Glycosyltransferase

Glycosyltransferases are enzymes (EC 2.4) that act as a catalyst for the transfer of a monosaccharide unit from an activated sugar phosphate (known as the "glycosyl donor") to an acceptor molecule, usually an alcohol.

The result of glycosyl transfer can be a monosaccharide glycoside, an oligosaccharide, or a polysaccharide, although some glycosyltransferases catalyse transfer to inorganic phosphate or water. Glycosyl transfer can also occur to protein residues, usually to tyrosine, serine or threonine to give O-linked glycoproteins, or to asparagine to give N-linked glycoproteins.

Commonly, sugar nucleotide derivatives are used as glycosyl donors. 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 for his work on carbohydrate metabolism.

Glycosyltransferases that utilize non-nucleotide donors, which may be polyprenol pyrophosphates, polyprenol phosphates, sugar-1-phosphates or sugar-1-pyrophosphates, are termed non-Leloir glycosyltransferases. Such non-Leloir enzymes occur in lower and higher organisms.

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Mechanism

Glycosyltransferases, by analogy with glycoside hydrolases, can catalyze the transfer of a glycosyl moiety with either retention or inversion of 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 sugar nucleotide donors. Many glycosyltransferases in higher and lower organisms use lipid linked glycosyl donors where the lipid is frequently a terpenoid such as dolichol or polyprenol.

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 86 families. The same three-dimensional fold is expected to occur within each of the families.^[1]

Structure

In contrast to the diversity of 3D structures observed for glycoside hydrolases, glycosyltransferase have a much smaller range of structures. In fact, according to the Structural Classification of Proteins" database only three different folds have been observed for glycosyltransferases^[2] Very recently, a new glycosyltransferase fold was identified for the glycosyltransferases involved in the biosynthesis of the NAG-NAM polymer backbone of peptidoglycan.^[3]

Uses

Glycosyltransferases have been widely used in the synthesis of glycoconjugates. Suitable enzymes can be isolated from natural sources or produced recombinantly. Alternatively, 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. Alternatively, nucleotide recycling systems have been developed that allow the resynthesis of glycosyl donors from the released nucleotide. 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

• Oligosaccharyltransferase
• Glucuronosyltransferase
• Glycogen synthase
• Glycoside hydrolase

References