Structural highlights
4q6r is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Ligands: | , , , |
| NonStd Res: | |
| Related: | 1hbx, 3mc6 |
| Gene: | KIAA1252, SGPL1 (HUMAN) |
| Activity: | Sphinganine-1-phosphate aldolase, with EC number 4.1.2.27 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[SGPL1_HUMAN] Cleaves phosphorylated sphingoid bases (PSBs), such as sphingosine-1-phosphate, into fatty aldehydes and phosphoethanolamine. Elevates stress-induced ceramide production and apoptosis.[1]
Publication Abstract from PubMed
Sphingosine-1-phosphate (S1P) lyase has recently been implicated as a therapeutic target for the treatment of multiple sclerosis (MS), based on studies in a genetic mouse model. Potent active-site directed inhibitors of the enzyme are not known so far. Here we describe the discovery of (4-benzyl-phthalazin-1-yl)-2-methyl-piperazin-1-yl]-nicotinonitrile 5 in a high-throughput screen using a biochemical assay, and its further optimization. This class of compounds was found to inhibit catalytic activity of S1PL by binding to the active site of the enzyme, as seen in the co-crystal structure of derivative 31 with the homodimeric human S1P lyase. 31 induces profound reduction of peripheral T cell numbers after oral dosage and confers pronounced protection in a rat model of multiple sclerosis. In conclusion, this novel class of direct S1P lyase inhibitors provides excellent tools to further explore the therapeutic potential of T cell-targeted therapies in multiple sclerosis and other autoimmune and inflammatory diseases.
Orally Active 7-Substituted (4-Benzyl-phthalazin-1-yl)-2-methyl-piperazin-1-yl]-nicotinonitriles as Active-site Inhibitors of Sphingosine-1-Phosphate Lyase for the Treatment of Multiple Sclerosis.,Weiler S, Braendlin N, Beerli C, Bergsdorf C, Schubart A, Srinivas H, Oberhauser B, Billich A J Med Chem. 2014 May 8. PMID:24809814[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Reiss U, Oskouian B, Zhou J, Gupta V, Sooriyakumaran P, Kelly S, Wang E, Merrill AH Jr, Saba JD. Sphingosine-phosphate lyase enhances stress-induced ceramide generation and apoptosis. J Biol Chem. 2004 Jan 9;279(2):1281-90. Epub 2003 Oct 21. PMID:14570870 doi:http://dx.doi.org/10.1074/jbc.M309646200
- ↑ Weiler S, Braendlin N, Beerli C, Bergsdorf C, Schubart A, Srinivas H, Oberhauser B, Billich A. Orally Active 7-Substituted (4-Benzyl-phthalazin-1-yl)-2-methyl-piperazin-1-yl]-nicotinonitriles as Active-site Inhibitors of Sphingosine-1-Phosphate Lyase for the Treatment of Multiple Sclerosis. J Med Chem. 2014 May 8. PMID:24809814 doi:http://dx.doi.org/10.1021/jm500338n
