Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
evolution
human MTHFR is a 656 amino acid multi-domain protein, and the catalytic domain is conserved across evolution
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
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
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
metabolism
-
the enzyme plays a key role in folate metabolism and in the homeostasis of homocysteine
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
physiological function
-
enzyme activity is involved in the plasma membrane redox system required for pigment biosynthesis in filamentous fungi
physiological function
-
enzyme activity is involved in the plasma membrane redox system required for pigment biosynthesis in filamentous fungi
physiological function
possible role of the enzyme in acetogenesis, overview
physiological function
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. Molecular regulation of MTHFR, overview. Phosphorylation does not alter MTHFR kinetic parameters. Phosphorylated MTHFR appeares to protect thermally unstable SAM from degradation to SAH, while the non-phosphorylated protein is unable to perform this function
physiological function
the folate and methionine cycles, constituting one-carbon metabolism, are critical pathways for cell survival. Intersecting these two cycles, 5,10-methylenetetrahydrofolate reductase (MTHFR) directs one-carbon units from the folate to methionine cycle, to be exclusively used for methionine and S-adenosylmethionine (AdoMet) synthesis
physiological function
-
possible role of the enzyme in acetogenesis, overview
-
physiological function
-
enzyme activity is involved in the plasma membrane redox system required for pigment biosynthesis in filamentous fungi
-
physiological function
-
enzyme activity is involved in the plasma membrane redox system required for pigment biosynthesis in filamentous fungi
-
additional information
depending on the electron donor for methylene-THF reduction, different amounts of ATP can be synthesized
additional information
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
additional information
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
additional information
-
depending on the electron donor for methylene-THF reduction, different amounts of ATP can be synthesized
-