Glycosyltransferase
Encyclopedia
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s (EC 2.4
EC number
The Enzyme Commission number is a numerical classification scheme for enzymes, based on the chemical reactions they catalyze....
) that act as a catalyst for the transfer of a monosaccharide
Monosaccharide
Monosaccharides are the most basic units of biologically important carbohydrates. They are the simplest form of sugar and are usually colorless, water-soluble, crystalline solids. Some monosaccharides have a sweet taste. Examples of monosaccharides include glucose , fructose , galactose, xylose...
unit from an activated nucleotide sugar
Nucleotide sugar
Nucleotide sugars are the activated forms of monosaccharides. Nucleotide sugars act as glycosyl donors in glycosylation reactions. Those reactions are catalyzed by a group of enzymes called glycosyltransferases.-History:...
(also known as the "glycosyl donor
Glycosyl donor
A 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 glycosidic bond...
") to a glycosyl acceptor
Glycosyl acceptor
A glycosyl acceptor is any suitable nucleophile-containing molecule that will react with a glycosyl donor to form a new glycosidic bond. By convention, the acceptor is the member of this pair which did not contain the resulting anomeric carbon of the new glycosidic bond...
molecule, usually an alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
.
The result of glycosyl transfer can be a carbohydrate
Monosaccharide
Monosaccharides are the most basic units of biologically important carbohydrates. They are the simplest form of sugar and are usually colorless, water-soluble, crystalline solids. Some monosaccharides have a sweet taste. Examples of monosaccharides include glucose , fructose , galactose, xylose...
, glycoside
Glycoside
In chemistry, a glycoside is a molecule in which a sugar is bound to a non-carbohydrate moiety, usually a small organic molecule. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. These can be activated by enzyme...
, oligosaccharide
Oligosaccharide
An oligosaccharide is a saccharide polymer containing a small number of component sugars, also known as simple sugars...
, or a polysaccharide
Polysaccharide
Polysaccharides are long carbohydrate molecules, of repeated monomer units joined together by glycosidic bonds. They range in structure from linear to highly branched. Polysaccharides are often quite heterogeneous, containing slight modifications of the repeating unit. Depending on the structure,...
. Some glycosyltransferases catalyse transfer to inorganic phosphate or water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
. Glycosyl transfer can also occur to protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
residues, usually to tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
, serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
, or threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
to give O-linked glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
s, or to asparagine
Asparagine
Asparagine is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side-chain's functional group. It is not an essential amino acid...
to give N-linked glycoproteins. Mannosyl groups may be transferred to tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
to generate C-mannosyl tryptophan, which is relatively abundant in eukaryotes. Transferases may also use lipids as an acceptor, forming glycolipids, or even lipid-linked sugar phosphate donors, such as dolichol
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 functional group.-Functions:...
phosphates.
It is common that sugar nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
derivatives are used as glycosyl donor
Glycosyl donor
A 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 glycosidic bond...
s. Glycosyltransferases that use sugar nucleotides are called Leloir enzymes, after Luis F. Leloir, the scientist who discovered the first sugar nucleotide and who received the 1970 Nobel Prize in Chemistry
Nobel Prize in Chemistry
The Nobel Prize in Chemistry is awarded annually by the Royal Swedish Academy of Sciences to scientists in the various fields of chemistry. It is one of the five Nobel Prizes established by the will of Alfred Nobel in 1895, awarded for outstanding contributions in chemistry, physics, literature,...
for his work on carbohydrate metabolism.
Glycosyltransferases that utilize non-nucleotide donors, which may be polyprenol
Polyprenol
Polyprenols are natural long-chain isoprenoid alcohols of the general formula H-n-OH where n is the number of isoprene units. Any prenol with more than 4 isoprene units is a polyprenol. Polyprenols play an important function acting as natural bioregulators and are found in small quantities in...
pyrophosphate
Pyrophosphate
In chemistry, the anion, the salts, and the esters of pyrophosphoric acid are called pyrophosphates. Any salt or ester containing two phosphate groups is called a diphosphate. As a food additive, diphosphates are known as E450.- Chemistry :...
s, polyprenol phosphates, sugar-1-phosphates, or sugar-1-pyrophosphates, are termed non-Leloir glycosyltransferases. Such non-Leloir enzymes occur in a variety of organisms.
Mechanism
Glycosyltransferases, by analogy with glycoside hydrolaseGlycoside hydrolase
Glycoside hydrolases catalyze the hydrolysis of the glycosidic linkage to release smaller sugars...
s, can catalyze the transfer of a glycosyl moiety with either retention or inversion of anomer
Configuration
The term configuration has several meanings.In computing it may refer to:* Computer configuration or system configuration* Configure is the output of Autotools and used to detect system configuration...
. Glycosyltransferases are usually metal ion-dependent, with metals such as magnesium or manganese being found in the active site and acting as a Lewis acid by binding to the (di)phosphate leaving group.
Mammals utilize only 9 sugar nucleotide donors for glycosyltransferases: UDP-glucose, UDP-galactose, UDP-GlcNAc, UDP-GalNAc, UDP-xylose, UDP-glucuronic acid, GDP-mannose, GDP-fucose, and CMP-sialic acid. Other organisms have an extensive range of nucleotide sugar
Nucleotide sugar
Nucleotide sugars are the activated forms of monosaccharides. Nucleotide sugars act as glycosyl donors in glycosylation reactions. Those reactions are catalyzed by a group of enzymes called glycosyltransferases.-History:...
donors. Many glycosyltransferases in a number of organisms use lipid-linked glycosyl donors wherein the lipid is frequently a terpenoid such as dolichol
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 functional group.-Functions:...
or polyprenol
Polyprenol
Polyprenols are natural long-chain isoprenoid alcohols of the general formula H-n-OH where n is the number of isoprene units. Any prenol with more than 4 isoprene units is a polyprenol. Polyprenols play an important function acting as natural bioregulators and are found in small quantities in...
.
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 hydrolaseGlycoside hydrolase
Glycoside hydrolases catalyze the hydrolysis of the glycosidic linkage to release smaller sugars...
s, glycosyltransferase have a much smaller range of structures. In fact, according to the Structural Classification of Proteins
Structural Classification of Proteins
The Structural Classification of Proteins database is a largely manual classification of protein structural domains based on similarities of their structures and amino acid sequences. A motivation for this classification is to determine the evolutionary relationship between proteins...
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
Peptidoglycan, also known as murein, is a polymer consisting of sugars and amino acids that forms a mesh-like layer outside the plasma membrane of bacteria , forming the cell wall. The sugar component consists of alternating residues of β- linked N-acetylglucosamine and N-acetylmuramic acid...
.
Inhibitors
Many inhibitors of glycosyltransferases are known. Some of these are natural products, such as moenomycin, an inhibitor of peptidoglycan glycosyltransferases, the nikkomycins, inhibitors of chitin synthase, and the echinocandins, inhibitors of fungal b-1,3-glucan synthases. Some glycosyltransferase inhibitors are of use as drugs or antibiotics. Moenimycin is used in animal feed as a growth promoter. CaspofunginCaspofungin
Caspofungin is an antifungal drug, the first of a new class termed the echinocandins from Merck & Co., Inc. It shows activity against infections with Aspergillus and Candida, and works by inhibiting the enzyme β-D-Glucan synthase and thereby disturbing the integrity of the fungal cell wall...
has been developed from the echinocandins and is in use as an antifungal agent. Ethambutol
Ethambutol
Ethambutol is a bacteriostatic antimycobacterial drug prescribed to treat tuberculosis. It is usually given in combination with other tuberculosis drugs, such as isoniazid, rifampicin and pyrazinamide....
is an inhibitor of mycobacterial arabinotransferases and is used for the treatment of tuberculosis. Lufenuron
Lufenuron
Lufenuron is the active ingredient in the veterinary flea control medication Program, and one of the active ingredients in the veterinary flea control, heartworm prevention, and anthelmintic medicine milbemycin oxime/lufenuron .Lufenuron is stored in the animal's body fat and transferred to adult...
is an inhibitor of insect chitin synthases and is used to control fleas in animals.
Determinant of blood type
The ABO blood group systemABO blood group system
The ABO blood group system is the most important blood type system in human blood transfusion. The associated anti-A antibodies and anti-B antibodies are usually IgM antibodies, which are usually produced in the first years of life by sensitization to environmental substances such as food,...
is determined by what type of glucosyltransferases are expressed in the body.
The ABO gene locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
expressing the glucosyltransferases has three main alleleic forms: A, B, and O. The A allele encodes a glycosyltransferase that bonds α-N-acetylgalactosamine
N-Acetylgalactosamine
N-Acetylgalactosamine , is an amino sugar derivative of galactose.-Function:In humans it is the terminal carbohydrate forming the antigen of blood group A....
to D-galactose end of H antigen, producing the A antigen. The B allele encodes a glycosyltransferase 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
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
at position 261. The deletion causes a frameshift 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 glucosyltransferases by both alleles present in each person determines whether there is a AB, A, B or O blood type.
Uses
Glycosyltransferases have been widely used in the synthesis of glycoconjugates. Suitable enzymes can be isolated from natural sources or produced recombinantly. As an alternative, whole cell-based systems utilizing 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
- OligosaccharyltransferaseOligosaccharyltransferaseOligosaccharyltransferase or OST is a membrane protein complex that transfers a 14-sugar oligosaccharide from dolichol to nascent protein. It is a type of glycosyltransferase...
- GlucuronosyltransferaseGlucuronosyltransferaseUridine 5'-diphospho-glucuronosyltransferase is a glycosyltransferase that catalyzes addition of the glycosyl group from a UTP-sugar to a small hydrophobic molecule.This is glucuronidation reaction.Alternative names:...
- GlycorandomizationGlycorandomizationGlycorandomization, which literally means “diversification of sugar-containing compounds”, is a tool currently used in the pharmaceutical industry to modify the sugar residues of the glycosylated natural products by using unique glycosylation strategies...
- Carbohydrate chemistryCarbohydrate chemistryCarbohydrate chemistry is a subdiscipline of chemistry primarily concerned with the synthesis, structure, and function of carbohydrate structures. Due to the general structure of carbohydrates, their synthesis is often preoccupied with the selective formation of glycosidic linkages and the...
- Glycogen synthaseGlycogen synthaseGlycogen synthase is an enzyme involved in converting glucose to glycogen. It takes short polymers of glucose and converts them into long polymers....
- Glycoside hydrolaseGlycoside hydrolaseGlycoside hydrolases catalyze the hydrolysis of the glycosidic linkage to release smaller sugars...
- GlycosylationGlycosylationGlycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
- Chemical glycosylationChemical glycosylationA chemical glycosylation reaction involves the coupling of a sugar to a glycosyl acceptor forming a glycoside. If the acceptor is another sugar, the product is an oligosaccharide. The reaction involves coupling a glycosyl donor to a glycosyl acceptor via activation utilizing a suitable activator...
- Glycosyl donorGlycosyl 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 glycosidic bond...
- Glycosyl acceptorGlycosyl acceptorA glycosyl acceptor is any suitable nucleophile-containing molecule that will react with a glycosyl donor to form a new glycosidic bond. By convention, the acceptor is the member of this pair which did not contain the resulting anomeric carbon of the new glycosidic bond...