Armando J. Parodi

For many years I have been studying the mechanism by which oligosaccharides are added to proteins in the lumen of the endoplasmic reticulum and the effect that such bulky, highly hydrophylic structures have on the acquisition by glycoproteins of their proper tertiary structures. I was the first to determine that in mammalian cells an oligosaccharide is transferred en bloc from a lipid (dolichol) pyrophosphate derivitive to asparagine units in proteins and to obtain hints that this compound was further processed once transferred. My further studies revealed that the same glycosylation mechanism is operative in the common yeast Saccharomyces cerevisiae, in which it may lead to synthesis of mannan, a cell wall polysaccharide. Studies on protein glycosylation conduced in my laboratory showed, first in trypanosomatid protozoa and then in mammalian cells, that protein-linked saccharides are transiently glucosylated in the endoplasmic reticulum. The enzyme responsible for glucosylation (UDP-Glc:glycoprotein glucosyltransferase) appeared to behave as a sensor of glycoprotein conformations as only glucosylates saccharides linked to improperly folded protein moieties. The glucosyltransferase is a key element in the endoplasmic reticulum retention of malfolded conformers and in the mechanism by which glycoproteins acquire their native three-dimensional structures.