1.5.1.20 (+)-5-methyl-5,6,7,8-tetrahydropteroylpentaglutamate inhibits at high concentrations 19819 1.5.1.20 (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 254723 1.5.1.20 (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 262439 1.5.1.20 2,4-dihydroxyphenylacetic acid at 0.01 M 107990 1.5.1.20 5,10-methylenetetrahydrofolate substrate inhibition 401 1.5.1.20 5,10-methylenetetrahydrofolate - 401 1.5.1.20 dicoumarol inhibits menadione reductase activity only 754 1.5.1.20 diethyldicarbonate 20 mM NADP+ and 20 mM NAD+ partially protected the enzyme against inactivation whereas 20 mM nicotinamide gives complete protection 310 1.5.1.20 dihydrofolate competitive with respect to 5,10-methylenetetrahydrofolate and uncompetitive with respect to NADPH 1351 1.5.1.20 dihydrofolate - 1351 1.5.1.20 dihydropteroylhexaglutamate - 32625 1.5.1.20 dihydropteroylpolyglutamate - 49992 1.5.1.20 dihydropteroylpolyglutamate most potent inhibitor is dihydropteroylhexaglutamate 49992 1.5.1.20 folylpolyglutamate overview 108975 1.5.1.20 LY309887 i.e. 6R-2’,5’-thienyl-5,10-dideazatetrahydrofolate monoglutamate 11738 1.5.1.20 menadione inhibits enzyme activity in yeast extracts 240 1.5.1.20 Mersalyl 80% inhibition at 1 mM 1982 1.5.1.20 methylenetetrahydrofolate - 934 1.5.1.20 additional information residues essential for enzyme activity: arginine, histidine, tryptophan 2 1.5.1.20 additional information vitamin B12 and methionine can repress enzyme biosynthesis 2 1.5.1.20 additional information not inhibited by S-adenosylmethionine 2 1.5.1.20 additional information gene contains a putative S-adenosylmethionione binding sequence, that is inhibitory in eukaryotic MTHFR 2 1.5.1.20 additional information no inhibition by S-adenosyl-L-methionine, which is no feed-back regulator of the methyl group biosynthesis pathway in plants 2 1.5.1.20 additional information not inhibitory: S-adenosyl-L-methionine, no substrate inhibition up to 0.25 mM 2 1.5.1.20 additional information inhibiting MTHFR with either antisense or siRNA decreases the viability of methionine-dependent transformed gastric cancer cells 2 1.5.1.20 additional information inhibited by a dominant-negative mutant of inositol-requiring enzyme-1, a reported inhibitor of c-Jun (SP600125) and a dominant-negative derivative of c-Jun N-terminal kinase-1 reduce MTHFR activation 2 1.5.1.20 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 2 1.5.1.20 N-(4-[[(2,4-diaminopteridin-6-yl)methyl](methyl)amino]benzoyl)-gamma-glutamyl-gamma-glutamyl-gamma-glutamyl-gamma-glutamylglutamic acid - 14813 1.5.1.20 N-(4-[[(2,4-diaminopteridin-6-yl)methyl](methyl)amino]benzoyl)-gamma-glutamyl-gamma-glutamylglutamic acid - 14812 1.5.1.20 N-(4-[[(2,4-diaminopteridin-6-yl)methyl](methyl)amino]benzoyl)glutamic acid - 7833 1.5.1.20 N-([5-[2-(2,4-diaminoquinazolin-6-yl)ethyl]-2,3-dihydrothiophen-2-yl]carbonyl)-4-methylideneglutamic acid - 7835 1.5.1.20 N-bromosuccinimide inactivates the enzyme by modification of tryptophan 208 1.5.1.20 N-[4-[2-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-4-methylideneglutamic acid - 7836 1.5.1.20 N-[4-[2-(2,4-diaminopyrido[3,2-d]pyrimidin-6-yl)ethyl]benzoyl]-4-methylideneglutamic acid - 7838 1.5.1.20 N-[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]-2-fluorobenzoyl]-4-methylideneglutamic acid - 7837 1.5.1.20 N-[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]-4-methylideneglutamic acid - 8822 1.5.1.20 N-[4-[2-(2-amino-4-methylquinazolin-6-yl)ethyl]benzoyl]-4-methylideneglutamic acid - 7834 1.5.1.20 NADH substrate inhibition above 1 mM 8 1.5.1.20 NADH - 8 1.5.1.20 NADPH 100 mM 5 1.5.1.20 p-chloromercuribenzoate 60% inhibition of the methylenetetrahydrofolate reductase activity at 0.04 mM, 83% inhibition of the menadione reductase activity at 0.04 mM 43 1.5.1.20 Phenylglyoxal - 301 1.5.1.20 Polyglutamate analogues - 46888 1.5.1.20 S-adenosyl-L-methionine feed-back regulation of the methyl group biosynthesis pathway in vivo, the chimeric mutant enzyme is insensitive to inhibition by S-adenosyl-L-methionine 24 1.5.1.20 S-adenosyl-L-methionine allosteric inhibition and control of phosphorylation 24 1.5.1.20 S-adenosyl-L-methionine AdoMet, allosteric inhibitor 24 1.5.1.20 S-adenosylmethionine allosteric inhibition; inhibition partially reversed by S-adenosylhomocysteine 404 1.5.1.20 S-adenosylmethionine inhibition partially reversed by S-adenosylhomocysteine 404 1.5.1.20 S-adenosylmethionine effect on equilibrium between active and inactive form of enzyme 404 1.5.1.20 S-adenosylmethionine inhibition of the enzyme in crude extracts from fresh liver biopsies, but not after purification from cadaver liver 404 1.5.1.20 S-adenosylmethionine 0.05 mM 404 1.5.1.20 S-adenosylmethionine inhibits both the reduction of the enzyme-bound flavin by 5-methyltetrahydrofolate and the reoxidation of reduced enzyme by 5,10-methylenetetrahydrofolate 404 1.5.1.20 S-adenosylmethionine - 404 1.5.1.20 S-adenosylmethionine allosteric inhibition 404 1.5.1.20 S-adenosylmethionine inhibitory effect at a physiological concentration, dependent on incubation temperature, binds to an allosteric regulatory site different from catalytic site, reversed by S-adenosylhomocysteine; in vivo feedback-inhibition 404 1.5.1.20 S-adenosylmethionine in vivo feedback-inhibition 404 1.5.1.20 S-adenosylmethionine strong, reversible allosteric inhibition, prevented by S-adenosylhomocysteine 404 1.5.1.20 S-adenosylmethionine SAM, allosteric inhibition by the reaction product. MTHFR phosphorylation, identified on 11 N-terminal residues (16 in total), increases sensitivity to SAM binding and inhibition 404 1.5.1.20 sinefungin - 659 1.5.1.20 tetrahydrofolate - 207