The sphingolipid anteome

Advances in mass spectrometry have led to the realization that the number and combinatorial complexity of lipids, including sphingolipids, is much greater than previously appreciated. Sphingolipids are generated de novo by four enzymes, namely serine palmitoyltransferase, 3-ketodihydrosphingosine reductase, ceramide synthase, and dihydroceramide D4-desaturase 1. Some of these enzymes depend on the availability of specific substrates and cofactors, which are themselves supplied by other complex metabolic pathways. The evolution of these four enzymes is poorly understood and likely depends on the co-evolution of the metabolic pathways that supply the other essential reaction components. Recently, we introduced the concept of the ‘anteome’, from the Latin ante (‘before’) to describe the network of metabolic (‘omic’) pathways that must have converged in order for these pathways to co-evolve and permit sphingolipid synthesis. We have also discussed whether current origin of life and evolutionary models have appropriate experimental support to explain the appearance of this complex metabolic pathway and its anteome. Moreover, a basic component of the Modern Synthesis (which includes Darwinian natural selection, Mendelian inheritance, molecular genetics, and population genetics) is gradual genetic variation by random mutation, with natural selection the mechanism by which mutations become fixed in the population. The evolutionary history of a given gene or pathway can therefore be described as a series of genetic changes, such as mutations, gene duplications, and other forms of genetic variation. We propose, and are currently studying, whether it is possible to construct realistic mutational trajectories of each of the proteins in the pathway, beginning in bacteria or archaea, in a logical order of emergence, with attempts made to integrate the occurrence of such mutations with the development of the anteome. We are aware that this is a significant undertaking, but in the absence of such trajectories, evolutionary biology is consigned to hand-waving and generalities. 

The anteome of the SL biosynthetic pathway in the ER and Golgi apparatus. The pathway for SL biosynthesis in the ER and Golgi apparatus make use of substrates which are themselves generated by a network of metabolic processes, enzymes, substrates, and transporters. Metabolites sourced from dietary intake (i.e., nicotinamide/NAM, pyridoxal phosphate/PLP, pantothenate, fatty acids, choline, and glucose), and vital to nucleotide synthesis (i.e., phosphoribosyl pyrophosphate/PRPP) are indicated in green italics. Metabolites and substrates which are directly involved in GSL biosynthesis in the ER and Golgi apparatus are shown in red. Dashed arrows indicate multiple reaction steps between metabolites, solid arrows indicate single enzymatic reactions. Note that for the purposes of clarity, the phosphatidylinositol phosphate phosphatase enzymes are not shown and likewise the sub compartments of the Golgi apparatus are not indicated.

Figure taken from: Biran A., et al. The Sphinx and the egg: Evolutionary enigmas of the (glyco)sphingolipid biosynthetic pathway. Biochimica et Biophysica Acta (BBA) – Molecular and Cell Biology of Lipids, 1869 (2024). https://doi.org/10.1016/j.bbalip.2024.159462