title: Inhibition of protein kinase C activity in mucolipidosis type-4: a model for a new pathogenetic mechanism in inborn errors of metabolism.
abstract: Inhibition of protein kinase C [PK-C] activity by sphingosine and its derivatives has been suggested to play a role in the pathogenesis of sphingolipidoses. In the present study, PK-C activity and PK-C-mediated phosphorylation of endogenous substrates were studied in skin fibroblasts from patients with mucolipidosis type 4 [ML-4], in which there is accumulation of the phospholipids phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine as well as gangliosides. Cytosolic PK-C activity in 5 ML-4 cell lines was comparable to that in control cells. PK-C activity in the particulate fraction of these cells was 84 +/- 14 pmol 32P/mg protein per min compared with 267 +/- 26 in control cells. Increasing the concentrations of the activating lipids in the reaction mixture did not enhance PK-C activity in ML-4 cells, suggesting a non-competitive inhibition of the kinase. Following partial purification of the enzyme from the particulate fraction PK-C activity increased to 288 +/- 14 and 339 +/- 12 pmol 32P/mg protein per min in ML-4 and control cells, respectively. The phosphorylation pattern of endogenous substrates in the particulate fraction of ML-4 cells differed from that in control cells both in the absence and in the presence of calcium and activating lipids. We suggest that PK-C may be involved in the pathogenesis of sphingolipidoses and that this may represent an example for a new type of pathogenetic mechanisms in inborn errors of metabolism.
authors.affiliation: Hadassah University Hospitals, Department of Paediatrics, Mt. Scopus, Jerusalem, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Boneh
authors.forename: G
authors.initials: G
authors.lastname: Bach
mesh_terms: D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D009081:Mucolipidoses / Q000201:enzymology* / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D013106:Sphingolipidoses / Q000209:etiology
chemical_list: D011493:Protein Kinase C