Chemistry Reference
In-Depth Information
Info Box 1
The sialic acids are unique among the monosaccharide components found
commonly in
O
-glycans as they are found in Nature as a family of over 50
forms. They were originally discovered in 1930s by Klenk and Blix, and named
on the basis of the sources used for isolation. Klenk used brain and termed the
products neuraminic acids (amino sugars from neuronal tissue), while Blix
used salivary glands and used the Greek root
sialos
( '
saliva
') for sialic acids. Both
terminologies remain in use.
The sialic acids are nine- carbon
-keto acids formed through the condensa-
tion of pyruvate with
N
- acetyl -
D
- mannosamine, having a six - membered pyra-
nose ring and adopt a
2
C
5
chair conformation (please see Figure 1.6 for structure).
Natural glycoconjugates are found in the
α
α
- confi guration except for the glycosyl
donor, that is CMP-
-
O
-sialic acids. The family is built due to the substitutions
found within the monosaccharide. Substitution of the C5 amino group may be
with acetyl or glycolyl groups, and each of these acts as a parent molecule car-
rying acetyl esters at C4, C7, C8 and C9 as mono, di and tri forms. C9 can also
be substituted with phosphate or lactyl esters. Sulfate esters and methyl ethers
are found at position 8. 1,7-Lactone and 2,7-anhydro forms exist, and 2-dehydro
analogs with a double bond between C2 and C3 are found as free monosaccha-
rides as they have no
β
-keto group. Substitution of the C5 amino group by a
hydroxyl generates 3 - deoxy -
D
-
glycero
-
D
-
galacto
- 2 - nonulosonic acid.
The various substitutions have biological importance especially in interac-
tions mediated by the siglecs and selectins (see Chapter 27) where sialic acids
form recognition epitopes on receptor proteins. Acetyl esters at positions 4 and
7-9 donate resistance to most sialidases and provide a mechanism for biological
protection of these sialic acid forms.
α
the peptide location of
O
-glycans include the following: (i) A primary peptide
sequence preference which varies for serine and threonine and correlates well with
higher levels of threonine substitution known. Proline is located adjacent to
O
- glycosylation sites. Specifi city windows predict positions for Ser/Thr/Pro and
exclude certain amino acids, including Cys, Trp, Met and Asp [4]. (ii) Only those
serine and threonine residues exposed on the surface of the molecule will be gly-
cosylated. Thus, a conformational role of the protein must be considered. The
recognition of
O
- glycans on
-turns, extended structures where proline residues
play a role, the absence of aromatic, bulky amino acids near to
O
- glycosylation
sites and lack of
O
-glycans in hydrophobic peptide domains are all signifi cant. (iii)
O
-Glycosylation patterns correlate with tissue location. This is governed by the
ppGaNTases and subsequent action of other glycosyltransferases. This has been
well demonstrated for the secreted mucin genes (for instance MUC5AC in
stomach, respiratory tract and conjunctiva), where the tandem repeat Ser/Thr/Pro
domains contain the same amino acid sequence, but where variable glycosylation
is found on a tissue- specifi c basis.
β
