Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities
Intensive research in the field of sphingolipids has revealed diverse roles in cell biological responses and human health and disease. This immense molecular family is primarily represented by the bioactive molecules ceramide, sphingosine, and sphingosine
- PDF / 903,630 Bytes
- 35 Pages / 504.567 x 720 pts Page_size
- 78 Downloads / 199 Views
Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities Victoria A. Blaho
Abstract
6.1
Intensive research in the field of sphingolipids has revealed diverse roles in cell biological responses and human health and disease. This immense molecular family is primarily represented by the bioactive molecules ceramide, sphingosine, and sphingosine 1-phosphate (S1P). The flux of sphingolipid metabolism at both the subcellular and extracellular levels provides multiple opportunities for pharmacological intervention. The caveat is that perturbation of any single node of this highly regulated flux may have effects that propagate throughout the metabolic network in a dramatic and sometimes unexpected manner. Beginning with S1P, the receptors for which have thus far been the most clinically tractable pharmacological targets, this review will describe recent advances in therapeutic modulators targeting sphingolipids, their chaperones, transporters, and metabolic enzymes.
The family of bioactive sphingolipid molecules is immense, but all are characterized by the same core component, the sphingoid backbone, which is simply an amino alcohol with a long carbon chain [1]. The canonical sphingolipid, sphingosine, can be enzymatically modified to add fatty acids, phosphorous-containing head groups (e.g., phosphocholine), sugar moieties, and changes in acyl chain saturation [1–3]. Flux through the sphingolipid pathway has far-ranging effects, from cellular architecture to multi-organ system coordination [4, 5]. The ubiquity of sphingolipids presents both challenges to and opportunities for their manipulation. Unlike other bioactive lipids with proposed shunting to different enzymatic pathways, the flow of sphingolipids rarely has an alternative for degradation or synthesis other than reversal [6–11]. Subsequently, while inhibition of a particular enzyme stops generation of a specific product, the biological outcome could be the result of increased concentrations of upstream precursors and not necessarily the most immediate parent molecule. For instance, a great deal of effort has focused on the inhibition of two enzymes, the sphingosine kinases (Sphk1/2), for the treatment of cancer. Although the desired decrease in product may be achieved, an increase in the parent molecule of the Sphk substrate is commonly credited with affecting the biological outcome.
Keywords
Sphingolipid · S1P · Fingolimod · Siponimod · Ozanimod V. A. Blaho (*) Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA e-mail: [email protected]
Introduction
© Springer Nature Switzerland AG 2020 Y. Kihara (ed.), Druggable Lipid Signaling Pathways, Advances in Experimental Medicine and Biology 1274, https://doi.org/10.1007/978-3-030-50621-6_6
101
102
Like a malfunctioning traffic light, a blockage at one sphingolipid node can often have repercussions throughout the metabolic pathway (Fig. 6.1). This review will present known mechanisms for therapies that target sphingolipid sig
Data Loading...
