Research
Sphingolipid complexity
Although the idea that cell membrane lipid bilayers do little more than give shape and form to cells and limit diffusion between cells and their environment is passé, the chemical and structural complexity of lipid bilayers often catches cell and molecular biologists by surprise. Tens of thousands of lipid species exist, and calculations of the potential combinatorial chemical space suggest that many more remain to be identified. Moreover, lipid classes are asymmetrically distributed across the two halves of the bilayer, and there is a remarkable correlation between the properties of the transmembrane domains of proteins and the lipid composition in each half of the bilayer. This unanticipated complexity has changed the face of lipid research and our understanding of the roles that lipids might play in cell biological and biochemical processes. Moreover, lipid complexity also has implications for origin of life (OoL) models, due to the presumed critical roles that lipids play in the OoL via their putative involvement in the formation of the membrane of the first protocell. Clearly, lipid complexity presents many challenges for OoL models, as does the apparent fine-tuning of lipid bilayers. Fine-tuning is a concept first described in cosmology and physics implying that certain parameters of the universe must occur within very stringent limits in order to support life.
In this research area, we work on three major issues: (a) The role of lipids in OoL models; (b) The fine-tuning of lipid bilayers; (c) Phylogeny of proteins and lipids. The latter (c) focuses largely around the ceramide synthases (CerS), an enzyme family that synthesizes ceramides with defined N-acyl chain lengths. Recently, using a combination of AlphaFold2, MPROSS, and molecular dynamics simulations, we have proposed a model demonstrating the substrate access routes of the CerS [Figure 3 from NatCom]. In addition, we are attempting to understand the evolutionary origins of the CerS, including the upstream metabolic pathways that are vital for ceramide synthesis [Anteome fig]. We coined the term ‘anteome’ to explain these pathways and are studying potential mechanisms by which these pathways could have co-evolved
Sphingolipids in human disease
A number of inherited human diseases are associated with defective sphingolipid metabolism, among these is Gaucher disease is a glycosphingolipid storage disease in which the simple glycosphingolipids, glucosylceramide and glucosylsphingosine accumulate intracellularly because of the defective activity of the lysosomal enzyme, acid beta-glucosidase (GCase), encoded by GBA1. We are attempting to delineate pathological pathways in forms of Gaucher disease which have a neurological component, with a view for developing new therapeutic modalities. In addition, heterozygous and homozygous mutations in GBA1 are the highest genetic risk factor for Parkinson’s disease, and we are attempting to determine the mechanistic association between these two apparently disparate diseases.
