Overall, the homologies among the different nSMase enzymes are low. However, in all but one (nSMase3), key residues involved in magnesium binding and catalytic activity – the so-called ‘catalytic core’ residues - are strongly conserved (Clarke et al., 2006). Consequently, all the nSMases identified so far are strongly dependent on magnesium (or manganese) for their catalytic activity. This conservation suggests a common catalytic mechanism, and thus, these N-SMases are considered to belong to an extended family. The mammalian N-SMases have been suggested to play major roles in the cellular stress response (Fig. 2) for many years. In contrast, the majority of knowledge about nSMase1, −2 and −3 has been reported relatively recently. Accordingly, here we review current knowledge of the mammalian N-SMase family members. For information on yeast ISC1 and the bacterial SMases, the following recent reviews are suggested (Milhas et al., 2009; Matmati and Hannun, 2008).
