Glycoproteins - Hughes R. 1985

Biosynthesis
Control of glycan biosynthesis
Genetic control

The Genetic Control of glycoprotein Biosynthesis is made possible by two circumstances. First, it can be exerted during Gene Translation via the well-known template mechanism, which leads to The formation of Polypeptides possessing a suitable Amino Acid Sequence (and possibly conformation) around specific amino acid residues recognized during glycosylation. Second, it is facilitated by the presence within The Cell of complex enzyme systems responsible both for the synthesis of activated sugars intended for transfer to acceptors and for Processing.

As we have already seen, the assembly of glycans requires the presence of multienzyme complexes: during the construction of the oligosaccharide sequence, the reaction product becomes a substrate for a discrete enzyme or for several Enzymes acting competitively. This metabolic interaction of enzyme systems gives rise to a diversity of carbohydrate structures in Glycoproteins. Of course, these enzymes are themselves direct gene products, and it goes without saying that their synthesis serves as one of the forms of genetic control. Direct proof of such control can be obtained from experiments with mutant cell lines, which will be described later. However, the fundamental principles are best illustrated by examining the genetic control of the biosynthesis (Fig. 3.16) of the major ABO(H) Blood group Specificity antigen complex [53].

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Fig. 3.16. Biochemical pathways for the assembly of A, B, and H structures. R — 3 (or 4) glcNAc linked to Oligosaccharides of various structures which, as far as is known, are not part of the group-specific antigenic determinants of the ABO(H) system.

The A and B determinants, whose unique tetrasaccharide structures are detected by Antibodies and which can be attached to various types of carriers, are synthesized, of course, by specific Glycosyltransferases. The presence of the latter in the cell is determined by the genotype of the individual. A necessary preliminary step in the assembly of the A and B determinants consists in the attachment of a fucose residue to the penultimate galactose residue in the precursor. This enzyme is present in all individuals, with rare exceptions such as carriers of the Bombay genotype discussed above. This antigen is formed by the attachment of fucose and is defined serologically as the H determinant. It is the product of an enzyme determined by the H gene. The rare h gene in Bombay group individuals either fails to encode an active enzyme altogether or the enzyme activity is so low that subsequent Modification of the oligosaccharide is effectively blocked under normal biosynthetic conditions. The product generated by The activity of H-transferase is then recognized by the enzymes encoded by the A and B genes. The transferase controlled by the A gene is UDP-N-acetylgalactosamine: O-a-L-fucosyl-(1→2)-D-galactose - a-3-N-acetylgalactosaminyltransferase. Individuals with the A genotype produce this transferase and, consequently, also synthesize complex carbohydrate chains terminating in such sequences. Individuals with the B genotype, in contrast, produce the enzyme UDP-galactose: O-a-L-fucosyl-(1→2)-D-galactose - a-3-galactosyltransferase, encoded by the B gene. Bombay group individuals carry functioning A and B genes that produce active A or B enzymes, but are unable to form A and B Antigens because the requisite first step is missing owing to the inactivity of either the H gene itself or its gene product. Individuals carrying both A and B genes produce both A and B transferases and synthesize carbohydrate chains terminating in sequences recognized as A and B determinants (Fig. 3.16).

Judging by all indications, the A and B genes are allelic. This is quite unusual, since they encode enzymes with qualitatively different specificities, whereas the products of allelic genes typically differ in their biochemical action only quantitatively. It is assumed that the third allele of the ABO system is a "silent" gene in the sense that it does not cause differences in the action of glycosyltransferases acting on the H gene product. In individuals with blood group O, the H-active Structure undergoes no further modification into a serologically recognizable form.