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Literature summary for 1.5.1.20 extracted from

  • Bezerra, G.A.; Holenstein, A.; Foster, W.R.; Xie, B.; Hicks, K.G.; Buerer, C.; Lutz, S.; Mukherjee, A.; Sarkar, D.; Bhattacharya, D.; Rutter, J.; Talukdar, A.; Brown, P.J.; Luo, M.; Shi, L.; Froese, D.S.; Yue, W.W.
    Identification of small molecule allosteric modulators of 5,10-methylenetetrahydrofolate reductase (MTHFR) by targeting its unique regulatory domain (2021), Biochimie, 183, 100-107 .
    View publication on PubMedView publication on EuropePMC
Search for more literature for 1.5.1.20

Protein Variants

Protein Variants Comment Organism
additional information construction of a full-length (amino acids 1-656, hsMTHFRFL) enzyme variant, a second variant encompassing just the catalytic domain and the regulatory domain (amino acids 38-644, hsMTHFRCD-RD), and a thrid variant encompassing the regulatory domain and part of the linker region (amino acids 348-656, hsMTHFRRD) Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
(S)-SKI-72 binds MTHFR via its allosteric domain with nanomolar affinity. Assay of MTHFR activity in the presence of (S)-SKI-72 demonstrates inhibition of purified enzyme with submicromolar potency and endogenous MTHFR from HEK293 cell lysate in the low micromolar range, both of which are lower than AdoMet. Nevertheless, unlike AdoMet, (S)-SKI-72 is unable to completely abolish MTHFR activity, even at very high concentrations Homo sapiens
(S)-SKI-73 a (S)-SKI-72 prodrug derivative, in which the 9'-amine moiety is cloaked with the trimethyl-locked quinone butanoate moiety, on intact HEK293 cells. Once (S)-SKI-73 passes inside the cell membrane, it is metabolised into (S)-SKI-72 and 60-N benzylhomosinefungin, which then accumulates inside the cell Homo sapiens
additional information the regulatory domain of MTHFR can be targeted by small molecules and presents (S)-SKI-72 as an excellent candidate for development of MTHFR inhibitors, docking study, overview. Phosphorylation of MTHFR, which occurs mainly in the N-terminal serine rich region, further sensitises the protein to this inhibition. Enzyme inhibition may be reversed by the binding of S-adenosylhomocysteine (AdoHcy), the demethylated form of Ado-Met, to the regulatory domain. (S)-SKI-72 exhibits poor membrane permeability Homo sapiens
S-adenosyl-L-methionine AdoMet, allosteric inhibitor Homo sapiens
sinefungin
-
 Homo sapiens

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
additional information
-
 additional information enzyme kinetics Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
5,10-methylenetetrahydrofolate + NADPH + H+ Homo sapiens
-
 5-methyltetrahydrofolate + NADP+
-
 r

Organism

Organism UniProt Comment Textmining
Homo sapiens P42898
-
-

Posttranslational Modification

Posttranslational Modification Comment Organism
phosphoprotein phosphorylation of MTHFR occurs mainly in the N-terminal serine rich region and further sensitises the protein to allosteric inhibition by adenosyl-L-methionine Homo sapiens

Source Tissue

Source Tissue Comment Organism Textmining
HEK-239 cell
-
 Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
5,10-methylenetetrahydrofolate + NADPH + H+
-
 Homo sapiens 5-methyltetrahydrofolate + NADP+
-
 r

Subunits

Subunits Comment Organism
More catalytic and regulatroy domain of the enzyme are connected by a linker sequence, domain organisation of MTHFR, structure mdoel (PDB ID 6FCX). Domain organisation of MTHFR overview Homo sapiens

Synonyms

Synonyms Comment Organism
5,10-methylenetetrahydrofolate reductase
-
 Homo sapiens
MTHFR
-
 Homo sapiens

Cofactor

Cofactor Comment Organism Structure
NADP+
-
 Homo sapiens
NADPH
-
 Homo sapiens

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
additional information
-
 additional information enzyme inhibition kinetics Homo sapiens

General Information

General Information Comment Organism
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 Homo sapiens
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 Homo sapiens
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 Homo sapiens