Sphingomyelin phosphodiesterase

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Sphingomyelin phosphodiesterase
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Sphingomyelin phosphodiesterase (EC 3.1.4.12, also known as neutral sphingomyelinase, sphingomyelinase, or SMase; systematic name sphingomyelin cholinephosphohydrolase) is a

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.[2]

Sphingomyelinase family

Five types of SMase have been identified. These are classified according to their cation dependence and pH optima of action and are:

Of these, the lysosomal acidic SMase and the magnesium-dependent neutral SMase are considered major candidates for the production of ceramide in the cellular response to stress.

Neutral sphingomyelinase

Neutral sphingomyelinase (N-SMase) activity was first described in fibroblasts from patients with

Niemann-Pick disease – a lysosomal storage disease characterized by deficiencies in acid SMase.[3] Subsequent study found that this enzyme was the product of a distinct gene, had an optimum pH of 7.4, was dependent on Mg2+ ions for activity, and was particularly enriched in brain.[4] However, a more recent study in bovine brain suggested the existence of multiple N-SMase isoforms with different biochemical and chromatographical properties.[5]

A major breakthrough came in the mid-1980s with the cloning of the first N-SMases from Bacillus cereus and Staphylococcus aureus.[6][7] Using the sequences of these bacterial sphingomyelinases in homology searches ultimately led to the identification of the yeast N-SMases ISC1 in the budding yeast Saccharomyces cerevisiae[8] and the mammalian N-SMase enzymes, nSMase1 and nSMase2.[9][10] The identity between mammalian, yeast and bacterial SMases is very low - being approximately 20% between nSMase2 and the B. cereus SMase. However, an alignment of the sequences (see figure) indicate a number of conserved residues throughout the family, particularly in the catalytic region of the enzymes.[11] This has led to the suggestion of a common catalytic mechanism for the N-SMase family.

A third N-SMase protein – termed nSMase3 – was cloned and characterized in 2006.[12] nSMase3 bears little sequence similarity to either nSMase1 or nSMase2. However, there appears to be a high degree of evolutionary conservation from lower to higher organisms, suggesting that it may comprise a unique and distinct N-SMase. The high expression of nSMase3 in heart and skeletal muscle also suggests potential roles in heart function.[13]

Active site

Magnified view of SMase active site with Co2+ ions bound showing residues responsible for divalent metal cation binding. From PDB: 2dds​.

The solving of the crystal structure of the neutral sphingomyelinase from

Lewis acids.[1]

Mechanism

The solving of the crystal structure of the neutral sphingomyelinase from

tetrahedral conformation and results in the products ceramide and phosphocholine.[1] In 2016 a model based on crystal structure of mammalian acid sphingomyelinase study was proposed whereby ASMase exists in equilibrium between open and closed forms of the saposin domain. In the absence of membranes, closed ASMasesap decoupled from ASMasecat would predominate and render the enzyme inactive. In the presence of anionic membranes, open ASMasesap becomes prevalent, docks onto the membrane surface and concomitantly forms an interface with the catalytic domain activating it for sphingomyelin hydrolysis.[14]

References

  1. ^
    PMID 16595670
    .
  2. PMID 12011103
    .
  3. PMID 4962590
    .
  4. PMID 9463
    .
  5. S2CID 46397368
    .
  6. PMID 3334158
    .
  7. PMID 2841128
    .
  8. PMID 11006294
    .
  9. PMID 9520418
    .
  10. PMID 10681556
    .
  11. PMID 16981685
    .
  12. PMID 16517606
    .
  13. PMID 16517606
    .
  14. S2CID 32841772
    .

Further reading

External links

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