MECHANISTIC INSIGHTS INTO THE ROLE OF METHIONINE SYNTHASE IN METABOLISM

Abstract

Cancer is characterized by unusually rapid cell growth, supported by the upregulation of biochemical pathways including one-carbon (1C) metabolism. 1C units associated with folate coenzymes are important in metabolic processes such as nucleotide synthesis. Consequently, multiple enzymes in the folate cycle have been identified as therapeutic targets. Methionine synthase (MS), coded for by the MTR gene, is an enzyme in the folate cycle that converts homocysteine into methionine through the transfer of a methyl group from the coenzyme 5-methyl tetrahydrofolate (5-meTHF). In this study, cancer cell lines in which MTR was knocked out were used to provide evidence that MS does not contribute significantly to methionine production. Rather, growth assays in vitro and xenograft studies in vivo revealed the necessity of MS for cell proliferation because of its role in folate metabolism. Metabolomic analysis via liquid chromatography-mass spectrometry (LC-MS) suggested that the loss of MS activity results in the buildup of 5-meTHF and depletion of other folate species. Moreover, global aqueous metabolomics demonstrated elevated levels of purine biosynthetic intermediates in the knockouts, again emphasizing the importance of MS in recycling folates to provide 1C units in other pathways. This work contributes toward a greater understanding of the importance of MS in folate cycling and 1C metabolism, highlighting its potential as a therapeutic target.