It is now appreciated that sphingolipids constitute a rich class of bioactive molecules that include ceramide, sphingosine, and sphingosine 1‐phosphate whose formation is controlled by a network of highly regulated enzymes (Hannun & Obeid, 2008). Notably, several stress stimuli induce the production of ceramide, which, as a single entity, has been traditionally associated with apoptotic and gro...

A 5-month-old Hereford calf with neurologic disease was euthanatized, and a necropsy was done. No gross lesions were seen in the brain. Microscopically, neurons throughout the brain and spinal cord had distended, foamy vacuolated cytoplasm. Ultrastructure showed clear vacuoles filling the neuronal cytoplasm. A lysosomal storage disease was suspected. Sphingomyelinase deficiency was confirmed by...

We performed experiments to screen for neutral sphingomyelinase inhibitors using rat brain microsomes as an enzyme source. Among more than 10,000 microbial extracts tested, a mycelial extract of Trichopeziza mollissima SANK 13892 exhibited potent inhibitory activity. The active compound, scyphostatin, was purified by a series of chromatographies. Scyphostatin inhibited the enzyme with an IC50 v...

Acid sphingomyelinase (ASMase, ASM, SMPD1) converts sphingomyelin into ceramide, modulating membrane properties and signal transduction. Inactivating mutations in ASMase cause Niemann-Pick disease, and its inhibition is also beneficial in models of depression and cancer. To gain a better understanding of this critical therapeutic target, we determined crystal structures of mammalian ASMase in v...