TY - JOUR
T1 - Activators of spleen glucocerebrosidase from controls and patients with various forms of Gaucher's disease
AU - Basu, A.
AU - Glew, R. H.
AU - Daniels, L. B.
AU - Clark, L. S.
N1 - Copyright:
Copyright 2004 Elsevier B.V., All rights reserved.
PY - 1984
Y1 - 1984
N2 - Glucocerebrosidase from normal human spleen, and spleen from cases of neurologic (types 2 and 3) and nonneurologic (type 1) Gaucher's disease, was delipidated and inactivated by extraction from membranes with sodium cholate and ice-cold 1-butanol. Control glucocerebrosidase was stimulated markedly by large quantities (20-30 μg/assay) of phosphatidylserine (PS), or by a combination of smaller amounts (1-2 μg) of PS and 3 μg of a heat-stable factor (HSF) derived from the spleen of a patient with Gaucher's disease. The residual glucocerebrosidase from a nonneurologic case, but not a neurologic case, was also responsive to PS and HSF. The combination of HSF and PS decreased the K(m) of the normal enzyme for 4-methylum-belliferyl-β-D-glucopyranoside from 8.0 to 1.6 mM. These effectors also increased the reactivity of glucocerebrosidase to the inhibitor conduritol B expoxide; HSF alone had no effect (t 1/2 = 19 ± 0.5 min) whereas the maximum rate of inactivation (t 1/2 = 4.0 min) by conduritol B epoxide was achieved in the presence of a mixture of PS (1 μg) and HSF (3 μg). Phosphatidylglycerol (PG) and phosphatidic acid, also acidic phospholipids, were effective activators of glucocerebrosidase. Varying the fatty acid composition of PG had little effect on its ability to stimulate glucocerebrosidase activity. However, in the case of phosphatidylcholine (PC), a weaker activator than PG or PS, fatty acid composition had a significant impact on the ability of this neutral lipid to activate glucocerebrosidase; dilinoleoyl-PC and dicaproyl-PC were moderately effective activators, but distearoyl-PC and dioleoyl-PC were almost totally inactive. The mono-, and di-, and trisialogangliosides (G(M1), G(D1), and G(T1) were less than half as effective as PS as activators of glucocerebrosidase. These results indicate that acidic phospholipids and the heat-stable factor may both play a role in explaining the genetic heterogeneity of Gaucher's disease.
AB - Glucocerebrosidase from normal human spleen, and spleen from cases of neurologic (types 2 and 3) and nonneurologic (type 1) Gaucher's disease, was delipidated and inactivated by extraction from membranes with sodium cholate and ice-cold 1-butanol. Control glucocerebrosidase was stimulated markedly by large quantities (20-30 μg/assay) of phosphatidylserine (PS), or by a combination of smaller amounts (1-2 μg) of PS and 3 μg of a heat-stable factor (HSF) derived from the spleen of a patient with Gaucher's disease. The residual glucocerebrosidase from a nonneurologic case, but not a neurologic case, was also responsive to PS and HSF. The combination of HSF and PS decreased the K(m) of the normal enzyme for 4-methylum-belliferyl-β-D-glucopyranoside from 8.0 to 1.6 mM. These effectors also increased the reactivity of glucocerebrosidase to the inhibitor conduritol B expoxide; HSF alone had no effect (t 1/2 = 19 ± 0.5 min) whereas the maximum rate of inactivation (t 1/2 = 4.0 min) by conduritol B epoxide was achieved in the presence of a mixture of PS (1 μg) and HSF (3 μg). Phosphatidylglycerol (PG) and phosphatidic acid, also acidic phospholipids, were effective activators of glucocerebrosidase. Varying the fatty acid composition of PG had little effect on its ability to stimulate glucocerebrosidase activity. However, in the case of phosphatidylcholine (PC), a weaker activator than PG or PS, fatty acid composition had a significant impact on the ability of this neutral lipid to activate glucocerebrosidase; dilinoleoyl-PC and dicaproyl-PC were moderately effective activators, but distearoyl-PC and dioleoyl-PC were almost totally inactive. The mono-, and di-, and trisialogangliosides (G(M1), G(D1), and G(T1) were less than half as effective as PS as activators of glucocerebrosidase. These results indicate that acidic phospholipids and the heat-stable factor may both play a role in explaining the genetic heterogeneity of Gaucher's disease.
UR - http://www.scopus.com/inward/record.url?scp=0021353276&partnerID=8YFLogxK
M3 - Article
C2 - 6693432
AN - SCOPUS:0021353276
SN - 0021-9258
VL - 259
SP - 1714
EP - 1719
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 3
ER -