Abstract
Ganglioside biosynthesis is strictly regulated by the activities of glycosyltransferases and is necessarily controlled at the levels of gene transcription and posttranslational modification. Cells can switch between expressing simple and complex gangliosides or between different series within these two groups during brain development. The sequential biosynthesis of gangliosides in parallel enzymatic pathways, however, requires fine-tuned subcellular sequestration and orchestration of glycosyltransferases. A popular model predicts that this regulation is achieved by the vectorial organization of ganglioside biosynthesis: sequential biosynthetic steps occur with the traffic of ganglioside intermediates through subsequent subcellular compartments. Here, we review current models for the subcellular distribution of glycosyltransferases and discuss results that suggest a critical role of N-glycosylation for the processing, transport, and complex formation of these enzymes. In this context, we attempt to illustrate the regulation of ganglioside biosynthesis as well as the biological significance of N-glycosylation as a posttranslational regulatory mechanism. We also review the results of analyses of the 5' regulatory sequences of several glycosyltransferases in ganglioside biosynthesis and provide insights into how their synthesis can be regulated at the level of transcription.
Highlights
Ganglioside biosynthesis is strictly regulated by the activities of glycosyltransferases and is necessarily controlled at the levels of gene transcription and posttranslational modification
It is possible to control the expression of gangliosides by regulating glycosyltransferase (GT) activities that are responsible for ganglioside biosynthesis
The overexpression of GD3-synthase or GM2/GD2-synthase in exclusively GM3-expressing cells resulted in an unexpected observation [33]: the occurrence of either GD3 or GM2 was predicted, we found that b-series complex gangliosides were synthesized in both cases (Fig. 1)
Summary
We showed that GD3-synthase binds tightly to GM3 [33, 60, 61]. we used GM3 as a ligand for affinity purification of GD3-synthase and incorporated GM3 into a ribosome display to stabilize active GD3-synthase during in vitro translation [60, 61]. The observation that the inhibition of N-glycoprotein processing as well as incubation with GM3 delayed the distribution of GD3-synthase to the Golgi suggests that both the binding of GM3 and N-glycosylation participate in protein folding or transport [30, 31, 33]. Even if GM3-synthase is localized in the Golgi in particular cell types, this does not exclude the retrograde distribution of GM3 to the ER This assumption is supported by our observation that exogenously added pyrene-labeled GM3 is transported to the ER [33]. Rapid regulation of ganglioside biosynthesis by lipid (e.g., GM3) chaperone-assisted protein folding, N-glycoprotein processing-controlled protein turnover and transport, and enzyme complex formation may be intimately linked to neuronal differentiation. Cotranslational and posttranslational modification of GTs is an emerging field of ganglioside research that will certainly surprise us with new insights regarding the function of gangliosides and the significance of protein modification, in particular N-glycosylation, for enzyme regulation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
