Disorders of lysosomal metabolism / Deficiency of enzyme activators of lysosomal hydrolases

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There are two types of activators:

  • Saposins = SAP (sphingolipid activator protein) - these are several peptides, they contain about 80 amino acids
  • GM2 activator (GM2A)

Saposins[edit | edit source]

Saposins are formed from a common precursor known as prosaposin (encoded by the PSAP gene), which is proteolytically cleaved into individual saposins in the early endosome phase - saposin A, B, C and D. Saposins are very stable proteins - resistant to strong proteases, high temperatures, extremely compact and rigid.

Saposins are sphingolipid-cleaving hydrolase activators

  • SAP A - galactosylceramidase and lactosylceramidase enzyme activator
  • SAP B - also known as GM1A, does not activate the enzyme directly, but reacts with the substrate; its function is to "pull" the glycolipid (substrate) from the lysosome membrane, i.e., without SAP B the hydrolase is active but has nothing to cleave
  • SAP C - activates glycosylceramidase and galactosylceramidase; The function of SAP C is to activate and attach the enzyme to the membrane
  • SAP D - participation in ceramide degradation

GM2A[edit | edit source]

The function of GM2A is to "pull" the glycolipid (GM2 ganglioside) from the membrane and allow contact of the substrate with β-hexosamidase; its function is therefore similar to that of SAP B (GM1A) - with the difference that it "pulls out" another substrate.

Diseases caused by a deficiency of lysosomal activators[edit | edit source]

In general, these diseases are very rare with the number of patients is in the tens. The deficit or mutation of activators causes the phenotype of the corresponding lysosomal sphingolipidosis.

  • Prosaposin defect - there is a logical lack of all SAPs, i.e., very severe complete sphingolipidosis of the newborn, or the infant dies within 4 to 17 weeks; 6 cases described worldwide; AR disease
  • SAP A deficiency or mutation causes the clinical picture of Krabbe disease
  • SAP B deficiency or mutation causes the clinical picture of Fabry disease or metachromatic leukodystrophy (15 cases described worldwide)
  • SAP C deficiency or mutation causes the clinical picture of Gaucher disease (3 cases described worldwide)
  • GM2 deficiency or mutation causes the clinical picture of Sandhoff disease
  • SAP D deficit was not recorded

Activator deficiency is considered if the enzyme is functional, but there are still signs of lysosomal disease.