Heparan Sulfate, Mucopolysaccharidosis IIIB and Sulfur Metabolism Disorders

Abstract

Mucopolysaccharidosis, type IIIB (MPS IIIB) is a rare disease caused by mutations in the N-alpha-acetylglucosaminidase (NAGLU) gene resulting in decreased or absent enzyme activity. On the cellular level, the disorder is characterized by the massive lysosomal storage of heparan sulfate (HS)—one species of glycosaminoglycans. HS is a sulfur-rich macromolecule, and its accumulation should affect the turnover of total sulfur in cells; according to the studies presented here, it, indeed, does. The lysosomal degradation of HS in cells produces monosaccharides and inorganic sulfate (SO42−). Sulfate is a product of L-cysteine metabolism, and any disruption of its levels affects the entire L-cysteine catabolism pathway, which was first reported in 2019. It is known that L-cysteine level is elevated in cells with the Naglu−/− gene mutation and in selected tissues of individuals with MPS IIIB. The level of glutathione and the Naglu−/− cells’ antioxidant potential are significantly reduced, as well as the activity of 3-mercaptopyruvate sulfurtransferase (MPST, EC 2.8.1.2) and the level of sulfane sulfur-containing compounds. The direct reason is not yet known. This paper attempts to identify some of cause-and-effect correlations that may lead to this condition and identifies research directions that should be explored.

CD44 Glycosylation as a Therapeutic Target in Oncology

“…HS proteoglycan is ubiquitously expressed on the surface of most animal cells and in the extracellular matrix, and its function mainly depends on the interaction of the HS side chain with various proteins such as cytokines, growth factors and their receptors, and it plays an important role in tumor progression ( 150 ). In HS polysaccharides, negatively charged sulfate and carboxylic acid groups are arranged in various domains and generated through tightly regulated biosynthetic reactions, with great potential for structural change ( 151 ). The CD44v3 isoform containing the HS attachment site is overexpressed on the tumor epithelium of colorectal adenomas and most carcinomas compared with normal colon ( 152 ).…”

Sanfilippo Syndrome: Optimizing Care with a Multidisciplinary Approach

“…The HS storage is caused by mutations in genes coding for enzymes involved in the decay of this complex carbohydrate. [1][2][3][4] There are five subtypes of MPS III (A, B, C, D, and E), classified on the basis of the kind of mutated gene, and deficiency of specific enzyme (Table 1). [5][6][7] Four of these subtypes (A, B, C, and D) have been found in humans, while subtype E is currently known only from studies on an animal model, a mutant mice, constructed in the laboratory, with dysfunctional ARSG gene.…”

“…All these diseases are inherited in an autosomal recessive manner, as residual activity of any enzyme involved in HS degradation at the level of 10-20% of the normal activity may ensure efficient decay process. [1][2][3][4][5][6][7] Because HS is present in virtually all tissues and organs, its storage affects majority of organs. Nevertheless, in Sanfilippo syndrome, symptoms occurring in visceral organs are milder than those in other types of MPS.…”

“…Importantly, MPS III patients are born without any disease symptoms which develop usually at the age of several months or a few years. [1][2][3][4] The disease is progressive, and symptoms become more and more severe in time, which leads to a significantly shortened life span, estimated for 2-3 decades on average. 2 Unfortunately, despite many attempts and intensive work of researches on various potential therapies, no specific and effective treatment of Sanfilippo syndrome is currently available.…”

Reactive Sulfur Species (RSS) in Physiological and Pathological Conditions and in Therapy

“…The impaired degradation of GAGs is the cause of several diseases collectively known as mucopolysaccharidoses (MPSs). The problem with MPS III, called Sanfilippo syndrome type B, is the subject of the review paper by Kaczor-Kamińska et al [ 19 ]. This disorder results in the massive lysosomal storage of heparan sulfate (HS) due to a deficit or complete lack of activity of alpha-N-acetylglucosaminidase (EC 3.2.1.50), caused by a mutation in the N-alpha-acetylglucosaminidase (NAGLU) gene.…”