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Although the discovery of glycogen in the liver, attributed to Claude Bernard, happened more than 160 years ago, the mechanism involved in the initiation of glucose polymerization remained unknown. The discovery of glycogenin at the core of glycogen's structure and the initiation of its glucopolymerization is among one of the most exciting and relatively recent findings in Biochemistry. This review focuses on the initial steps leading to the seminal discoveries of proteoglycogen and glycogenin at the beginning of the 1980s, which paved the way for subsequent foundational breakthroughs that propelled forward this new research field. We also explore the current, as well as potential, impact this research field is having on human health and disease from the perspective of glycogen storage diseases. Important new questions arising from recent studies, their links to basic mechanisms involved in the de novo glycogen biogenesis, and the pervading presence of glycogenin across the evolutionary scale, fueled by high throughput -omics technologies, are also addressed., (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

The incorporation of [14C]glucose from UDP-[14C]glucose into proteoglycogen fractions of a retinal microsomal preparation was studied. From the rate of labelling of acid-insoluble and -soluble proteoglycogen at different sugar-donor concentrations, and from the conversion of the labelled acid-insoluble into an acid-soluble form measured by a 'chase' with unlabelled UDP-glucose, it was concluded that acid-insoluble 42 kDa protein (p42)-bound glycogen of weight-average Mr 4.7 x 10(5) and acid-soluble p42-bound glycogen of weight-average Mr 7.0 x 10(5) [Miozzo, Lacoste & Curtino (1989) Biochem. J. 260, 287-289] are related as precursor and product respectively. About one-third of the acid-insoluble proteoglycogen was excluded from a Sephacryl S-500 column and was associated with large membrane vesicles. Proteoglycogen was not dissociated from the membranes by treatment with saline solutions or with SDS at a low detergent-to-protein ratio. It was dissociated by treatment with detergents under conditions which were shown to solubilize integral membrane sialoglycoconjugates of retina. These results lead us to postulate that the biogenesis of retina glycogen starts on membrane-associated p42 to form acid-insoluble proteoglycogen, which is then dissociated from membranes and converted into acid-soluble proteoglycogen by the 'growth' of its polysaccharide moiety.

The trichloroacetic acid-insoluble 1,4-alpha-glucan fraction from bovine retina was purified and characterized. It is a proteoglycogen fraction containing a 42 kDa protein moiety similar in size to the protein moiety of the trichloroacetic acid-soluble proteoglycogen fraction. The apparent weight-average Mr of acid-insoluble and acid-soluble proteoglycogens are 4.7 x 10(5) and 7.0 x 10(5) respectively. The present results support suggestions from earlier studies indicating that acid-insoluble proteoglycogen is the precursor of the acid-soluble form.

Tyrosine-glycogen obtained from retina proteoglycogen by exhaustive proteolytic digestion was radiolabelled with 125I. The 125I-labelled tyrosine-glycogen was degraded by amylolytic digestion to a very small radioactive product, which was identified as iodotyrosine by h.p.l.c. The amylolytic mixture used released glucose and maltose that were alpha-linked to the phenolic hydroxy group of p-nitrophenol. No free iodotyrosine was found before or after the intact [125I]iodotyrosine-glycogen was subjected to two cycles of the Edman degradation procedure. The linkage between protein and glycogen was alkali-stable. Therefore it is concluded that the protein-bound glycogen was O-glycosidically linked to the phenolic hydroxy group of tyrosine. The amino acid has not been heretofore found to be involved in the linkage of carbohydrates to proteins.