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Departmental Seminar Graduate Students Seminar Department of Chemistry Sunday March 21, 2021 Time 16:00 ZOOM https://us02web.zoom.us/j/81056120346 Meeting ID: 810 5612 0346 Gail Albin Supervised by: Prof. Eyal Arbely Understanding the role of site-specific lysine-acetylation in the regulation of human phosphofructokinase-1 P type Cancer cells reprogram their metabolic pathways to support the unique metabolic requirements of proliferating cells. In particular, cancer cells favor aerobic glycolysis that can provide energy and secondary metabolites for biosynthesis (a.k.a. the Warburg effect). However, the biochemical mechanisms that lead to enhanced glycolytic rate are not fully understood. All ten glycolytic enzymes are post-translationally modified by lysine acetylation, and based on this observation we hypothesized that the glycolytic pathway is regulated by acetylation. To test our hypothesis, we focused on platelet- derived phosphofructokinase (PFKP), the enzyme that catalyzes the phosphorylation of fructose-6-phosphate, and is subjected to the most complex regulation among the glycolytic enzymes. To measure the effect of acetylation on PFKP activity, we used genetic code expansion technology to genetically encode the site-specific incorporation of acetylated lysine into ribosomally expressed proteins. We then established an experimental system for expression of site-specific acetylated PFKP in mammalian cells and expressed nine different acetylated variants of PFKP. We also established an in vitro biochemical assay to measure the effect of acetylation on PFKP activity. Our data show that some acetylation sites decrease PFKP activity, while one acetylation site increases PFKP activity. Furthermore, we found that acetylation on five different positions reduces the inhibitory effect of citrate, one of the potent allosteric inhibitors of PFKP. Taken together, we found that acetylation plays an important role in the regulation of PFKP activity, which may affect glycolytic flux in normal and cancerous cells. 1–9 References 1. Moreno-Sánchez R, Rodríguez-Enríquez S, Marín-Hernández A, Saavedra E. Energy metabolism in tumor cells. FEBS J. 2007;274(6):1393-1418. doi:10.1111/j.1742-4658.2007.05686.x 2. Wang L, Xie J, Schultz PG. Expanding the genetic code. Annu Rev Biophys Biomol Struct. 2006;35:225- 249. doi:10.1146/annurev.biophys.35.101105.121507 3. Zhao S, Xu W, Jiang W, et al. Regulation of cellular metabolism by protein lysine acetylation. Science (80- ). 2010;327(5968):1000-1004. doi:10.1126/science.1179689 4. egulation of Mammalian Muscle Type 6-Phosphofructo-1-kinaseand Its Implication for the Control of the Metabolism. 5. Wang Q, Zhang Y, Yang C, Xiong H, Lin Y. Acetylation of Metabolic Enzymes and Metabolic Flux. Science (80- ). 2010;327(May):1004-1007. doi:10.1126/science.1179687 6. Kosaku Uyeda B. PHOSPHOFRUCTOKINASE.; 1979. 7. Mlakar T, Legiša M. Citrate inhibition-resistant form of 6-phosphofructo-1-kinase from Aspergillus niger. Appl Environ Microbiol. 2006;72(7):4515-4521. doi:10.1128/AEM.00539-06 8. Lee JH, Liu R, Li J, et al. Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis. Nat Commun. 2017;8(1). doi:10.1038/s41467-017-00906-9 9. Webb BA, Forouhar F, Szu FE, Seetharaman J, Tong L, Barber DL. Structures of human phosphofructokinase-1 and atomic basis of cancer-associated mutations. Nature. 2015;523(7558):111- 114. doi:10.1038/nature14405 .
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