Chemistry Reference
In-Depth Information
the CMP-Neu5Ac transporter is exported to the Golgi apparatus by its C-terminal
amino acids (IIGV). The NSTs are antiporters since import of activated nucleotide
sugars is obligatory, coupled with an equimolar exchange of the corresponding
free nucleoside monophosphate. These originated from effi cient hydrolysis of
nucleotide pyrophosphates that are produced during the sugar elongation reac-
tions (Figures 6.2b and 6.5b). Mutations in NSTs result in drastic changes of gly-
cosylation patterns and may cause severe diseases (CDG-IIf, please see Chapter
22.1). Differences in NSTs between parasites, like
Candida albicans
, and humans
have been characterized and defi ned as targets for therapeutic approaches.
6.6.3
Glycosyltransferases: The Orderly Maturation Reactions
The many Golgi glycosyltransferases that are responsible for glycan's diversity
(Figure 6.5) are type II transmembrane glycoproteins with short (5- 12 amino
acids) N-terminal cytoplasmic tails, an
- helical transmembrane (17 - 24 amino
acids) and luminal stem region, and a C-terminal luminal domain providing cata-
lytic activity. Tail and membrane-spanning regions are responsible for Golgi appa-
ratus localization, and the stem region for the ketosidic linkage specifi city of the
transferases. Some glycosylation events may be protein specifi c (see below);
however, in general, cell type- specifi c glycosyltransferases identify discrete mono-
or disaccharide structures as acceptor substrates (Figure 6.5a). Therefore, most
elongation reactions are independent of the core structure of the
N
- glycan and
some glycosyltransferases modify any acceptor saccharide on both
N
- and
O
-
glycans, and even process glycolipids. Note that the various glycosyltransferases
may compete for the same donor and/or acceptor substrate. Another general
principle is that glycosyltransferases depend on each other since one produces the
acceptor substrates required by others (Figure 6.5c, dotted border light gray boxes
for nonlinear ones). To achieve such orderly trimming and elongation reactions,
components of the glycosylation machinery have to be arranged properly. It is still
a mystery how the machinery for protein synthesis and glycosylation in the rough
ER is organized into subcompartments. In the Golgi apparatus, however, glyco-
proteins travel along hierarchically arranged enzymes that modify glycans step by
step. Two models have been proposed to explain this dynamic process along a
rather static enzyme arrangement - vesicular transport or cisternal maturation. In
the fi rst, the secretory cargo moves anterogradely along glycosylation machinery
stably tied up in Golgi cisternae. In the second, glycosylation machinery moves
retrogradely along maturing cisternae fi lled with secretory cargo. Neither model
seems to be correct for animal professional secretory cells, but their combination
explains most morphological and biochemical features observed. In the Golgi
apparatus running at full capacity, cargo is transported along tubular connec-
tions between functionally different Golgi compartments. This transport is com-
plemented with a permanent fl ow of retrograde - oriented vesicles [14] . Proper
localization of the glycosyltransferases in the Golgi apparatus depends on the
conserved oligomeric Golgi (COG) complexes. Mutations in COG components, as
α
