Correlation Engine 2.0
Clear Search sequence regions


  • cellular (1)
  • DYRK1A (1)
  • GSK3A (1)
  • human (2)
  • layer (1)
  • MTHFR (17)
  • protein human (1)
  • Sizes of these terms reflect their relevance to your search.

    Methylenetetrahydrofolate reductase (MTHFR) catalyzes the irreversible conversion of 5,10-methylene-tetrahydrofolate (THF) to 5-methyl-THF, thereby committing one-carbon units to the methionine cycle. While MTHFR has long been known to be allosterically inhibited by S-adenosylmethionine (SAM), only relatively recently has N-terminal multisite phosphorylation been shown to provide an additional layer of regulation. In vitro, the multiply phosphorylated form of MTHFR is more sensitive to allosteric inhibition by SAM. Here we sought to investigate the kinases responsible for MTHFR multisite phosphorylation and the physiological function of MTHFR phosphorylation in cells. We identified DYRK1A/2 and GSK3A/B among the kinases that phosphorylate MTHFR. In addition, we found that MTHFR phosphorylation is maintained by adequate cellular SAM levels, which are sensed through the C-terminal SAM binding domain of MTHFR. To understand the function of MTHFR phosphorylation in cells, we generated MTHFR CRISPR knockin mutant lines that effectively abolished MTHFR phosphorylation and compared them with the parental cell lines. Whereas the parental cell lines showed increased 5-methyl-THF production in response to homocysteine treatment, the knockin cell lines had high basal levels of 5-methyl-THF and did not respond to homocysteine treatment. Overall, our results suggest that MTHFR multisite phosphorylation coordinates with SAM binding to inhibit MTHFR activity in cells.

    Citation

    Yuxiang Zheng, Shivan Ramsamooj, Qian Li, Jared L Johnson, Tomer M Yaron, Klaus Sharra, Lewis C Cantley. Regulation of folate and methionine metabolism by multisite phosphorylation of human methylenetetrahydrofolate reductase. Scientific reports. 2019 Mar 12;9(1):4190

    Expand section icon Mesh Tags

    Expand section icon Substances


    PMID: 30862944

    View Full Text