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Review
. 2022 Mar 30;11(4):678.
doi: 10.3390/antiox11040678.

Heparan Sulfate, Mucopolysaccharidosis IIIB and Sulfur Metabolism Disorders

Marta Kaczor-Kamińska  1 , Kamil Kamiński  2 , Maria Wróbel  1
Affiliations
Review

Heparan Sulfate, Mucopolysaccharidosis IIIB and Sulfur Metabolism Disorders

Marta Kaczor-Kamińska et al. Antioxidants (Basel). .

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.

Keywords: 3-mercaptopyruvate sulfurtransferase; Sanfilippo B syndrome; cysteine; glycosaminoglycans; heparin; sulfane sulfur; sulfate; sulfurtransferases.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A) Haworth projection of the heparin/HS monosaccharide units; (B) repeating GlcUA-GlcNAc disaccharide units of HS; (C) scheme of structural organization of the residues in HS. In the mature form of HS, two main types of domains can be distinguished: NA domains build mostly by non-modified N-acetyl-glucosamine moiety linked mainly to glucuronic acid residues, and NS domains that are composed by highly sulfated disaccharides units).
Figure 2
Figure 2
Biological activities modulated by the interaction of heparan sulfate with proteins. The diagram was prepared based on the information included in the following papers: [32,46,55,56,57,58,59,60,61,62].
Figure 3
Figure 3
An example of how the subsequential degradation from the non-reducing end of the tetrasaccharide IdUA2S (α 1−4)—GlcNS6S (α 1−4)—GlcA2S (β 1−4)—GlcNAc6S occurs in the lysosome by HS degrading enzymes. Abbreviations: IdUA = iduronic acid; GlcN = glucosamine; GlcUA = glucuronic acid; GlcNAc = N−acetylglucosamine; IDS—iduronate−2−sulfatase (EC 3.1.6.13); IDUA—α−L−iduronidase (EC 3.2.1.76); SGSH—N−sulfoglucosamine sulfohydrolase (EC 3.10.1.1); HGNAT heparan−α−glucosaminide N−acetyltransferase (EC 2.3.1.78); 6S—N−acetylglucosamine−6−sulfatase (EC 3.1.6.14); NAGLU—α−N−acetylglucosaminidase (EC 3.2.1.50); GDS—glucuronate−2−sulfatase (EC 3.1.6.18); GUSB—β−glucuronidase (EC 3.2.1.21).
Figure 4
Figure 4
The tertiary structure of human N-acetyl-alpha-glucosaminidase (EC 3.2.1.50). A modified image from the RCSB PDB (rcsb.org) of PDB ID 4XWH_1 [68].
Figure 5
Figure 5
Cellular sulfate reuse pathway. Abbreviations: ATP—adenosine triphosphate; ADP—adenosine diphosphate; AMP—adenosine monophosphate; PPi—pyrophosphate; APS—adenosine−5′−phosphosulfate; PAPS—3′−phosphoadenosine−5′−phosphosulfate, PAP—3′−phosphoadenosine−5′−monophosphate; 1—ATP−sulfurylase (EC 2.7.7.4); 2—APS kinase (EC 2.7.1.25); 3—sulfotransferase (EC 2.8.2.-); 4—sulfatase (3.1.6.-).
Figure 6
Figure 6
Cysteine metabolism map. The catabolism of cysteine involves seven pathways producing pyruvate, hydrogen sulfide, alanine or taurine. (1) In the first step, cysteine is converted to mercaptopyruvate in deamination reaction catalyzed by cysteine transaminase (CGT, EC 2.6.1.3). Subsequently, mercaptopyruvate is changed to pyruvate on the trans-sulfuration way by 3−mercaptopyruvate sulfurtransferase (MPST, EC 2.8.1.2)—the ‘mercaptopyruvate pathway’. Cysteine in reactions catalyzed by (2) cysteine desulfhydrase (CDS, EC 4.4.1.15) and (3) cystathionine β−lyase (CBL, EC 4.4.1.8) is directly converted to pyruvate and H2S (only CBL). (4) D−cysteine is formed from L−cysteine by the action of amino acid racemase (AAR, EC 5.1.1.10). (5) Cysteine is in dynamic equilibrium with cystine, which can be converted to thiocysteine in a reaction catalyzed by cystathionine γ−lyase (CTH, EC 4.4.1.1) and, in the following step, into H2S or persulfide. Conversion of persulfide into thiosulfate is catalyzed by thiosulfate sulfurtransferase (TST, EC 2.8.1.1) in the ‘thiosulfate cycle’. (6) Cysteine is transformed to 3−sulfinoalanine by cysteine dioxygenase (CDO, EC 1.13.11.20) via oxidation of a sulfhydryl group. Then, 3−sulfinoalanine can be converted to: (a) 3−sulfinopyruvate in a reaction catalyzed by aspartate transaminase (AAT, EC 2.6.1.1), which is further transformed to pyruvate; (b) to alanine by desulfinase (EC 4.1.1.12) in the ‘alanine pathway’; and (c) to taurine by sulfinoalanine decarboxylase (CSAD, EC 4.1.1.29) and hypotaurine dehydrogenase (EC 1.8.1.3) in the ‘taurine pathway’. (7) Cysteine can also be transformed to cysteate in reaction catalyzed by cysteine lyase (EC 4.4.1.10) and then to taurine by action of CSAD. Glutamate cystine ligase (GCL, EC 6.3.2.2) and glutathione synthase (GSS, EC 6.3.2.3) catalyze glutathione synthesis from cysteine. Further metabolism between methionine and cysteine is regulated by CTH, cystathionine β−synthase (CBS, EC 4.2.1.22) and methionine synthase (MS, EC 2.1.1.13). Red arrows show changes in sulfur metabolism caused by the GAGs accumulation (modified according to [97]).
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References

    1. Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on Orphan Medicinal Products. European Union; Maastricht, The Netherlands: 2000. pp. 1–5. The Official Journal of the European Union.
    1. Gaffke L., Pierzynowska K., Piotrowska E., Węgrzyn G. How close are we to therapies for Sanfilippo disease? Metab. Brain Dis. 2018;33:1–10. doi: 10.1007/s11011-017-0111-4. - DOI - PMC - PubMed
    1. Fu H., Dirosario J., Killedar S., Zarapse K., McCarty D.M. Correction of neurological disease of mucopolysaccharidosis IIIB in adult mice by rAAV9 trans-blood-brain barrier gene delivery. Mol. Ther. 2011;19:1025–1033. doi: 10.1038/mt.2011.34. - DOI - PMC - PubMed
    1. Kan S.H., Aoyagai-Scharber M., Le S.Q., Vincelette J., Ohmi K., Bullens S., Wendt D.J., Christianson T.M., Tiger P.M.N., Brown J.R., et al. Delivery of an enzyme-IGFII fusion protein to the mouse brain is therapeutic for mucopolysaccharidosis type IIIB. Proc. Natl. Acad. Sci. USA. 2014;111:14870–14875. doi: 10.1073/pnas.1416660111. - DOI - PMC - PubMed
    1. Kan S.H., Troitskaya L.A., Sinow C.S., Haitz K., Todd A.K., Di Stefano A., Le S.Q., Dickson P.I., Tippin B.L. Insulin-like growth factor II peptide fusion enables uptake and lysosomal delivery of α-N-acetylglucosaminidase to mucopolysaccharidosis type IIIB fibroblasts. Biochem. J. 2014;458:281–289. doi: 10.1042/BJ20130845. - DOI - PMC - PubMed

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