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Updated: Feb 6, 2026
Assessment of de novo Protein Synthesis Rates in Caenorhabditis elegans
Published on: September 12, 2020
CARM1 suppresses de novo serine synthesis by promoting PKM2 activity
Tharindumala Abeywardana1, Myungeun Oh2, Lei Jiang2
1From the Departments of Cancer Genetics and Epigenetics and.
Abstract:
Glucose is a critical nutrient for cell proliferation. However, the molecular pathways that regulate glucose metabolism are still elusive. We discovered that co-activator-associated arginine methyltransferase 1 (CARM1) suppresses glucose metabolism toward serine biosynthesis. By tracing the 13C-labeled glucose, we found that Carm1 knockout mouse embryonic fibroblasts exhibit significantly increased de novo serine synthesis than WT cells. This is caused, at least in part, by the reduced pyruvate kinase (PK) activity in these cells. The M2 isoform of PK (PKM2) is arginine-methylated by CARM1, and methylation enhances its activity. Mechanistically, CARM1 methylates PKM2 at arginines 445 and 447, which enhances PKM2 tetramer formation. Consequently, Carm1 knockout cells exhibit significant survival advantages over WT cells when extracellular serine is limited, likely due to their enhanced de novo serine synthesis capacity. Altogether, we identified CARM1 as an important regulator of glucose metabolism and serine synthesis.
Insights
Co-activator-associated arginine methyltransferase 1 (CARM1) regulates glucose metabolism by suppressing serine synthesis. CARM1 methylation of pyruvate kinase M2 enhances its activity, impacting cell survival.
Area of Science:
- Cellular Metabolism
- Molecular Biology
- Biochemistry
Background:
- Glucose is essential for cell proliferation, but its metabolic regulation pathways remain incompletely understood.
- Understanding glucose metabolism is crucial for various biological processes, including cancer cell growth.
Purpose of the Study:
- To investigate the role of co-activator-associated arginine methyltransferase 1 (CARM1) in regulating glucose metabolism.
- To elucidate the molecular mechanisms by which CARM1 influences glucose flux towards serine biosynthesis.
Main Methods:
- Utilized 13C-labeled glucose tracing in wild-type (WT) and Carm1 knockout mouse embryonic fibroblasts (MEFs).
- Assessed pyruvate kinase (PK) activity and its M2 isoform (PKM2) methylation status.
- Investigated the effect of CARM1-mediated PKM2 methylation on PKM2 tetramer formation and enzyme activity.
Main Results:
- Carm1 knockout MEFs demonstrated significantly increased de novo serine synthesis compared to WT cells.
- Reduced pyruvate kinase activity was observed in Carm1 knockout cells, linked to CARM1's regulation of PKM2.
- CARM1 directly methylates PKM2 at arginines 445 and 447, enhancing PKM2 tetramerization and activity.
Conclusions:
- CARM1 acts as a suppressor of glucose metabolism towards serine biosynthesis.
- CARM1-mediated methylation of PKM2 is a key mechanism controlling serine synthesis and impacting cell survival under nutrient stress.
- CARM1 is identified as a critical regulator of glucose metabolism and de novo serine synthesis.
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