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=Structure and Function= | =Structure and Function= | ||
Recently, in the 1980's, the primary structure of sphingomyelinase was determined by cloning the first N-SMases from ''Bacillus cereus'' and ''Staphylococcus aureus'' and by the subsequent sequencing of their cDNAs <ref name="gp4">PMID: 2127932 </ref>. | Recently, in the 1980's, the primary structure of sphingomyelinase was determined by cloning the first N-SMases from ''Bacillus cereus'' and ''Staphylococcus aureus'' and by the subsequent sequencing of their cDNAs <ref name="gp4">PMID: 2127932 </ref>. | ||
The crystal structure of sphingomyelinase has been solved using ''Listeria ivanovii'' and ''Bacillus cereus(Bc-SMase)'' to gain further insight into its catalytic activities <ref name="gp5">PMID: 16595670 </ref>. | The crystal structure of sphingomyelinase has been solved using ''Listeria ivanovii'' and ''Bacillus cereus(Bc-SMase)'' to gain further insight into its catalytic activities <ref name="gp5">PMID: 16595670 </ref>. THrough SMase structure identification, it has been determined to be a member of the DNA I-like superfamily having geometrically identical amino acid residues as the enzymes in this superfamily. The only different with SMase, is that it has a unique hydrophobic beta-hairpin structure. The crystal structure revealed that this unique beta-hairpin region has two solvent exposed aromatic amino acids on the top which bind to the cell surfaces to catalyze hemolysis. | ||
=Mechanism= | =Mechanism= | ||
Revision as of 22:50, 29 March 2011
| This Sandbox is Reserved from January 10, 2010, through April 10, 2011 for use in BCMB 307-Proteins course taught by Andrea Gorrell at the University of Northern British Columbia, Prince George, BC, Canada. |
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| 2dds, resolution 1.80Å () | |||||||||
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| Ligands: | |||||||||
| Activity: | Sphingomyelin phosphodiesterase, with EC number 3.1.4.12 | ||||||||
| Related: | 2ddr, 2ddt | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB, TOPSAN | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
IntroductionIntroduction
Sphingomyelin phosphodiesterase (Sphingomyelinase): (SMase) is an enzyme which catalyzes the hydrolysis of sphingomyelin to ceramide and phosphocholine [1]. This enzyme has become the object of renewed interest since the discovery of the sphingomyelin signal transduction pathway which is involved in apoptosis. This pathway is initiated by a neutral sphingomyelinase hydrolysis of sphingomyelin in the plasma membrane to generate ceramide. Ceramide acts as a secondary messenger which causes the stimulation of the cascade effect of kinases and transcription factors which activate programmed cell death[2]. There are 6 known types of sphingomyelinases[3]. :
Acid sphingomyelinase (aSMase) -
Secretory sphingomyelinase (sSMase) -
Neutral Mg2+-dependent sphingomyelinases (nSMase) -
Neutral Mg2+-independent sphingomyelinases -
Alkaline sphingomyelinase -
Bacterial sphingomyelinase -
Structure and FunctionStructure and Function
Recently, in the 1980's, the primary structure of sphingomyelinase was determined by cloning the first N-SMases from Bacillus cereus and Staphylococcus aureus and by the subsequent sequencing of their cDNAs [4]. The crystal structure of sphingomyelinase has been solved using Listeria ivanovii and Bacillus cereus(Bc-SMase) to gain further insight into its catalytic activities [5]. THrough SMase structure identification, it has been determined to be a member of the DNA I-like superfamily having geometrically identical amino acid residues as the enzymes in this superfamily. The only different with SMase, is that it has a unique hydrophobic beta-hairpin structure. The crystal structure revealed that this unique beta-hairpin region has two solvent exposed aromatic amino acids on the top which bind to the cell surfaces to catalyze hemolysis.
MechanismMechanism
The mechanism of shingomyelinase catalytic activity is not fully understood in atomic detail because the cystal structures of SMase in complex with the essential divalent metal ions, Co2+, Mn2+, Mg2+, Ca2+, and Sr2+, has not been clarified [5]. It has been proposed that the mechanism is similar to that of bovine pancreatic DNase 1 because Bc-SMase and bovine DNase 1 are homologous proteins which both have conserved alleged catalytic amino acid residues and a similar molecular structure. The proposed hydrolytic activity of Bc-SMAse cloned from Bacillus cereus is an acid-base catalysis, where His296 is thought to generate an activated water. The essential Mg2+ ion at Glu-53 has been proposed to stabilize a negatively chanrge transition state [5].
Importance of SMaseImportance of SMase
ReferencesReferences
- ↑ Ago H, Oda M, Takahashi M, Tsuge H, Ochi S, Katunuma N, Miyano M, Sakurai J. Structural basis of the sphingomyelin phosphodiesterase activity in neutral sphingomyelinase from Bacillus cereus. J Biol Chem. 2006 Jun 9;281(23):16157-67. Epub 2006 Apr 4. PMID:16595670 doi:10.1074/jbc.M601089200
- ↑ Kolesnick RN, Haimovitz-Friedman A, Fuks Z. The sphingomyelin signal transduction pathway mediates apoptosis for tumor necrosis factor, Fas, and ionizing radiation. Biochem Cell Biol. 1994 Nov-Dec;72(11-12):471-4. PMID:7544586
- ↑ Goni FM, Alonso A. Sphingomyelinases: enzymology and membrane activity. FEBS Lett. 2002 Oct 30;531(1):38-46. PMID:12401200
- ↑ Tomita M, Nakai K, Yamada A, Taguchi R, Ikezawa H. Secondary structure of sphingomyelinase from Bacillus cereus. J Biochem. 1990 Nov;108(5):811-5. PMID:2127932
- ↑ 5.0 5.1 5.2 Ago H, Oda M, Takahashi M, Tsuge H, Ochi S, Katunuma N, Miyano M, Sakurai J. Structural basis of the sphingomyelin phosphodiesterase activity in neutral sphingomyelinase from Bacillus cereus. J Biol Chem. 2006 Jun 9;281(23):16157-67. Epub 2006 Apr 4. PMID:16595670 doi:10.1074/jbc.M601089200