Sphingolipids as coenzymes in anion transfer and tumor death.

Many kinds of natural sphingolipids and their analogs stimulate or inhibit a wide assortment of biochemical phenomena and enzymes. The puzzle considered here is: how can these lipids control so many different kinds of processes? In almost every study in which a structural comparison was made, an allylic alcohol moiety [-CH=CH-CH(OH)-] was found to be an essential feature of the sphingolipid. Many of those stimulations lead to cell death, emphasizing the importance of allylic sphingolipid structure in the design of chemotherapeutic agents. The proposal offered here is that these lipids function as coenzymes, in which the allylic moiety acts as an anion transferring agent, forming transient phosphate or acyl or peptidyl esters for the synthesis or hydrolysis of phosphoproteins, proteins, and phospholipids. Sphingolipids that inhibit these reactions may simply displace the active sphingolipids from their sites in the enzymes' active regions, or bind to the enzymes' allosteric region. This kind of competition could act as a major homeostatic control mechanism. Some of the allylic sphingolipids also generate reactive oxygen, possibly by oxidation of the allylic alcohol group. This explains the need to control redox-controlling metabolites in sphingolipid-controlled processes (e.g., glutathione). Many anticancer drugs that produce apoptosis in tumors possess an allylic alcohol residue, affect protein phosphorylation, and produce reactive oxygen species. They may be therapeutically useful because they control the action of sphingolipids as anion transfer agonists or inhibitors.