Human Methylene- tetrahydrofolate reductase (MTHFR) A Target Enabling Package (TEP)
- 1. Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford
- 2. Division of Metabolism and Children's Research Center, University Children's Hospital, Zürich
- 3. Department of Biochemistry, University of Utah School of Medicine
- 4. Memorial Sloan Kettering Cancer Center, New York.
Description
The folate and methionine cycles are essential metabolic pathways for life, involved respectively in DNA synthesis and generation of the ubiquitous methyl donor S-adenosylmethionine (SAM). The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) represents a key regulatory connection between these cycles, hence exerting a strong influence on an array of diseases. This TEP presents the first structures for any eukaryotic MTHFR, revealing a novel SAM-binding fold. The TEP provides additional mass spectrometry, activity assay and biophysical binding methods yielding mechanistic insights into how phosphorylation and allosteric binding of SAM act in concert to inhibit MTHFR activity. This work further provides the starting point for the design of tool molecules (e.g. SAM-analogues) aimed at disrupting the SAM-induced inhibition of MTHFR activity.
Notes
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MTHFR_TEP.pdf
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Additional details
Related works
- Is part of
- https://www.thesgc.org/tep (URL)
Funding
- Wellcome Trust
- A UK Hub to Catalyse Open Target Discovery. 106169