Glycosaminoglycan (Dermatan sulfate and Heparan sulfate) (GAGs)

Lysosomal glycosaminoglycans (GAGs), specifically dermatan sulfate and heparan sulfate, are the primary substrates for the lysosomal enzyme iduronate-2-sulfatase (IDS) (UniProt P22304) [1]. These complex polysaccharides are essential components of the extracellular matrix and play critical roles in cell signaling and structural integrity (PubChem) [2,3]. In the absence of functional IDS, as seen in Mucopolysaccharidosis II (MPS II or Hunter syndrome), these GAGs fail to be degraded and instead accumulate within the lysosomes of various tissues (StatPearls) [4]. This progressive accumulation leads to cellular dysfunction and multi-organ system failure, manifesting as skeletal abnormalities, cardiovascular issues, and cognitive decline [4]. Therapeutic interventions, such as enzyme replacement therapy (ERT) with idursulfase, utilize recombinant IDS to catalyze the breakdown of these accumulated substrates (FDA) [5]. Monitoring GAG levels in urine and blood serves as a key biomarker for assessing treatment efficacy and disease progression [5]. Recent advancements also include fusion proteins like pabinafusp alfa designed to cross the blood-brain barrier to address the neurological accumulation of these substrates [6].

Other names

MucopolysaccharidesDermatan sulfateHeparan sulfateIDS substratesLysosomal glycosaminoglycans

Enzymatic hydrolysis of 2-sulfate groups from L-iduronate residues in dermatan sulfate and heparan sulfate to facilitate their lysosomal degradation and clearance.