The action of recombinant human lysosomal alpha-glucosidase (rhGAA) on human liver glycogen was described to improve the outcomes of enzyme replacement therapy (ERT) in patients with Pompe disease, as published in the International Journal of Translational Medicine.

“The complexity of the structure of glycogen and the different activities of the enzyme are often not included in discussions about the deficiency in Pompe disease,” Allen K. Murray from Glycan Technologies wrote.

In many flow chart depictions of metabolic pathways, lysosomal alpha-glucosidase (GAA) is often written with an arrow pointing down to glucose, excluding all the other metabolic activities that are taking place simultaneously.


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ERT involves treating patients with rhGAA. “Can rhGAA completely degrade Pompe glycogen? Secondarily, can it completely degrade all glycogen?” Murray wrote. The goal of asking these questions was to improve ERT and identify and treat possible residual cytoplasmic carbohydrates.

To conduct his study, Murray obtained autopsy liver tissue from an 18-month old female patient with Pompe disease and 2 adult male accident patients (as controls). Human glycogen was isolated and the type 9 sigma bovine liver glycogen was extracted. RhGAA was provided by Sanofi Genzyme.

Read more about Pompe disease etiology 

Murray covered many different angles in his study, including the discovery that glycogens of different sources and preparations have different degradation rates by rhGAA. “These are differences in the complexity of the glycogen which shows that the number of glycosyl linkages which must be cleaved to release a glucose residue vary within the glycogen particle,” he wrote.

“The residual material that cannot be degraded by rhGAA consists of glycosylated proteins associated with oligosaccharides in acid hydrolyzates of glycogen.” He also discovered that glycogen cannot be completely degraded by rhGAA because it contains constituents other than glucose, a glycosylated protein component.

As for the residual material, its carbohydrate composition is close to that of the soluble glycosylated protein reported earlier, which can also function as a biomarker for GAA degradation of glycogen. However, investigating the functions of these glycosylated proteins is not straightforward for many reasons; for example, it’s not found in the serum of mice with Pompe disease.

“As discussed earlier, there is a commonly held belief that GAA only breaks glycogen down to glucose, but it breaks down glycogen to some oligosaccharides which then are later degraded to glucose as well as the glycosylated proteins,” Murray concluded.

Reference

Murray AK. The action of recombinant human lysosomal α-glucosidase (rhGAA) on human liver glycogen: pathway to complete degradation. Int J Translate Med. Published online December 14, 2021. doi:10.3390/ijtm1030023