The Sphinx and the egg: Evolutionary enigmas of the (glyco)sphingolipid biosynthetic pathway

In eukaryotes, the de novo synthesis of sphingolipids (SLs) consists of multiple sequential steps which are compartmentalized between the endoplasmic reticulum and the Golgi apparatus. Studies over many decades have identified the enzymes in the pathway, their localization, topology and an array of regulatory mechanisms. However, little is known about the evolutionary forces that underly the generation of this complex pathway or of its anteome, i.e., the metabolic pathways that converge on the SL biosynthetic pathway and are essential for its activity. After briefly describing the pathway, we discuss the mechanisms by which the enzymes of the SL biosynthetic pathway are targeted to their different subcellular locations, how the pathway per se may have evolved, including its compartmentalization, and the relationship of the pathway to eukaryogenesis. We discuss the circular interdependence of the evolution of the SL pathway, and comment on whether current Darwinian evolutionary models are able to provide genuine mechanistic insight into how the pathway came into being. [Display omitted] •(Glyco)sphingolipid biosynthesis requires multiple enzymes and transporters.•Biosynthesis is compartmentalized between the endoplasmic reticulum and the Golgi.•Mutational trajectories are lacking for most proteins in the pathway.•Little is known about how the pathway evolved in relation to eukaryogenesis.•We discuss whether Darwinian mechanisms can explain the development of the pathway.