Markus Ralser

Molecular Biology of Metabolism Laboratory

Metabolism has been thought of, for a long time, as a static series of biochemical reactions. Recent research, however, reveals that cellular metabolism indeed is highly dynamic, and is implicated in many biologically important phenomena, such as ageing, cellular robustness and adaptation to ever-changing environments. These properties bring metabolism center-stage both for developing therapies against cancer and neurodegenerative disorders and for understanding the ageing process.

We investigate regulatory functions of the metabolic network and how its dynamics are maintained. A model situation where the metabolome has regulatory function is the adaptation to stress conditions. When cells are exposed to oxidants, when cells age or when a cancer cell starts proliferation, their metabolism changes. We found that under those conditions the metabolic network can reconfigure very quickly, and that metabolism can temporarily adjust without requiring regulation at the transcriptome and proteome layer. There is also evidence that these quick metabolic adjustments can be involved in the induction of transcriptional stress responses.

We address these questions often in the yeast Saccharomyces cerevisiae. Working with this single-cellular eukaryote removes some complexity from our investigations, as a plethora of genetic and biochemical techniques are available. This reduces bias resulting from altered metabolic activity that is found in cell culture systems, allowing us to work with hundreds of mutants in parallel. To study the metabolic network, we use quantitative mass spectrometry coupled to high-pressure and/or nano-flow liquid chromatography for targeted analysis of proteins and small molecules.

Our research team was founded as the 'Molecular Biology of Metabolism group' at the Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics in Berlin in 2007. It then moved to the Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge. The laboratory also has a team based in Dept of Systems Biology Centre, University of Cambridge.

Selected publications

Mülleder, M; Calvani, E; Alam, MT; Wang, RK; Eckerstorfer, F; Zelezniak, A and Ralser, M (2016) Functional metabolomics describes the yeast biosynthetic regulome. Cell 167, 553-565 e512 PubMed abstract

Alam, MT; Zelezniak, A; Mülleder, M; Shliaha, P; Schwarz, R; Capuano, F; Vowinckel, J; Radmaneshfar, E; Krüger, A; Calvani, E; Michel, S; Börno, S; Christen, S; Patil, KR; Timmermann, B; Lilley, KS and Ralser, M (2016)
The metabolic background is a global player in Saccharomyces gene expression epistasis. Nature Microbiology 1, 15030 PubMed abstract

Keller, MA; Turchyn, AV and Ralser, M (2014) Non-enzymatic glycolysis and pentose phosphate pathway-like reactions in a plausible Archean ocean. Molecular Systems Biology 10, 725 PubMed abstract

Mülleder, M; Capuano, F; Pir, P; Christen, S; Sauer, U; Oliver, SG and Ralser, M (2012) A prototrophic deletion mutant collection for yeast metabolomics and systems biology Nature Biotechnology 30, 1176-1178

Grüning, N-M; Rinnerthaler, M; Bluemlein, K; Mülleder, M; Wamelink, MMC; Lehrach, H; Jakobs, C; Breitenbach, M and Ralser, M (2011) Pyruvate kinase triggers a metabolic feedback loop that controls redox metabolism in respiring cells Cell Metabolism 14, 415-427

Bluemlein, K and Ralser, M (2011) Monitoring protein expression in whole-cell extracts by targeted label- and standard-free LC-MS/MS Nature Protocolsocols 6, 859-869

Ralser, M; Wamelink, MMC; Latkolik, S; Jansen, EEW; Lehrach, H and Jakobs, C (2009) Metabolic reconfiguration precedes transcriptional regulation in the antioxidant response Nature Biotechnology 27, 604 - 605

Ralser, M; Wamelink, MM; Kowald, A; Gerisch, B; Heeren, G; Struys, EA; Klipp, E; Jakobs, C; Breitenbach, M; Lehrach, H and Krobitsch, SC, Breitenbach M, Lehrach H, Krobitsch S (2007) Dynamic rerouting of the carbohydrate flux is key to counteracting oxidative stress Journal of Biology 6, 10

Markus Ralser

markus.ralser@crick.ac.uk
+44 (0)20 379 62385