The effects of chondroitin/dermatan sulphate disaccharides towards the activity of iduronate-2-sulphatase

Affandi Omar¹*, Balqis Kamarudin¹, Fatimah Diana Amin Nordin¹, Salina Abdul Rahman¹, Nur Jannaim Mohamad¹, Rosnani Mohamed¹, Sofwatul Mukhtaroh Nasohah² , Muhd Irfan Bukhari Ahmad Nazri², Marleena Mamat², Norzahidah Khalid², Noornatisha Salleh², Nor Azimah Abdul Azize³, Julaina Abdul Jalil¹

1. Inborn Errors of Metabolism & Genetics Unit, Nutrition, Metabolism & Cardiovascular Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Setia Alam, 40170 Selangor, Malaysia

2. Biochemistry Unit, Specialised Diagnostic Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Jalan Pahang, 50588 Kuala Lumpur, Malaysia

3. Molecular Diagnostic Unit, Specialised Diagnostic Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Jalan Pahang, 50588 Kuala Lumpur, Malaysia

*Corresponding author: Affandi Omar, Inborn Errors of Metabolism & Genetics Unit, Nutrition, Metabolism & Cardiovascular Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Setia Alam, 40170 Selangor, Malaysia, This email address is being protected from spambots. You need JavaScript enabled to view it.

CITATION: Omar A, Kamarudin B, Amin Nordin FD, Abdul Rahman S, Mohamad NJ, Mohamed R, et al. The effects of chondroitin/dermatan sulphate disaccharides towards the activity of iduronate-2-sulphatase. International Medical Research Journal. 2021 Jun;7(1):21–8.

Download Full Article 

ABSTRACT
Mucopolysaccharidoses Type II (MPS II) is a rare inherited disease caused by a mutation in IDS gene encoding iduronate- 2-sulphatase (IDS) enzyme which is responsible for the degradation pathway of dermatan sulphate (DS) and heparan sulphate (HS). The current treatment for MPS II patients is enzyme replacement therapy (ERT) or haematopoietic stem cell transplantation (HSCT). Recently, pharmacological chaperone (PC) has been an alternative approach for managing MPS II patients. This study described the inhibition and specificity study of chondroitin/dermatan (CD) sulphate disaccharide using recombinant human iduronate-2-sulphatase (rhIDS). Potential PC labelled as ΔUA,2SGalNAc, 4S; ΔUA,2S-GalNAc,6S; ΔUA,2S-GalNAc,4S,6S and ΔUA,2S-GalNAc were diluted into several concentrations before incubated with rhIDS for 10 minutes at 0 ºC. Fifty μL of 2 mM ρ-nitrocatechol sulphate was added into 50 μL of each concentration of the respective CD candidates in the microplate and incubated at 37 ºC for 24 hours. The reaction was terminated with 100 μL of 0.2 M sodium hydroxide. The liberated ρ-nitrocatechol was measured using a spectrophotometer at 515 nm. The inhibition concentration, IC50 of ΔUA,2S-GalNAc,4S; ΔUA,2S-GalNAc,6S; ΔUA,2SGalNAc, 4S,6S and ΔUA,2S-GalNAc were calculated as 221 μM, 385 μM, 44 μM and 44 μM. The inhibition constant, Ki were 0.6, 3.5, 24.4 and 2.2 for ΔUA,2S-GalNAc,4S; ΔUA,2S-GalNAc,6S; ΔUA,2S-GalNAc,4S,6S and ΔUA,2S-GalNAc, respectively. In conclusion, ΔUA,2S-GalNAc,4S,6S with the lowest IC50 and highest Ki may become the potential small molecules as PC. Analysis of thermal stability and cell-based experiments should be the direction for future study.

KEYWORDS: Lysosomal storage diseases; mucopolysaccharidoses type II; pharmacological chaperone; iduronate-2-sulphatase