B allele encodes 1-3-galactosyltransferase that joins α-D-galactose bonded to D-galactose end of H antigen, creating the B antigen. In case of O allele the exon 6 contains a deletion that results in a loss of enzymatic activity. The O allele differs slightly from the A allele by deletion of a single nucleotide -
Guanine Guanine () (symbol A symbol is a mark, sign, or word In linguistics, a word of a spoken language can be defined as the smallest sequence of phonemes that can be uttered in isolation with semantic, objective or pragmatics, practical me ...

Guanine
at position 261. The deletion causes a
frameshift Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during Translation (biology), translation that results in the production of multiple, unique proteins from a single ...
and results in translation of an almost entirely different protein that lacks enzymatic activity. This results in H antigen remaining unchanged in case of O groups. The combination of glycosyltransferases by both alleles present in each person determines whether there is an AB, A, B or O blood type.


Uses

Glycosyltransferases have been widely used in both the targeted synthesis of specific glycoconjugates as well as the synthesis of differentially glycosylated libraries of drugs, biological probes or natural products in the context of
drug discovery In the fields of medicine, biotechnology Biotechnology is a broad area of biology, involving the use of living systems and organisms to develop or make products. Depending on the tools and applications, it often overlaps with related scientif ...
and
drug development Drug development is the process of bringing a new pharmaceutical drug A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, therapy, treat ...
(a process known as
glycorandomizationGlycorandomization, is a drug discovery and drug development technology platform to enable the rapid diversification of bioactive small molecules, drug leads and/or approved drugs through the attachment of sugars. Initially developed as a facile meth ...
). Suitable enzymes can be isolated from natural sources or produced recombinantly. As an alternative, whole cell-based systems using either endogenous glycosyl donors or cell-based systems containing cloned and expressed systems for synthesis of glycosyl donors have been developed. In cell-free approaches, the large-scale application of glycosyltransferases for glycoconjugate synthesis has required access to large quantities of the glycosyl donors. On the flip-side, nucleotide recycling systems that allow the resynthesis of glycosyl donors from the released nucleotide have been developed. The nucleotide recycling approach has a further benefit of reducing the amount of nucleotide formed as a by-product, thereby reducing the amount of inhibition caused to the glycosyltransferase of interest – a commonly observed feature of the nucleotide byproduct.


See also

*
Carbohydrate chemistry Carbohydrate chemistry is a subdiscipline of 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, beha ...
*
Chemical glycosylationA chemical glycosylation reaction involves the coupling of a glycosyl donor, to a glycosyl acceptor forming a glycoside. If both the donor and acceptor are sugars, then the product is an oligosaccharide. The reaction requires activation with a sui ...
*
Glucuronosyltransferase Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UGT) is a microsomal glycosyltransferase () that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule. This is a ...
*
Glycogen synthase Glycogen synthase (UDP-glucose-glycogen glucosyltransferase) is a key enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are call ...
*
Glycosyl acceptorA glycosyl acceptor is any suitable nucleophile In chemistry, a nucleophile is a chemical species that forms bonds with Electrophile, electrophiles by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi ...
*
Glycosyl donorA glycosyl donor is a carbohydrate mono- or oligosaccharide that will react with a suitable glycosyl acceptor to form a new glycosidic bond. By convention, the donor is the member of this pair that contains the resulting anomeric carbon of the new gl ...
*
Glycosylation Glycosylation (see also chemical glycosylationA chemical glycosylation reaction involves the coupling of a glycosyl donor, to a glycosyl acceptor forming a glycoside. If both the donor and acceptor are sugars, then the product is an oligosacchar ...

Glycosylation
*
Oligosaccharyltransferase Oligosaccharyltransferase or OST () is a membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integra ...


References

{{Portal bar, Biology, border=no Carbohydrates Carbohydrate chemistry Transferases EC 2.4 EC 2.4.1 EC 2.4.2 Peripheral membrane proteins Glycobiology