Question

Many different mutations in the iduronate 2-sulfatase have been identified that disrupt the active site, alter glycosylation, or lead to folding defects. Interestingly, the mutations that lead to misfolding do not always disrupt catalytic activity of iduronate 2-sulfatase, but the patients still suffer from Hunter syndrome symptoms as the protein is not properly transported to the correct location. These patients may be candidates for pharmacological chaperone therapy. Where would the misfolded iduronate 2-sulfatase enzyme be located in these patients? Explain why

Answer 1

Misfolded iduronate 2-sulfatase resulting from mutations is typically located in the endoplasmic reticulum due to folding defects, preventing its transportation to the lysosome and leading to symptoms of Hunter syndrome.

Step-by-step explanation:

Location and Impact of Misfolded Iduronate 2-Sulfatase in Hunter Syndrome

When mutations in the iduronate 2-sulfatase gene give rise to folding defects, the enzyme, despite retaining catalytic activity, could end up being located in the endoplasmic reticulum (ER). This mislocalization occurs because proteins must correctly fold to be transported from the ER to their functional destination, which, in the case of lysosomal enzymes like iduronate 2-sulfatase, is the lysosome. Misfolded enzymes are typically recognized by the quality control system of the ER and are targeted for degradation, preventing their transport to lysosomes, which are pivotal in the breakdown of glycosaminoglycans. Consequently, the enzymes fail to reach the lysosomes, leading to the symptoms of Hunter syndrome. This relationship between folding, trafficking, and enzymatic function seems consistent with various metabolic disorders that reflect defects in enzyme shape, localization, or function. As an example, mutations affecting the shape of phenylalanine hydroxylase lead to phenylketonuria, demonstrating how critical proper protein folding and function are intertwined.

Pharmacological chaperone therapy has potential as a treatment for patients with such misfolding mutations. By stabilizing the correct folding of the enzyme, these chaperone molecules may enable its proper trafficking to the lysosome and alleviate disease symptoms.