Sphingomyelin Phosphodiesterase - Neutral Sphingomyelinase

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. 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. However, a more recent study in bovine brain suggested the existence of multiple N-SMase isoforms with different biochemical and chromatographical properties.

A major breakthrough came in the mid 1980s with the cloning of the first N-SMases from Bacillus cereus and Staphylococcus aureus. 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 and the mammalian N-SMase enzymes, nSMase1 and nSMase2. 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. This has led to the suggestion of a common catalytic mechanism for the N-SMase family.

Interestingly, a third N-SMase protein - termed nSMase3 - was recently cloned and characterized. Surprisingly, 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.