Sphingomyelin phosphodiesterase
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| Sphingomyelin Phosphodiesterase
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| Systematic name | Sphingomyelin Phosphodiesterase |
| Other names | Sphingomyelinase |
| EC number | EC 3.1.4.12 |
| CAS number | 9031-54-3 |
| From | PDB 2ddt |
| Disclaimer and references | |
Sphingomyelinase phosphodiesterase or simply Sphingomyelinase (SMase) is a hydrolase enzyme that is involved in sphingolipid metabolism reactions. SMase is a member of the DNase I superfamily of enzymes and is responsible for breaking sphingomyelin (SM) down into phosphocholine and ceramide. The activation of SMase has been suggested as a major route for the production of ceramide in response to cellular stresses. [1]
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[edit] The Sphingomyelinase Family
Currently, five types of SMase have been identified. These are classified according to their cation dependence and pH optima of action and are:
- Lysosomal Acid SMase
- Secreted zinc-dependent Acid SMase
- Magnesium-dependent Neutral SMase
- Magnesium-independent Neutral SMase
- Alkaline SMase
[edit] Active Site
The solving of the crystal structure of the neutral sphingomyelinase from Listeria ivanovii and Bacillus cereus have allowed a fuller understanding of their enzymatic site. The active site of the B cereus SMase is the central cleft and is made up of Asn-16, Glu-53, Asp-195, Asn-197, and His-296, of which only Glu-53, Asp-195, and His-296 are known to be essential for activity. The relative catalytic activities of SMase when metal ions are bound to the active site have been studied for divalent metal ions Co2+, Mn2+, Mg2+, Ca2+, and Sr2+. Of these five metal ions, Co2+, Mn2+, and Mg2+ bound to the active site result in high catalytic activity of SMase. Ca2+ and Sr2+ bound to the active site exhibit much lower catalytic activity of SMase. When one Mg2+ ion or two Co2+ ions bind to the active site, double hexa-coordinated geometry results with two octahedral bi-pyramids for Co2+ and one octahedral bi-pyramid for Mg2+. When one Ca2+ ion binds to the active site, a hepta-coordinated geometry results. Therefore, the difference in catalytic activity for metal ions is predicted to be due to geometrical differences. Of Co2+ and Mg2+, SMase has better reactivity when two Co2+ ions are bound to SMase; when these Co2+ ions are bound, Glu-53 and His-296 each bind one divalent metal cation. These cations are surrounded by bridged water molecules and function as Lewis acids[2].
[edit] Mechanism
The solving of the crystal structure of the neutral sphingomyelinase from Listeria ivanovii and Bacillus cereus has also shed light on their catalytic mechanisms. The active site of SMase contains Glu and His residues that are each bound to one or two divalent metal cations, usually Co2+, Mg2+, or Ca2+ for optimum performance. These two cations assist in catalysis by recruiting SM to the active site of SMase. The divalent cation bound to the Glu residue interacts with the amido-oxygen and ester-oxygen between C1 and the phosphate group of SM; an Asn residue and the divalent metal cation bound to the His residue bind to the oxygen atoms of the phosphate group of SM. This stabilizes the phosphate group’s negative charge. The metal cation bound to the His residue and Asp and Asn side chains lower the pKa value of one of the bridged water molecules, thus activating a water molecule. This water molecule then acts as a nucleophile and attacks the phosphate group of SM, creating a pentavalent phosphorus atom whose negative charge is stabilized by the divalent metal cations. The phosphate then reforms its tetrahedral conformation and results in the products ceramide and phosphocholine[2]. However, it is currently not clear if the mechanism of action of the acidic sphingomyelinase is the same, owing to the lack of a crystal structure.
[edit] References
- ^ Hannun, Y.A. and Obeid, L.M. (2002). "The Ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind.". J. Biol. Chem. 277 (9): 25847-50. PMID 12011103.
- ^ a b Ago H, Oda M, Takahashi M, et al (2006). "Structural basis of the sphingomyelin phosphodiesterase activity in neutral sphingomyelinase from Bacillus cereus". J. Biol. Chem. 281 (23): 16157–67. doi:. PMID 16595670.
