Preparation of the active isomer of 1-phenyl-2-decanoylamino-3-morpholino-1-propanol, inhibitor of murine glucocerebroside synthetase

Inokuchi, Jin-ichi; Radin, Norman S.

doi:10.1016/s0022-2275(20)38673-9

Cited by 239 publications

(30 citation statements)

References 11 publications

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“…The use of MDCK cells also allowed us to examine whether NFA-and HFA-GaICer are synthesized by the same or by different galactosyltransferases. This question was addressed by comparing the influence of an inhibitor of sphingolipid synthesis, PDMP (27), on GalCer synthesis from NFA-or HFA-ceramide (Fig. 1).…”

Section: • Sphingolipid Galactosylation In Hepg2 and M D C K H Cellsmentioning

confidence: 99%

Topology of sphingolipid galactosyltransferases in ER and Golgi: transbilayer movement of monohexosyl sphingolipids is required for higher glycosphingolipid biosynthesis.

Burger

Bijl

Meer

1996

The Journal of Cell Biology

102

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Abstract. Glucosylceramide (GlcCer) is synthesized at the cytosolic surface of the Golgi complex while enzymes acting in late steps of glycosphingolipid biosynthesis have their active centers in the Golgi lumen. However, the topology of the "early" galactose-transferring enzymes is largely unknown. We used shortchain ceramides with either a 2-hydroxy fatty acid (HFA) or a normal fatty acid (NFA) to determine the topology of the galactosyltransferases involved in the formation of HFA-and NFA-galactosylceramide (GalCer), lactosylceramide (LacCer), and galabiosylceramide (GaECer).Although the HFA-GaICer synthesizing activity colocalized with an E R marker, the other enzyme activities fractionated at the Golgi density of a sucrose gradient. In cell homogenates and permeabilized cells, newly synthesized short-chain GlcCer and GalCer were accessible to serum albumin, whereas LacCer and Ga2Cer were protected. From this and from the results obtained after protease treatment, and after interfering with UDP-Gal import into the Golgi, we conclude that (a) GlcCer and NFA-GaICer are synthesized in the cytosolic leaflet, while LacCer and GaECer are synthesized in the lumenal leaflet of the Golgi. (b) HFA-GalCer is synthesized in the lumenal leaflet of the ER, but has rapid access to the cytosolic leaflet. (c) GlcCer, NFA-GaICer, and HFA-GaICer translocate from the cytosolic to the lumenal leaflet of the Golgi membrane. The transbilayer movement of GlcCer and NFA-GalCer in the Golgi complex is an absolute requirement for higher glycosphingolipid biosynthesis and for the cell surface expression of these monohexosyl sphingolipids.LYCOSPHINGOLIPIDS are universal membrane components of eukaryotic cells. They are enriched at the cell surface and in the lumen of endosomes and lysosomes (60). At the cell surface the glycosphingolipids not only exert functions in cell-cell interaction, cell-substrate interaction, and signal transduction, but are also used as receptors by bacteria, bacterial toxins, and viruses. Glycosphingolipids are a relatively minor constituent of most membranes, but a major component of myelin and of the apical plasma membrane of the polarized epithelial cells that line the gastrointestinal and urinary tract. In the latter tissues, glycosphingolipids play a structural role in rigidifying and protecting the cell surface. The apical plasma membrane of polarized epithelial cells is enriched in glycosphingolipids relative to the basolateral plasma membrane which contains less glycosphingolipids Please address all correspondence to K. Burger, Department of Cell Biology, Universiteit Utrecht, AZU H02.314, 3584 CX Utrecht, The Netherlands, Tel: 31 30 2506480. Fax: 31 30 2541797. E-mail: K.N.J.Burger @med.ruu.nl but more of the phospholipid phosphatidylcholine and the (sphingo)phospholipid sphingomyelin (SM). t Studies using epithelial cells in culture indicate that glycosphingolipids and phospholipids are sorted intracellularly before reaching the cell surface. Moreover, glycosphingolipids are thought to play a key role ...

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Section: • Sphingolipid Galactosylation In Hepg2 and M D C K H Cellsmentioning

confidence: 99%

Topology of sphingolipid galactosyltransferases in ER and Golgi: transbilayer movement of monohexosyl sphingolipids is required for higher glycosphingolipid biosynthesis.

Burger

Bijl

Meer

1996

The Journal of Cell Biology

102

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“…The buildup of undegraded heparan gag in the brain cells of affected MPS children results in a progressive neurological deterioration. One approach is substrate deprivation therapy (SDT), which acts by inhibiting the synthesis of the substrate for the missing enzyme [59]. Unfortunately chemical SDT agents tested reduce the synthesis of all gag type.…”

Section: The Spectrum Of the Use Of Rnai In Vari-ous Diseasesmentioning

confidence: 99%

RNAi in Clinical Studies

Kubowicz¹,

Zelaszczyk²,

Pekala³

2013

CMC

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RNA interference (RNAi) is an efficient process of posttranscriptional gene silencing. In recent years it has been developed into a new technology in biopharmaceutical fields of science. RNAi products include short interference RNA (siRNA) but also short hairpin RNA (shRNA), bifunctional short hairpin RNA (bi-shRNA) and microRNA (miRNA). They combine with homologous fragments of the mRNA and cause its degradation. It results in inhibition of protein synthesis, or in mutation in the gene encoding it. RNAi has been used in analysis of genomes and creation of new animal models to test drugs. From the pharmaceutical point of view, what is the most important is its therapeutic application. So far the basic and clinical research has been focused on the following targets: macular degeneration, cancer and antiviral therapy. But there are also reports on clinical trials in asthma, hypercholesterolemia and genetic diseases such as inherited skin disorders and amyloidosis. Among over 20 therapeutics that reached clinical trials, only few are still investigated. Another few are clinical candidates. The review focuses on RNAi products under clinical evaluation and their most promising new applications.

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“…Both compounds contain phenyl N-acyl groups and a morpholine ring, which might mimic ceramide fatty acid chains and the charged transition state of the enzyme/UDP-glucose/ceramide complex, respectively. PDMP is a reversible, mixed-type inhibitor for ceramide: it has an inhibitory constant (K i ) of 0.7 mM, but is uncompetitive for the nucleotide sugar donor (Inokuchi & Radin 1987). More recently, a new generation of PDMP analogues have been synthesized by Lee et al (1999), which are well tolerated in the short term in mice and are candidates for the treatment of Fabry disease (Abe et al 2000).…”

Section: Inhibitors Of Glycosphingolipid Biosynthesismentioning

confidence: 99%

Substrate reduction therapy in mouse models of the glycosphingolipidoses

Platt

Jeyakumar

Andersson

et al. 2003

Phil. Trans. R. Soc. Lond. B

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Substrate reduction therapy uses small molecules to slow the rate of glycolipid biosynthesis. One of these drugs, N-butyldeoxynojirimycin (NB-DNJ), shows efficacy in mouse models of Tay-Sachs, Sandhoff and Fabry diseases. This offers the prospect that NB-DNJ may be of therapeutic benefit, at least in the juvenile and adult onset variants of these disorders. The infantile onset variants will require an additional enzyme-augmenting modality if the pathology is to be significantly improved. A second drug, N-butyldeoxyglactonojirimycin, looks very promising for treating storage diseases with neurological involvement as high systemic dosing is achievable without any side-effects.

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Preparation of the active isomer of 1-phenyl-2-decanoylamino-3-morpholino-1-propanol, inhibitor of murine glucocerebroside synthetase

Cited by 239 publications

References 11 publications

Topology of sphingolipid galactosyltransferases in ER and Golgi: transbilayer movement of monohexosyl sphingolipids is required for higher glycosphingolipid biosynthesis.

Topology of sphingolipid galactosyltransferases in ER and Golgi: transbilayer movement of monohexosyl sphingolipids is required for higher glycosphingolipid biosynthesis.

RNAi in Clinical Studies

Substrate reduction therapy in mouse models of the glycosphingolipidoses

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