Chemistry Seminar presented by Gregory S. Ducker (’06, Chemistry/Political Economy)
Lewis-Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University
Friday, October 27, 2017
3:30 p.m. in Old Music Hall 103
Our lab utilizes a combination of genetics and isotope tracing mass spectrometry to quantify metabolic reactions in cells and in animals. One-carbon (1C) metabolism, mediated by the folate cofactor, supports multiple physiological processes. These include biosynthesis (purines and thymidine), amino acid homeostasis (glycine, serine, and methionine), epigenetic maintenance, and redox defense. Both within eukaryotic cells and across organs, 1C metabolic reactions are compartmentalized; expression data from patient tumors reveals that the mitochondrial 1C pathway is consistently overexpressed in cancer. We show that most proliferating mammalian cell lines make 1C units by catabolizing serine in the mitochondria, making glycine and 5,10-methylene tetrahydrofolate (THF). Clustered regularly interspaced short palindromic repeats (CRISPR)- mediated mitochondrial pathway knockout activates cytosolic 1C-unit production. This pathway flexibility is nutrient dependent; loss of the mitochondrial pathway renders cells dependent on extracellular serine to make 1C units and on extracellular glycine to make glutathione, exposing cells to redox stress. Surprisingly, selective loss of mitochondrial 5,10-methyleneTHF also leads to a defect in oxidative phosphorylation. This is due to impaired mitochondrial translation resulting from loss of a folate mediated posttranscriptional tRNA modification. Tumors generated from mitochondrial 1C metabolism mutant cell lines grow more slowly in vivo. Dual inhibition of both cytosolic and mitochondrial serine catabolism fully inhibits growth using both genetic and pharmacological methods. Mitochondrial 1C metabolism supports diverse biochemical processes and selectively inhibiting serine catabolism is a novel antifolate mechanism with potential therapeutic applications.