Sphingosine inhibition of protein kinase C activity and of phorbol dibutyrate binding in vitro and in human platelets

Inhibition of sphingolipid biosynthesis by fumonisins. Implications for diseases associated with Fusarium moniliforme.

Ceramide in apoptosis: an overview and current perspectives.

Much has been made about J. L. W. Thudichum’s colorful, and one could say clairvoyant, naming of sphingosine “in commemoration of the many enigmas which it presented to the inquirer” in his 1884 treatise The Chemistry of the Brain(1) because many of the riddles of sphingolipids (as the broader field was later named)(2) remained unanswered for the following century. This changed radically over the past several decades as researchers explored, and ultimately established, what seemed at the time to be radical concepts: that sphingolipids are not just structural elements of cells but also participate in intra- and extracellular signaling; that not only the complex glycan headgroups, but also the lipid backbones, are highly specified metabolically and have selective biochemical functions; and that even the longest known function of these lipids, as structural components of the “fluid mosaic” of cell membrane lipids, is not so simple, and often involves the dynamic clustering of sphingolipids in nontraditional microdomains referred to as rafts. We still know only a fraction of their secrets, but this enlightenment has defined models for thinking about these compounds that remove them from their enigmatic “black box.”

Now, a major challenge is to keep up with the rapid growth in knowledge about the sphingolipidome, that is, the ensemble of all sphingolipids.(3) A major goal of the review is to help the reader more easily grasp the metabolic interrelationships that account for the tens of thousands of molecular subspecies (and perhaps more) that appear in nature, with a focus on mammals. The magnitude of this subject precludes the inclusion of all of the enzymes and metabolites, and the author apologizes for the omission of many interesting topics. To put this information in context, there is a brief background discussion of their structures and functions, which have been dealt with also in a recent Chemical Reviews article(4) on the chemicophysical features of sphingolipids and raft formation, and by excellent reviews on sphingolipid signaling5,6 and the biological functions of complex glycosphingolipids.7−10

Sphingolipid and Glycosphingolipid Metabolic Pathways in the Era of Sphingolipidomics

Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism.

Enzymology of long-chain base synthesis by liver: Characterization of serine palmitoyltransferase in rat liver microsomes

Activities of serine palmitoyltransferase (3-ketosphinganine synthase) in microsomes from different rat tissues.

Utilization of different fatty acyl-CoA thioesters by serine palmitoyltransferase from rat brain.

Serine palmitoyltransferase (EC 2.3.1.50) catalyzes an initial and regulatory reaction of sphingolipid biosynthesis, the formation of a homologue of 3-ketosphinganine from l-serine and a fatty acyl coenzyme A thioester. We have demonstrated that this enzyme exists in microsomes from Morris hepatoma 7777 and, moreover, found that its specific activity was 199 ± 23 pmol/min/mg of microsomal protein, which was significantly higher than that for microsomes from host (69 ± 4.2 pmol/min/mg; S.D.) or control (43 ± 4.1 pmol/min/mg) rat livers when assayed under optimal conditions. The activities varied with tumor weight. For comparison, the activities of microsomes from regenerating liver were also higher; whereas fetal and neonatal rat livers had substantially lower activities. Assays conducted without added pyridoxal 5′-phosphate revealed that the enzyme in microsomes isolated from the tumor was more readily depleted of this cofactor than was that in control microsomes; this phenomenon was most pronounced with the larger tumors. The other properties of the enzyme resembled those for liver.

On the basis of these experiments, we propose that the elevated proportions of sphingomyelin and other sphingolipids found in hepatomas and regenerating rat liver are related to increases in long-chain base synthesis by serine palmitoyltransferase. Since the activity is apparently more sensitive to the availability of pyridoxal 5′-phosphate in the hepatoma, this reaction could become limiting under more severe vitamin B6 deficiencies.

https://cancerres.aacrjournals.org/content/canres/44/5/1918.full.pdf

Robert D. Williams

Papers

Enzymology of long-chain base synthesis by liver: Characterization of serine palmitoyltransferase in rat liver microsomes

Activities of serine palmitoyltransferase (3-ketosphinganine synthase) in microsomes from different rat tissues.

Utilization of different fatty acyl-CoA thioesters by serine palmitoyltransferase from rat brain.

Comparison of Serine Palmitoyltransferase in Morris Hepatoma 7777 and Rat Liver

Inhibition of serine palmitoyltransferase activity in rabbit aorta by L-cycloserine.