Glycoproteins - Hughes R. 1985

Biosynthesis
Donors

The direct donors of Monosaccharides in glycosylation reactions are a- or ß-glycosyl nucleotide esters, designated as nucleotide sugars (Fig. 3.2). The nucleotide component of these compounds can be uridine, guanine, or cytidine, presented in nucleotide sugars as pyrophosphoric acid esters, with the exception of sialic acid derivatives, which feature a phosphodiester bond between the ribose residue of the nucleotide and the sialic acid. These nucleotide sugars are the primary compounds involved in protein glycosylation. However, other derivatives exist in nature; for example, in plants, glucose is transferred by uridine diphosphate (UDP), adenosine diphosphate (ADP), or guanosine diphosphate (GDP), whereas in Bacteria, it is transferred by UDP, thymidine diphosphate (TDP), and cytidine diphosphate (CTP), all of which are implicated in The Biosynthesis of complex CARBOHYDRATES.

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Fig. 3.2. Nucleotide sugars.

Nucleotide sugars containing glucose, mannose, and N-acetylglucosamine are synthesized by specific synthetases utilizing a-glycosyl phosphates and nucleotide triphosphates with the simultaneous release of pyrophosphate (Fig. 3.3, A).

Although these reactions are readily reversible in vitro, they become virtually irreversible within The Cell due to the rapid Hydrolysis of pyrophosphate by pyrophosphatases. The resulting nucleotide sugars enter secondary enzymatic reactions: UDP-glucose, for instance, undergoes C-4 epimerization to yield UDP-galactose and C-6 carboxylation to yield UDP-glucuronic acid, which can subsequently be decarboxylated to form UDP-xylose. Similarly, UDP-N-acetylgalactosamine is converted into UDP-N-acetylglucosamine via C-4 epimerization, whereas GDP-mannose undergoes C-6 reduction to form GDP-fucose. Further configurational inversions can also occur: GDP-D-mannose is converted into GDP-L-fucose, and L-fucose is consistently found in Glycoproteins.

Fig. 3.3. Biosynthesis of nucleotide sugar and lactose disaccharide.

The synthesis of activated sialic acids differs from the general reaction just described: a) the synthesis involves sialic acids (N-acetyl, N-glycolyl, or N,O-polyacyl derivatives) and CTP, leading to The formation of sialic acid monophosphate derivatives with the concurrent release of pyrophosphate; b) unlike other nucleotide sugar synthetases present in the Cytoplasm, CMP-sialic acid synthetase is predominantly localized in the cell nuclei.

The monosaccharide moieties of nucleotide sugars are transferred to appropriate acceptors to form specific glycosidic bonds. The simplest illustration of such transferase reactions is the synthesis of lactose (Fig. 3.3, B). Lactose synthase, or UDP-galactose:glucose galactosyltransferase, catalyzes the Second Stage (B) of the reaction and, like all known Glycosyltransferases, is strictly specific for the donor; GDP-galactose and other nucleotide derivatives of galactose cannot replace UDP-galactose in this reaction.