Abstract
The experimental approach to deplete cellular glycosphingolipids (GSLs) with the specific inhibitors of glycosphingolipid biosynthesis has the potential to identify functions of endogenous GSLs. Most GSLs are derived from glucosylceramide (GlcCer). D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) inhibits GIcCer synthase and has been used extensively to study the biological functions of living cells. D-PDMP inhibits mTORC1 activity, which is independent of its inhibitory activity on GlcCer synthase. We also developed an analog of D-PDMP, D-threo-1-phenyl-2-benzyloxycarbonylamino-3-pyrrolidino-1-propanol (D-PBPP) lacking the effect on mTORC1. Here, we summarize the effects of D-PDMP and D-PBPP on the metabolism of GSLs and cell growth.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Inokuchi J, Radin NS (1987) Preparation of the active isomer of 1-phenyl-2-decanoylamino-3-morpholino-1-propanol, inhibitor of murine glucocerebroside synthetase. J Lipid Res 28(5):565–571
Inokuchi J, Momosaki K, Shimeno H, Nagamatsu A, Radin NS (1989) Effects of D-threo-PDMP, an inhibitor of glucosylceramide synthetase, on expression of cell surface glycolipid antigen and binding to adhesive proteins by B16 melanoma cells. J Cell Physiol 141(3):573–583. https://doi.org/10.1002/jcp.1041410316
Inokuchi J, Jimbo M, Momosaki K, Shimeno H, Nagamatsu A, Radin NS (1990) Inhibition of experimental metastasis of murine Lewis lung carcinoma by an inhibitor of glucosylceramide synthase and its possible mechanism of action. Cancer Res 50(20):6731–6737
Radin NS, Inokuchi J (1991) Roles of glycosphingolipids revealed by D-PDMP, an inhibitor of glucosylceramide synthase. Trends Glycosci Glycotechnol 9:S37–S45
Chatterjee S, Bedja D, Mishra S, Amuzie C, Avolio A, Kass DA, Berkowitz D, Renehan M (2014) Inhibition of glycosphingolipid synthesis ameliorates atherosclerosis and arterial stiffness in apolipoprotein E−/− mice and rabbits fed a high-fat and -cholesterol diet. Circulation 129(23):2403–2413. https://doi.org/10.1161/CIRCULATIONAHA.113.007559
Mishra S, Bedja D, Amuzie C, Foss CA, Pomper MG, Bhattacharya R, Yarema KJ, Chatterjee S (2015) Improved intervention of atherosclerosis and cardiac hypertrophy through biodegradable polymer-encapsulated delivery of glycosphingolipid inhibitor. Biomaterials 64:125–135. https://doi.org/10.1016/j.biomaterials.2015.06.001
Rosenwald AG, Pagano RE (1994) Effects of the glucosphingolipid synthesis inhibitor, PDMP, on lysosomes in cultured cells. J Lipid Res 35(7):1232–1240
Makino A, Ishii K, Murate M, Hayakawa T, Suzuki Y, Suzuki M, Ito K, Fujisawa T, Matsuo H, Ishitsuka R, Kobayashi T (2006) D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol alters cellular cholesterol homeostasis by modulating the endosome lipid domains. Biochemistry 45(14):4530–4541. https://doi.org/10.1021/bi052104y
Sprocati T, Ronchi P, Raimondi A, Francolini M, Borgese N (2006) Dynamic and reversible restructuring of the ER induced by PDMP in cultured cells. J Cell Sci 119(Pt 15):3249–3260. https://doi.org/10.1242/jcs.03058
Ode T, Podyma-Inoue KA, Terasawa K, Inokuchi JI, Kobayashi T, Watabe T, Izumi Y, Hara-Yokoyama M (2017) PDMP, a ceramide analogue, acts as an inhibitor of mTORC1 by inducing its translocation from lysosome to endoplasmic reticulum. Exp Cell Res 350(1):103–114. https://doi.org/10.1016/j.yexcr.2016.11.011
Jimbo M, Yamagishi K, Yamaki T, Nunomura K, Kabayama K, Igarashi Y, Inokuchi JI (2000) Development of a new inhibitor of glucosylceramide synthase. J Biochem 127(3):485–491
Sudo H, Kodama HA, Amagai Y, Yamamoto S, Kasai S (1983) In vitro differentiation and calcification in a new clonal osteogenic cell line derived from newborn mouse calvaria. J Cell Biol 96(1):191–198
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Inokuchi, Ji., Ode, T., Hara-Yokoyama, M. (2018). Pharmacological Modulation of Glycosphingolipid Metabolism. In: Sonnino, S., Prinetti, A. (eds) Gangliosides. Methods in Molecular Biology, vol 1804. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8552-4_19
Download citation
DOI: https://doi.org/10.1007/978-1-4939-8552-4_19
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-8551-7
Online ISBN: 978-1-4939-8552-4
eBook Packages: Springer Protocols