AI Article Synopsis

  • MTHFR is an enzyme that converts folate-derived units into S-adenosyl-L-methionine (SAM), a crucial methyl donor for various biological processes.
  • Researchers used cryo-electron microscopy to study human MTHFR in both an active state, where it binds to S-adenosyl-L-homocysteine (SAH), and an inhibited state with dual SAM binding.
  • The study reveals how MTHFR's regulatory domain undergoes significant structural changes to inhibit enzyme activity, providing insight into how the enzyme responds to the cell's methylation levels.

Article Abstract

5,10-methylenetetrahydrofolate reductase (MTHFR) commits folate-derived one-carbon units to generate the methyl-donor S-adenosyl-L-methionine (SAM). Eukaryotic MTHFR appends to the well-conserved catalytic domain (CD) a unique regulatory domain (RD) that confers feedback inhibition by SAM. Here we determine the cryo-electron microscopy structures of human MTHFR bound to SAM and its demethylated product S-adenosyl-L-homocysteine (SAH). In the active state, with the RD bound to a single SAH, the CD is flexible and exposes its active site for catalysis. However, in the inhibited state the RD pocket is remodelled, exposing a second SAM-binding site that was previously occluded. Dual-SAM bound MTHFR demonstrates a substantially rearranged inter-domain linker that reorients the CD, inserts a loop into the active site, positions Tyr404 to bind the cofactor FAD, and blocks substrate access. Our data therefore explain the long-distance regulatory mechanism of MTHFR inhibition, underpinned by the transition between dual-SAM and single-SAH binding in response to cellular methylation status.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11018872PMC
http://dx.doi.org/10.1038/s41467-024-47174-yDOI Listing

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