EC Number   |
General Information |
Reference |
|---|
    1.5.1.20 | evolution |
human MTHFR is a 656 amino acid multi-domain protein, and the catalytic domain is conserved across evolution |
761998 |
| 1.5.1.20 | malfunction |
in accordance with its essential role, major and minor deficiencies of human MTHFR are the direct or indirect causes of human disease. Severe MTHFR deficiency is inherited in an autosomal recessive manner and is the most common inborn error of folate deficiency. Milder enzyme deficiencies, due to single nucleotide polymorphisms of the MTHFR gene, have been associated with various common disorders |
761998 |
| 1.5.1.20 | malfunction |
MTHFR deficiency and upregulation result in diverse disease states, rendering it an attractive drug target. The activity of MTHFR is inhibited by the binding of S-adenosylmethionine (AdoMet) to an allosteric regulatory domain distal to the enzyme's active site |
760654 |
| 1.5.1.20 | malfunction |
mutations in the enzyme lead to hyperhomocysteinemia. A C677T polymorphism is associated with an increased risk for the development of cardiovascular disease, Alzheimer's disease, and depression in adults and of neural tube defects in the fetus |
724809 |
| 1.5.1.20 | metabolism |
the enzyme plays a key role in folate metabolism and in the homeostasis of homocysteine |
724809 |
| 1.5.1.20 | metabolism |
the folate and methionine cycles are crucial for biosynthesis of lipids, nucleotides and proteins, and production of the methyl donor S-adenosylmethionine (SAM). 5,10-methylenetetrahydrofolate reductase (MTHFR) represents a key regulatory connection between these cycles, generating 5-methyltetrahydrofolate for initiation of the methionine cycle, and undergoing allosteric inhibition by its end product SAM |
761998 |
| 1.5.1.20 | more |
depending on the electron donor for methylene-THF reduction, different amounts of ATP can be synthesized |
-, 764937 |
| 1.5.1.20 | more |
human MTHFR reveals a unique architecture, appending the well-conserved catalytic TIM-barrel to a eukaryote-only SAM-binding domain. The latter domain of distinct fold provides the predominant interface for MTHFR homodimerization, positioning the N-terminal serine-rich phosphorylation region near the C-terminal SAM-binding domain. This explains how MTHFR phosphorylation, identified on 11 N-terminal residues (16 in total), increases sensitivity to SAM binding and inhibition. The 25-amino-acid inter-domain linker enables conformational plasticity and is proposed to be a key mediator of SAM regulation, molecular regulation of MTHFR, overview. The catalytic domain to form a beta8alpha8 (TIM) barrel, with residues critical for binding the cofactor FAD, the electron donor NADPH, and the product CH3-THF. The catalytic domain is sufficient for the entire catalytic cycle. Structure-function analysis, overview |
761998 |
| 1.5.1.20 | more |
the active site constitutes a distinct fold with a druggable pocket. Identification of 4 compounds that stabilize the regulatory domain. Three compounds are sinefungin analogues, closely related to AdoMet and S-adenosylhomocysteine (AdoHcy). The strongest thermal stabilisation is provided by (S)-SKI-72, a potent inhibitor originally developed for protein arginine methyltransferase 4 (PRMT4), docking study, overview |
760654 |
| 1.5.1.20 | physiological function |
enzyme activity is involved in the plasma membrane redox system required for pigment biosynthesis in filamentous fungi |
-, 724892 |
