Formation of ceramide in mammalian cells. Many stress stimuli, including anticancer drugs, γ-radiation, ultraviolet, cytokines, and growth factor withdrawal, activate sphingomyelinases, which remove the head group from the membrane phospholipid sphingomyelin, forming ceramide. An opposing reaction, catalyzed by sphingomyelin synthase, occurs when phosphocholine is transferred from phosphatidylcholine to the primary hydroxyl of ceramide, producing sphingomyelin and diacylglycerol. In addition, ceramide can be produced through a de novo biosynthetic pathway, described in the text. Sphingosine is not produced by the de novo pathway and can only be formed by deacylation of ceramide catalyzed by ceramidases.