Weizmann Institute scientists pursue evolution of sphingolipids, implications for Darwinian theory

Sphingolipids are a type of fatty material (lipids) in cell membranes that are critical for membrane structure and cell signaling. When they malfunction, sphingolipids can cause human illnesses, such as Gaucher disease, a rare inherited metabolic disorder. 

In a recent article, a team of researchers in the Department of Biomolecular Sciences at the Weizmann Institute of Science in Israel examined how four enzymes that generate sphingolipids and their precursor metabolic pathways might have evolved.

The researchers conclude that current models for the origin of life fail to provide evidence for the evolution of these metabolic pathways, which are necessary for sphingolipid synthesis.

The research article, by Tania Santos, Tamir Dingjan and Anthony Futerman, was published in the July 22 FEBS Letters, the online journal of the Federation of European Biochemical Societies.

Futerman, the Joseph Meyerhoff Professor of Biochemistry at the Weizmann Institute, heads a lab that investigates how sphingolipids work, their complexity and their role in rare human diseases, including Niemann-Pick disease, Fabry disease, Krabbe disease, Gaucher disease, Tay–Sachs disease, and metachromatic leukodystrophy. The lab also focuses on potential therapeutic pathways for treating sphingolipid diseases. 

"In addition to these disorders," Futerman said, "sphingolipids are involved in various other diseases such as diabetes, coronary artery disease and cancer, meaning that many laboratories are trying to work the details of how they are made.

What are sphingolipids?

Sphingolipids were first identified in the 1870s by the German-born physician and biochemist John Louis William Thudicum. Thudicum emigrated to the United Kingdom in 1853, where he pioneered advances in biochemistry and biomedical research. The functions of these lipids puzzled Thudicum and so he named sphingolipids after the Greek mythological creature sphinx, a woman with a lion's body and eagle wings, who gobbled up those who failed to solve the riddles she posed.

Advances in mass spectrometry have made it possible to observe the complexity of lipids in cell membranes, and there are many more complex lipids than previously thought. The authors note that about 5,000 different sphingolipids have been identified, and there are dozens of enzymes involved in their metabolism. Computer calculations suggest that as many as 40,000 sphingolipids may exist. 

Futerman says that "this complexity was totally unexpected, even as short a time as 20 years ago. This of course raises the question of what they all do and whether each specific sphingolipid has a specific function in life."

The four main enzymes that generate sphingolipids are serine palmitoyltransferase, 3-ketodihydrosphingosine reductase, ceramide synthase and dihydroceramide Δ4-desaturase 1. The researchers investigated how these enzymes themselves may have evolved and combined to allow the synthesis of sphingolipids.

They propose a new concept, the anteome, to describe these precursory metabolic pathways. The word comes from the Latin prefix ante, meaning before, and metabolome, which means the total number of metabolites in an organism, cell, or tissue.

"We came up with the term anteome to indicate that understanding the sphingolipid metabolic pathway itself is not sufficient to understand how this pathway is regulated," Futerman said. "Many other pathways, i.e. the anteome, provide vital components needed for the function of the sphingolipid pathway. This of course presents a huge challenge for evolutionary mechanisms, as it implies that all these pathways need to evolve simultaneously." 

Sphingolipid origin

The researchers identify the first five carbon atoms of the sphingoid base, an amino alcohol with two carbon chains, as the "sphingoid motif." The hydrogen bonds in the sphingoid motif play an important role in determining the membrane structure and cell function and other sphingolipid interactions with the rest of the cell membrane.

"The exquisite chemistry of this motif also has implications for evolutionary biology as even the smallest change in the structure would have a significant effect on sphingolipid function," the researchers wrote.

The researchers consider each of the enzymes involved in forming sphingolipids and suggest possible pathways for their sphingolipid biosynthesis. In particular they focus on possible evolutionary scenarios for the enzyme serine palmitoyltransferase (SPT). They also examined how SPT was modified after it emerges de novo to acquire its specialized functions. 

The authors provide a systematic guide to a de novo biosynthetic pathway of each of the four enzymes, a kind of road map that looks at possibilities and branch points in the evolution of each enzyme. They also examined different models proposed for enzyme evolution, including co-evolution of the biosynthetic pathway and its anteome and possibilities for merging.

They conclude, however, that it is extremely difficult to envisage how these pathways arose via classical Darwinian evolutionary pathways by random and gradual processes. Darwin’s ideas were largely based on morphological observations and not on the complexities of modern biochemistry known today, they emphasize.

Future research

The researchers note that systematic lipidomic studies of prokaryotes could help delineate the origin of sphingolipids, stating "This is of course a laborious and herculean effort, but it might be the best way to start to understand the origin of biological complexity and the contribution of Darwinian processes."

"Whether Darwinian pathways have the explanatory power to explain the emergence of this complexity is an open question," Futerman said. "But the onus is on the school of Darwin to provide detailed mechanistic understanding of how such pathways might have evolved."

The authors provide a list of several research approaches that could test some of the evolutionary models the authors mention.

The article concludes, "We would like to suggest that many more experiments and conceptual advances are required to allow definitive conclusions to be drawn about whether current Darwinian hypotheses can explain the emergence and development of the SL [sphingolipid] de novo biosynthetic pathway along with its anteome."

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Tania Santos et al., "The sphingolipid anteome: Implications for evolution of the sphingolipid metabolic pathway." FEBS Letters, July 27, 2022.

https://doi.org/10.1002/1873-3468.14457