Glucosylceramide synthase glycosphingolipids. Medical search. Frequent questions

It is also possible to regenerate sphingomyelin from ceramide by accepting a phosphocholine headgroup from phosphatidylcholine (PC) by the action of an enzyme called sphingomyelin synthase. (wikipedia.org)
Additionally, ceramide is also converted to sphingomyelin by the addition of a phosphorylcholine headgroup by sphingomyelin synthase (SMS). (frontiersin.org)

2023 ) Pyrazole Ureas as Low Dose, CNS Penetrant Glucosylceramide Synthase Inhibitors for the Treatment of Parkinson's Disease. (neurotree.org)
The glucosylceramide synthase inhibitors, miglustat and eliglustat, were approved for adults with type 1 Gaucher disease in 2003 and 2014 respectively. (medscape.com)
GCS inhibitors reduce the synthesis of glycosphingolipids, thereby exerting beneficial effects to diseases such as Fabry and Gaucher diseases, which are caused by the accumulation of these lipids. (vivabioinnovator.com)

Eliglustat is a specific inhibitor of glucosylceramide synthase, thereby reducing production of glucosylceramide. (medscape.com)

Alternatively, this sphingosine-derived lipid (sphingolipid) can be synthesized from scratch (de novo) by the enzymes serine palmitoyl transferase (SPT) and ceramide synthase in organelles such as the endoplasmic reticulum (ER) and possibly, in the mitochondria-associated membranes (MAMs) and the perinuclear membranes. (wikipedia.org)
A sugar can be attached to ceramide (glycosylation) through the action of the enzymes, glucosyl or galactosyl ceramide synthases. (wikipedia.org)
Next, 3-keto-dihydrosphingosine is reduced to form dihydrosphingosine, which is acylated by a ceramide synthase (CerS) to form dihydroceramide. (frontiersin.org)
It is phosphorylated by ceramide kinase (CK) to form ceramide-1-phosphate or it can be glycosylated by glucosylceramide synthase to form glycosphingolipids (cerebrosides, globosides, gangliosides). (frontiersin.org)
In addition, ceramide can be converted to sulfatides by the action of galactosylceramide synthase followed by cerebroside sulfotransferase (CST). (frontiersin.org)
The addition of a phosphocholine group to ceramide yields sphingomyelin, but the addition of glucose or galactose to ceramide yields glycosphingolipids and sulfatides. (frontiersin.org)
The D- threo isomer has been shown to be the active glucosylceramide synthase inhibitor.2 Due to PDMP's ability to inhibit the joining of ceramides with carbohydrates there can be an accumulation of ceramide in the cells and this can lead to apoptosis. (matreya.com)
That is accompanied by some reactions (catalysed by enzymes in crimson) resulting in development of ceramide and following development of sphingomyelin and glycosphingolipids. (moonphase2018.com)
Cer is normally shipped by ceramide transportation proteins (CERT) or vesicular transportation towards the Golgi for synthesis of ceramide-1-phosphate (C1P) (by ceramide kinase, CERK), sphingomyelin (SM), and glucosylceramide (GluCer). (moonphase2018.com)
Moreover, PAF-induced development of ceramide microdomains drives endothelial nitric oxide synthase (eNOS) activation and plays a part in barrier dysfunction56. (moonphase2018.com)

AceLink is developing the next generation oral substrate reduction therapies (SRTs) to address significant unmet medical needs and improve the quality of life of patients with inherited disorders of glycosphingolipid metabolism. (vivabioinnovator.com)
Pathways of glycosphingolipid metabolism in both nervous tissue and visceral organs are elucidated, and for each catabolic step, a genetically determined metabolic derangement is identified. (medscape.com)
However, modulation of transmembrane signaling by cholesterol and/or glycosphingolipids (GSLs), both enriched in lipid rafts, and their interlinked metabolism [ 3 ] , could provide the basis of such an all-encompassing axis. (biomedgrid.com)
Prosaposin (PSAP) modulates glycosphingolipid metabolism and variants have been linked to Parkinson's disease (PD). (nature.com)

These agents inhibit the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions that result in the synthesis of most glycosphingolipids, including glucocerebroside. (medscape.com)
This product is a glucosylceramide synthase inhibitor, an enzyme that is essential for the synthesis of a very large number of different glycolipids that are found in many organisms.1 PDMP has four possible isomers due to its two chiral centers (D- threo , L- threo , D- erythro , and L- erythro ). (matreya.com)

Glycosphingolipids (GSLs) are a subclass of glycolipids that are found in cell membranes of various organisms ranging from bacteria to humans. (springer.com)

2021 ) Decreased glucocerebrosidase activity and substrate accumulation of glycosphingolipids in a novel GBA1 D409V knock-in mouse model. (neurotree.org)
Because glycosphingolipids are essential components of all cell membranes, inability to degrade these substances and their subsequent accumulation results in physiologic and morphologic alterations of specific tissues and organs that lead to characteristic clinical manifestations. (medscape.com)

GCS catalyzes the first step in the synthesis of glycosphingolipids, a group of bioactive molecules that play important roles in various cellular processes and diseases. (vivabioinnovator.com)
While most studies use Gb 3 extracts, chemical synthesis provides a unique tool to access different tailor-made Gb 3 glycosphingolipids. (springer.com)

2021 ) A novel glucosylceramide synthase inhibitor attenuates alpha synuclein pathology and lysosomal dysfunction in preclinical models of synucleinopathy. (neurotree.org)

Glucosylceramide, the accumulated glycolipid, is primarily derived from the phagocytosis and degradation of senescent leukocytes and erythrocyte membranes. (medscape.com)
Glycolipid GD3 and GD3 synthase are key drivers for glioblastoma stem cells and tumorigenicity. (sinica.edu.tw)

Both trials showed that AL01211 is generally well tolerated without significant AEs and that the expected plasma glycosphingolipids were reduced with increasing dose demonstrating a clear PK and PD correlation. (vivabioinnovator.com)

Abstract High expression of nitric oxide (NO)-synthase has been found in different cancers like cervical, breast, and central nervous system. (sciencegate.app)

NO-synthase activity inhibition has been suggested as a possible tool to prevent breast cancer. (sciencegate.app)

The treatment included 200 µmol of heavy metals (Pb and Cd) alone and in combination with 200 µM SNP: NO donor, 0.1% Hb, bovine hemoglobin (NO scavenger), and 50 µM L-NAME, N(G)-nitro-L-arginine methyl ester (NO synthase inhibitor) in four replications in comparison to controls. (sciencegate.app)

SRT works via global reduction of glucosylceramide synthase and has been shown to yield outcomes similar to those of ERT in adults. (medscape.com)

Acute exposure ofMCF-7 and MDA-MB-231 cells to C8-glucosylceramide (10 μg/ml culture medium), a cell-permeable analog of glucosylceramide, increased MDR1 mRNA levels by 2- and 4-fold, respectively. (sphingolipidclub.com)
Extended globo-series glycosphingolipids that mediate cell adhesion and signaling. (or.jp)

Gb 3 glycosphingolipids are the specific receptors for bacterial Shiga toxin. (springer.com)

However, the role of glucosylceramide synthase (GCS)-key enzyme that catalyzes the first glycosylation step, in liver injury is still vague. (engreen.com.cn)
UDP-glucose ceramide glucosyltransferase catalyzes the first glycosylation step in glycosphingolipid biosynthesis. (novusbio.com)
Glucosylceramide synthase catalyzes the first glycosylation step of glycosphingolipid synthesis. (unl.edu)
UDP-glucose:N-acylsphingosine D-glucosyltransferase (glucosylceramide synthase or ceramide glucosyltransferase) catalyzes the first glycosylation step of glycosphingolipid synthesis. (unl.edu)

Co-treatment of macrophages with conduritol B-epoxide and 12-25 microM N-butyldeoxygalactonojirimycin, an inhibitor of glycosphingolipid biosynthesis, prevented the mistargeting of lactosylceramide to the lysosomes and restored trafficking to the Golgi. (ox.ac.uk)
Miglustat helps reduce the rate of glycosphingolipid biosynthesis so that the amount of glycosphingolipid substrate is reduced to a level which allows the residual activity of the deficient glucocerebrosidase enzyme to be more effective (substrate reduction therapy). (nih.gov)
Is key in the biosynthesis of glycosphingolipids and gangliosides. (hmdb.ca)

We have identified a novel inhibitor of glucosylceramide synthase (Genz-112638) and assessed its activity in a murine model of Gaucher disease (D409V/null). (nih.gov)
Eliglustat is a specific inhibitor of glucosylceramide synthase, thereby reducing production of glucosylceramide. (medscape.com)

within the endoplasmic reticulum, are transferred to cis-Golgi, where they are employed as substrates to UDP-glucose ceramide glucosyltransferase (UGCG) to form glucosylceramide (GlcCer), the precursor to all glycosphingolipids (GSL). (ipa2014.org)

An approach to treating Gaucher disease is substrate inhibition therapy which seeks to abate the aberrant lysosomal accumulation of glucosylceramide. (nih.gov)
AZ-3102 is an orally available azasugar designed to reach the central nervous system and to interfere with the metabolism of glycosphingolipids through a unique and selective dual mode of action with equally potent inhibition of glucosylceramide synthase (GCS) and non-lysosomal glucosylceramidase (GbA2). (azafaros.com)
2. Inhibition of glucosylceramide synthase eliminates the oncogenic function of p53 R273H mutant in the epithelial-mesenchymal transition and induced pluripotency of colon cancer cells. (nih.gov)

These agents inhibit the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions that result in the synthesis of most glycosphingolipids, including glucocerebroside. (medscape.com)
Miglustat functions as a competitive and reversible inhibitor of the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions which results in the synthesis of most glycosphingolipids. (nih.gov)

In contrast, all of the aforementioned genes were significantly downregulated after the administration of a GCS siRNA or Genz-123346 ( i.e. , a glucosylceramide synthase inhibitor) to inhibit the GCS gene. (engreen.com.cn)
Substrate reduction therapy utilizes imino sugars to inhibit glucosylceramide synthase and potentially abrogate the effects of storage. (ox.ac.uk)

The glucosylceramide synthase inhibitors, miglustat and eliglustat, were approved for adults with type 1 Gaucher disease in 2003 and 2014 respectively. (medscape.com)
Miglustat capsules are a glucosylceramide synthase inhibitor indicated as monotherapy for treatment of adult patients with mild/moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option ( 1.1 ). (nih.gov)
In vitro and in vivo studies have shown that miglustat can reduce the synthesis of glucosylceramide-based glycosphingolipids. (nih.gov)

15. Suppression of glucosylceramide synthase restores p53-dependent apoptosis in mutant p53 cancer cells. (nih.gov)
Materials and Method: The roles of GM3 synthase (α2,3-sialyltransferase, ST3Gal V) in attenuating Taxol-induced apoptosis and triggering drug resistance were determined by cloning and overexpressing this enzyme in the SKOV3 human ovarian cancer cell line, treating SKOV3 and the transfectants (SKOV3/GS) with Taxol and determining apoptosis, cell survival, clonogenic ability, and caspase-3 activation. (scirp.org)
Moreover, we cloned the full-length GM3 synthase gene and showed for the first time that forced expression of GM3 synthase attenuated Taxol-induced apoptosis and increased resistance to Taxol in SKOV3 cells. (scirp.org)
Conclusions: GM3 synthase overexpression inhibited Taxol-triggered caspase-3 activation, revealing that upregulation of GM3 synthase prevents apoptosis and hence reduces the efficacy of Taxol therapy. (scirp.org)
15] established GM3 synthase overexpressing cells by transfecting the cDNA of GM3 synthase into a GM3-deficient subclone of the 3LL Lewis lung carcinoma cell line and demonstrated that these cells were resistant to apoptosis induced by etoposide and doxorubicin by upregulating Bcl-2 expression in these cells. (scirp.org)

Michael Babcock, Ying Feng, Benjamin Liou, Venette Fannin, Yi Lin, Jerry Shen, Ying Sun. Development of AL00804, a novel brain penetrant glucosylceramide synthase inhibitor, to treat Gaucher disease and other neuronopathic glycosphingolipid storage diseases. (acelinktherapeutics.com)

Glucosylceramide synthase - encoded by the Ugcg gene - controls the first committed step in the major pathway of glycosphingolipid synthesis. (nih.gov)
When cre recombinase was expressed in the nervous system under control of the nestin promoter, the floxed gene underwent recombination, resulting in a substantial reduction of Ugcg expression and of glycosphingolipid ganglio-series levels. (nih.gov)
These mice carrying floxed Ugcg alleles will be useful for delineating the functional roles of glycosphingolipid synthesis in the nervous system and in other physiologic systems. (nih.gov)
The floxed Ugcg allele will facilitate analysis of the function of glycosphingolipids in development, physiology, and in diseases such as diabetes and cancer. (nih.gov)

Simplifying complexity: genetically resculpting glycosphingolipid synthesis pathways in mice to reveal function. (nih.gov)
Pathways of glycosphingolipid metabolism in both nervous tissue and visceral organs are elucidated, and for each catabolic step, a genetically determined metabolic derangement is identified. (medscape.com)

Here we demonstrate that kidney glucosylceramide (GlcCer) and ganglioside GM3 levels are higher in human and mouse PKD tissue as compared to normal tissue, regardless of the causative mutation. (nih.gov)

[3] Ceramides and glycosphingolipids are N -acyl derivatives of these compounds. (cloudfront.net)
Glycosphingolipids are ceramides with one or more sugar residues joined in a β- glycosidic linkage at the 1-hydroxyl position (see image). (cloudfront.net)

Niemann-Pick type C (NPC) disease is a disorder of intracellular transport where glycosphingolipids (GSLs) and cholesterol accumulate in endosomal compartments. (ox.ac.uk)

We sought to evaluate the therapeutic potential for glycosphingolipid modulation as a new approach to treat PKD. (nih.gov)

Reduces GSL production by inhibiting glucosylceramide synthase. (medscape.com)

Glucosylceramide modulates membrane traffic along the endocytic pathway. (ox.ac.uk)
The results suggest that in the secretory pathway of Vero cells O-glycan initiation and sphingomyelin as well as glucosylceramide synthesis mainly occur beyond the ERGIC in the Golgi apparatus. (unibas.ch)

Glycosphingolipids are endocytosed and targeted to the Golgi apparatus but are mistargeted to lysosomes in sphingolipid storage disorders. (ox.ac.uk)

Study of the functional roles of glycosphingolipid synthesis in the nervous system and other physiologic systems. (nih.gov)

Alternatively, this sphingosine-derived lipid (sphingolipid) can be synthesized from scratch (de novo) by the enzymes serine palmitoyl transferase (SPT) and ceramide synthase in organelles such as the endoplasmic reticulum (ER) and possibly, in the mitochondria-associated membranes (MAMs) and the perinuclear membranes. (wikipedia.org)

These data demonstrate that both increases and decreases in glucosylceramide levels can dramatically alter the endocytic targeting of lactosylceramide and suggest a role for glucosylceramide in regulation of membrane transport. (ox.ac.uk)

The acquisition of anticancer drug resistance by transfecting the GM3 synthase cDNA into these cells was associated with selective attenuation of both caspase-9 and caspase-3, indicating that the antiapoptosis signaling effect of GM3 synthase could be involved upstream of caspase-9 [15]. (scirp.org)

It was reported that the mRNA and activity levels of a member of the ST family, α2,3-sialyltransferase ST3Gal V (GM3 synthase) [13], positively correlated with resistance to the synthetic retinoid N-(4-hydroxyphenyl)-retinamide [14] in A2780 human ovarian carcinoma cells. (scirp.org)
Recent data revealed that elevated mRNA levels of GM3 synthase positively correlate with a high risk of pediatric acute leukemia [16]. (scirp.org)

Its product, glucosylceramide, serves as the core of more than 300 glycosphingolipids (GSL). (unl.edu)

Development of AL01211, an oral, non-brain penetrant glucosylceramide synthase inhibitor (GCSi), to treat Fabry disease. (acelinktherapeutics.com)

3. Gb3-cSrc complex in glycosphingolipid-enriched microdomains contributes to the expression of p53 mutant protein and cancer drug resistance via β-catenin-activated RNA methylation. (nih.gov)

Dihydrosphingosine is acylated by one of six (dihydro)-ceramide synthase, CerS - originally termed LASS - to form dihydroceramide. (cloudfront.net)

Sphingolipids and glycosphingolipids are emerging as major regulators of these cellular processes. (nih.gov)

A sugar can be attached to ceramide (glycosylation) through the action of the enzymes, glucosyl or galactosyl ceramide synthases. (wikipedia.org)

Anatomy10

Organisms3

Diseases4

Chemicals and Drugs83

Analytical, Diagnostic and Therapeutic Techniques and Equipment9

Phenomena and Processes16

Technology, Industry, Agriculture2

Information Science3

Sphingomyelin synthase2

Inhibitors3

Inhibitor of glucosylceramide1

Ceramide10

Metabolism4

Enzyme2

GSLs1

Accumulation2

Synthesis2

Lysosomal1

Glycolipid2

Dose1

Abstract1

Activity1

Treatment1

Shown1

Cell2

Specific1

Catalyzes the first glycosylation step4

Biosynthesis3

Inhibitor of glucosylceramide synthase2

Ceramide glucosyltransferase1

Inhibition3

Synthesis of most glycosphingolipids2

Inhibit2

Miglustat3

Apoptosis5

Gaucher1

Ugcg4

Pathways2

GlcCer1

Ceramides2

Intracellular1

Therapeutic1

Reduces1

Pathway2

Golgi1

Roles1

Endoplasmic1

Lactosylceramide1

Selective1

Levels2

Product1

Treat1

Expression1

Form1

Major1

Action1