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Cancer Research and Treatments · Journal article
Journal of the American Chemical Society · August 13, 2026
Raises a question worth testing. It does not answer one.
This mechanistic study identifies PKM2 as a methionine-sensing protein that interacts with GATOR2 and modulates mTORC1 signalling via a novel methionine-binding pocket, independent of PKM2 enzymatic activity. The finding is based on chemoproteomic profiling and biochemical characterization in cultured cells and does not include in vivo validation or therapeutic efficacy testing.
Mechanistic cell biology study with chemoproteomic profiling and biochemical validation. Cultured mammalian cells. Intervention: Photoaffinity analogue of methionine for capture of methionine-binding proteins.
PKM2 identified as a specific methionine sensor through photoaffinity labelling and chemoproteomic profiling Methionine sensing by PKM2 occurs through interaction with GATOR2 complex and modulation of mTORC1 pathway Methionine recognition is independent of PKM2 enzymatic activity
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This is a mechanistic study identifying PKM2 as a methionine sensor via chemoproteomic profiling and biochemical validation in cells, with therapeutic speculation but no clinical efficacy data or in vivo validation.
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Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
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Abstract Methionine (Met) plays a pivotal role in numerous cellular functions. Methionine restriction has been demonstrated to provide metabolic benefits in aging, obesity, diabetes and as an adjunct to cancer therapy. However, the methionine-sensing proteins and how cells directly sense the methionine level have remained elusive. In this study, we developed a photoaffinity analogue of methionine to capture proteins that specifically recognize and sense methionine in living cells. Using chemoproteomic profiling and biochemical validation, we found that PKM2 is a specific methionine sensor that transduces methionine availability signals through the interaction with the GATOR2 complex, which, in turn, modulates the downstream response of the mTORC1 pathway through a novel methionine-recognition pocket on PKM2. As our findings indicate that the sensing of methionine by PKM2 is independent of its enzymatic activity, we envision that disrupting the binding of methionine to PKM2 or stabilizing the PKM2-GATOR2 interaction would create a methionine pseudostarvation state in living cells, which holds promise as a novel therapeutic avenue that could emulate the physiological benefits of a methionine-restricted diet and circumvent the drawbacks of dietary methionine restriction.
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