BSB Seminar Series: Chemical Biology of Sphingolipids – From Live-Cell Assays to Lipid Library Development

ABSTRACT
Sphingolipids constitute an important class of lipids found in all eukaryotes. In addition to their essential structural roles in cellular membranes, sphingolipids act as signalling molecules and regulate a wide range of cellular processes. Their biological functions are intimately linked to their membrane topology and subcellular distribution, making it essential to study sphingolipid metabolism, transport, and signalling in the context of living cells.

To address this challenge, we have developed a range of FRET- and BRET-based assays that enable the investigation of sphingolipid metabolism and transport in living cells. These approaches provide a means to monitor sphingolipid-dependent processes in their native cellular environment and offer opportunities for the identification and characterization of chemical modulators.

To validate these assays and to enable the discovery of first-in-class inhibitors, we have initiated the development of a diverse library of sphingolipid analogues using complementary synthetic strategies. The library encompasses analogues of sphingosine, ceramide, and glycosphingolipids, designed to probe different aspects of sphingolipid biology while providing chemical starting points for modulator discovery. These compounds are being used to develop inhibitors of sphingolipid metabolism and transport, as well as novel anti-infective agents.

Together, the combination of live-cell biosensors and chemical sphingolipid libraries provides a versatile chemical biology platform for dissecting sphingolipid function and for discovering new pharmacological tools and therapeutic leads.

References: 
1) T. Pinkert, D. Furkert, T. Korte, A. Herrmann, C. Arenz* "Lipid-Water Partition-Amplified FRET Probe for Life-Cell Detection of Acid Sphingomyelinase" Angew. Chem. 2017, 129, 2834–2838. 

2) Z. Mohamed, C. Rhein, E. M. Saied, J. Kornhuber, C. Arenz* “FRET probes for measuring sphingolipid metabolizing enzyme activity” Chem Phys Lipids 2018, 216, 152-161.

3) C. Kappe, Z. H. Mohamed, E. Naser, A. Carpinteiro, C. Arenz* "A novel visible range FRET probe for monitoring acid sphingomyelinase activity in living cells" Chemistry2020, 26, 5780-5783. 

4) D. Samaha, H.H. Hamdo, X. Cong, F. Schumacher, S. Banhart, Ö. Aglar, H. M. Möller, D. Heuer, B. Kleuser, E. M. Saied* and C. Arenz* A liposomal FRET assay identifies potent drug-like inhibitors of the ceramide transport protein CERT” Chemistry 2020, 26, 16616-16621.

5) M.-A. Kirmpaki, E.M. Saied, F. Schumacher, K. Prause, B. Kleuser and C. Arenz* "Live-Cell Identification of Inhibitors of the Lipid Transfer Protein CERT Using Nanoluciferase Bioluminescence Resonance Energy Transfer (NanoBRET)"   Angew. Chem. Int. Ed. 2024, doi/10.1002/anie. 202413562.   

BIOGRAPHY
Prof. Dr. Christoph Arenz bridges organic chemistry, molecular biology, biochemistry, and biophysics. He studied chemistry at the University of Bonn and earned his PhD in organic chemistry from the University of Karlsruhe. He subsequently expanded his research focus during a postdoctoral stay in molecular biology at the University of Bonn under Konrad Sandhoff. In 2005, he was appointed Assistant Professor at Humboldt University of Berlin, where he has been a Full Professor of Organic Chemistry since 2012. His research combines synthetic organic chemistry with life sciences approaches, leading to more than 115 peer-reviewed publications in leading journals such as Nature, Nature Communications, Angewandte Chemie, Blood, Cancer Cell, and PNAS. He has received several prestigious awards, including the Helmuth Bredereck Award for Bioorganic Chemistry, a Heisenberg Fellowship from the DFG, and the Mark Kester Award for Translational Science in Sphingolipids. Prof. Arenz maintains strong international collaborations, including ties to India as a visiting faculty member at the University of Delhi (Faculty of Medical Sciences, Institute of Nanomedical Sciences). He is currently a principal investigator in a DAAD-SPARC funded program on molecular medicine of sphingolipids together with Prof. Shailja Singh from JNU Delhi. In addition to his research and teaching, he has served as Director of the Institute for Chemistry at Humboldt University.