A. Boneh et G. Bach, INHIBITION OF PROTEIN-KINASE-C ACTIVITY IN MUCOLIPIDOSIS TYPE-4 - A MODEL FOR A NEW PATHOGENETIC MECHANISM IN INBORN-ERRORS OF METABOLISM, Biochimica et biophysica acta, 1182(1), 1993, pp. 64-68
Inhibition of protein kinase C [PK-C] activity by sphingosine and its
derivatives has been suggested to play a role in the pathogenesis of s
phingolipidoses. In the present study, PK-C activity and PK-C-mediated
phosphorylation of endogenous substrates were studied in skin fibrobl
asts from patients with mucolipidosis type 4 [ML-4], in which there is
accumulation of the phospholipids phosphatidylcholine, lysophosphatid
ylcholine, 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 P-32/mg protein per min compared with 267 +/- 26 in contr
ol cells. Increasing the concentrations of the activating lipids in th
e reaction mixture did not enhance PK-C activity in ML-4 cells, sugges
ting a non-competitive inhibition of the kinase. Following partial pur
ification of the enzyme from the particulate fraction PK-C activity in
creased to 288 +/- 14 and 339 +/- 12 pmol P-32/mg protein per min in M
L-4 and control cells, respectively. The phosphorylation pattern of en
dogenous 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 i
n the pathogenesis of sphingolipidoses and that this may represent an
example for a new type of pathogenetic mechanisms in inborn errors of
metabolism.