Sphingosine kinase

Structure Highlights

Ligand Key: SQS: Sphingosine, EDO: 1,2-ETHANEDIOL, SO4: SULFATE ION

Structure Overview

The Sphingosine Kinase Type 1 (SphK1) structure reveals a two domain alpha-beta architecture. ^[1] The (used in converting sphingosine to S1P-see below in "Sphingolipids" section for more details) is in a hydrophobic cleft, located between the two domains. ^[1] This hydrophobic cleft is an ideal binding pocket for a hydrophobic lipid, like (an 18-carbon amino alcohol with an unsaturated hydrocarbon chain). ^[1]

SphKs are Evolutionarily Conserved

Sphingolipids

Sphingolipids are a class of lipids, containing a sphingosine base moiety, essential for eukaryotic cell membrane structure and function. ^[2] Importantly, sphingolipids can additionally act as critical signaling molecules used in many eukaryotic homeostatic cellular processes, such as inflammation, proliferation, apoptosis, cell migration, and pathogen defense. ^[2] Because of this, it is critical for sphingolipids and their metabolizing enzymes to exist in a delicate homeostatic balance within the eukaryotic cell system.

Sphingosine-1-Phosphate (S1P), a lipid within the sphingolipid class, is an important signaling molecule that can participate in intracellular and extracellular signaling. ^{[2] [3]} If meant to be an intracellular signaling molecule, S1P is important for cell survival, growth, and overall cell function.^[3] Alternatively, if S1P is meant to be an extracellular signaling molecule, later binding to one of five different S1P G-Protein Coupled Receptors on the same or different cell type, it is used to activate many signaling cascades important for cell response. ^[3] One important function of S1P, whether its fate serves intracellularly or extracellularly, is eliciting the immune response (i.e. lymphocyte trafficking), especially as a mechanism in pathogen defense. ^[3]

Sphingosine Kinase (SphK1 and SphK2)

Sphingosine Kinase, existing in two isoenzyme forms, SphK1 and SphK2, creates S1P via the phosphorylation of sphingosine, the base moiety of all sphingolipids. ^[3] This enzymatic reaction is catalyzed via an ATP-dependent phosphorylation event on sphingosine's hydroxyl group.^[1] Sphingosine Kinase is a key enzyme controlling the levels of S1P within the eukaryotic cell, and thus, is an important regulator of diverse cellular functions. ^[1] There are two isoforms of sphingosine kinase, SphK1 and SphK2. ^[4] These isoforms are tissue specific. SphK1 is prevalent in the lung and spleen, whereas SphK2 is prevalent in the liver and heart. ^[3]

Typically sphingolipid metabolizing enzymes are located along the Endoplasmic Reticulum (ER). ^[3] Here, SphK2 has 4 transmembrane domains and is located within the membrane of the ER.^[3] SphK1 has no transmembrane domains (being located within the cytoplasm close to the ER organelle). ^[3] Although SphK1 and SphK2 are similar in function, they are diverse in the localization within the eukaryotic cell with differing kinetic properties (kinetic regulation differences). ^[3]

Relevance

References

1. ↑ ^{1.0 1.1 1.2 1.3 1.4} Wang Z, Min X, Xiao SH, Johnstone S, Romanow W, Meininger D, Xu H, Liu J, Dai J, An S, Thibault S, Walker N. Molecular Basis of Sphingosine Kinase 1 Substrate Recognition and Catalysis. Structure. 2013 Apr 16. pii: S0969-2126(13)00086-5. doi:, 10.1016/j.str.2013.02.025. PMID:23602659 doi:http://dx.doi.org/10.1016/j.str.2013.02.025
2. ↑ ^{2.0 2.1 2.2} Futerman AH, Hannun YA. The complex life of simple sphingolipids. EMBO Rep. 2004 Aug;5(8):777-82. doi: 10.1038/sj.embor.7400208. PMID:15289826 doi:http://dx.doi.org/10.1038/sj.embor.7400208
3. ↑ ^{3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9} Spiegel S, Milstien S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol. 2003 May;4(5):397-407. doi: 10.1038/nrm1103. PMID:12728273 doi:http://dx.doi.org/10.1038/nrm1103
4. ↑ Futerman AH, Hannun YA. The complex life of simple sphingolipids. EMBO Rep. 2004 Aug;5(8):777-82. doi: 10.1038/sj.embor.7400208. PMID:15289826 doi:http://dx.doi.org/10.1038/sj.embor.7400208