Disorders of lysosomal metabolism / Deficiency of enzyme activators of lysosomal hydrolases
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]
- 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.