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Human glucocerebrosidase catalyses transglucosylation between glucocerebroside and retinol.

ABSTRACT: The basal activity of human placental glucocerebrosidase is elevated 16-fold by n-pentanol when assayed using p-nitrophenyl beta-D-glucopyranoside (pNPGlc) as the beta-glucosidase substrate. This enhancement of activity is the result of the formation of a transglucosylation product, n-pentyl beta-D-glucoside, in rate-determining competition with the hydrolytic reaction. The transglucosylation product accounts for approximately 80% of the reaction product generated in the presence of n-pentanol (0.18 M) when either glucocerebroside or pNPGlc was used as the substrate. This stimulatory effect can be increased an additional 3-fold by the inclusion of phosphatidylserine (20 micrograms/ml) or sodium taurodeoxycholate (0.3%, w/v) in the incubation medium. In the presence of retinol, glucocerebrosidase also catalyses the synthesis of a novel lipid glucoside, retinyl glucoside, when either glucocerebroside or pNPGlc serves as the substrate. The reaction product was identified as retinyl beta-D-glucoside, based on its susceptibility to hydrolysis by almond beta-D-glucosidase and the subsequent release of equimolar amounts of retinol and glucose. The rate of retinyl-beta-glucoside formation is dependent on the concentration of retinol in the incubation medium, reaching saturation at approximately 0.3 mM retinol. Retinyl beta-D-glucoside is a substrate for two broad-specificity mammalian beta-glucosidases, namely the cytosolic and membrane-associated beta-glucosidases of guinea pig liver. However, retinyl beta-D-glucoside is not hydrolysed by placental glucocerebrosidase. These data indicate that the glucocerebrosidase-catalysed transfer of glucose from glucocerebroside to natural endogenous lipid alcohols, followed by the action of a broad-specificity beta-glucosidase on the transglucosylation product, could provide mammals with an alternative pathway for the breakdown of glucocerebroside to glucose and ceramide.

SUBMITTER: Vanderjagt DJ

PROVIDER: S-EPMC1138163 | biostudies-other | 1994 Jun

REPOSITORIES: biostudies-other

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Project description:Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease, whereas Gaucher disease (GD) is the most frequent lysosomal storage disorder caused by homozygous mutations in the glucocerebrosidase (GBA1) gene. Increased risk of developing PD has been observed in both GD patients and carriers. It has been estimated that GBA1 mutations confer a 20- to 30-fold increased risk for the development of PD, and that at least 7-10% of PD patients have a GBA1 mutation. To date, mutations in the GBA1 gene constitute numerically the most important risk factor for PD. The type of PD associated with GBA1 mutations (PD-GBA1) is almost identical to idiopathic PD, except for a slightly younger age of onset and a tendency to more cognitive impairment. Importantly, the pathology of PD-GBA1 is identical to idiopathic PD, with nigral dopamine cell loss, Lewy bodies, and neurites containing alpha-synuclein. The mechanism by which GBA1 mutations increase the risk for PD is still unknown. However, given that clinical manifestation and pathological findings in PD-GBA1 patients are almost identical to those in idiopathic PD individuals, it is likely that, as in idiopathic PD, alpha-synuclein accumulation, mitochondrial dysfunction, autophagic impairment, oxidative and endoplasmic reticulum stress may contribute to the development and progression of PD-GBA1. Here, we review the GBA1 gene, its role in GD, and its link with PD. The impact of glucocerebrosidase 1 (GBA1) mutations on functioning of endoplasmic reticulum (ER), lysosomes, and mitochondria. GBA1 mutations resulting in production of misfolded glucocerebrosidase (GCase) significantly affect the ER functioning. Misfolded GCase trapped in the ER leads to both an increase in the ubiquitin-proteasome system (UPS) and the ER stress. The presence of ER stress triggers the unfolded protein response (UPR) and/or endoplasmic reticulum-associated degradation (ERAD). The prolonged activation of UPR and ERAD subsequently leads to increased apoptosis. The presence of misfolded GCase in the lysosomes together with a reduction in wild-type GCase levels lead to a retardation of alpha-synuclein degradation via chaperone-mediated autophagy (CMA), which subsequently results in alpha-synuclein accumulation and aggregation. Impaired lysosomal functioning also causes a decrease in the clearance of autophagosomes, and so their accumulation. GBA1 mutations perturb normal mitochondria functioning by increasing generation of free radical species (ROS) and decreasing adenosine triphosphate (ATP) production, oxygen consumption, and membrane potential. GBA1 mutations also lead to accumulation of dysfunctional and fragmented mitochondria. This article is part of a special issue on Parkinson disease.

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Human glucocerebrosidase catalyses transglucosylation between glucocerebroside and retinol.

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