In 1967, Scheider and colleagues first reported neutral SMase (N-SMase) activity identified in tissues from Niemann-Pick disease patients (Schneider and Kennedy, 1967); however, it was 20 years until the first N-SMase family members were cloned and identified from Staphylococcus aureus and Bacillus cereus (Coleman et al., 1986; Yamada et al., 1988). Based on homology with the bacterial SMases, the yeast N-SMase homologue, ISC1 was also identified (Sawai et al., 2000). Further, the first mammalian homologues (Fig. 1) nSMase1 (SMPD2) (Tomiuk et al., 1998) and nSMase2 (SMPD3) were identified (Hofmann et al., 2000), again based on homology to the identified bacterial SMases. More recently, the third mammalian isoform nSMase3 (SMPD4) was identified based on sequence obtained from purified bovine SMases (Krut et al., 2006). Finally, very recent studies identified N-SMase homologues in zebrafish cells (Yabu et al., 2008; Yabu et al., 2009). Notably, one of the zebrafish nSMase identified was localized to the mitochondria (Yabu et al., 2008), an important organelle for sphingolipid metabolism (Birbes et al., 2002; Futerman, 2006; Novgorodov and Gudz, 2009). This raises the possibility of additional unidentified
