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Chemical Compound Review:

SureCN8030 2-[[4-[(2-amino-4-oxo- 5,6,7,8-tetrahydro...

Synonyms: SureCN4535490, HMDB01846, AC1L1ASH, AR-1J1194, AC1Q5SG4, ...

Lucock, M.D. et al., Shin, H.C. et al., Houghton, J.A. et al., Voeller, D.M. et al., Cook, R.J. et al., et al.

Contestabile, Paiardini, Pascarella, di Salvo, D'Aguanno, Bossa,

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Disease relevance of tetrahydropteroyl mono-L-glutamate

The distribution of polyglutamates of CH2-H4PteGlu and the combined pools of CH2-H4PteGlu plus H4PteGlu were subsequently examined in three human colon adenocarcinoma xenografts [1].
The method for measuring polyglutamate forms of CH2-H4PteGlu and H4PteGlu, by entrapment in ternary complexes with [6-3H]5-fluoro-2'-deoxyuridylate and Lactobacillus casei thymidylate synthase has been characterized [1].
We describe here the structure at 2.4 A resolution of Escherichia coli serine hydroxymethyltransferase in ternary complex with glycine and 5-formyl tetrahydropteroylglutamate, refined to an R-factor value of 17.4 % and R(free) value of 19.6 % [2].
Thus, in vitamin B12 deficiency H4PteGlu is not available in sufficient concentration to maintain the de novo synthesis of thymidylate and purines, and accords with the methyl-folate-trap hypothesis [3].

High impact information on tetrahydropteroyl mono-L-glutamate

Primary structure and tetrahydropteroylglutamate binding site of rabbit liver cytosolic 5,10-methenyltetrahydrofolate synthetase [4].
Erythrocyte methylfolates (mono- to hexaglutamate-5CH3H4PteGlu1-6), formylfolates (tri- to pentaglutamate-5CHOH4PteGlu3-5),formiminotetrahydrofolate (formiminoH4PteGlu1), unsubstituted tetrahydrofolate (H4PteGlu1), andpara-aminobenzoylglutamate (P-ABG) have been measured by HPLC with fluorescence detection [5].
Furthermore, the apparent equilibrium between substrate (5CH3H4PteGlu1) and product (H4PteGlu1) of methionine synthase is significantly associated with the abundance of 5CHOH4PteGlu5 (r = -0.53, 99% CI -0. 79, -0.11, P = 0.0018) [5].
10-Formyltetrahydrofolate dehydrogenase (10-FTH-FDH: EC 1.5.1.6) catalyzes the NADP(+)-dependent oxidation of 10-formyltetrahydrofolate (10-HCO-H4PteGlu) to tetrahydrofolate (H4PteGlu) and CO2 and the NADP(+)-independent hydrolytic cleavage of 10-HCO-H4PteGlu to H4PteGlu and formate [6].
In the absence of vitamin B12, exposure to 5-methyl-H4PteGlu resulted in 154 +/- 17 pmol/mg 5-methyl-H4PteGlu along with only 8 +/- 5 pmol/mg 10-formyl-H4PteGlu and 4 +/- 2 pmol/mg H4PteGlu, thus demonstrating the marked dependence on vitamin B12 for the metabolism of 5-methyl-H4PteGlu to the other intracellular folates [7].

Chemical compound and disease context of tetrahydropteroyl mono-L-glutamate

1. In vitamin B12 deficiency the activity of tetrahydropteroylglutamate methyltransferase (EC 2.1.1.13) is depressed and the synthesis of methionine is reduced [8].

Biological context of tetrahydropteroyl mono-L-glutamate

The nonmethylated folates, 10-HCO-H4PteGlu and H4PteGlu, may also play an important role in folate homeostasis [9].

Anatomical context of tetrahydropteroyl mono-L-glutamate

This increase was at the expense of a decrease in different folate derivatives in different tissues--in bone marrow cells, kidney, and liver 5-HCO-H4PteGlu, 10-HCO-H4PteGlu, and H4PteGlu decreased; in brain only H4PteGlu decreased significantly [10].

Associations of tetrahydropteroyl mono-L-glutamate with other chemical compounds

From the retention-time profiles and hydrodynamic voltammograms, and the profiles of ultraviolet (UV) absorbance spectra obtained by HPLC with photodiode array detection, these 3 peaks were identified as 10-formyltetrahydrofolate (10-HCO-H4PteGlu), tetrahydrofolate (H4PteGlu) and 5-methyltetrahydrofolate (5-CH3-H4PteGlu) [9].
The reaction catalysed by SHMT, the transfer of Cbeta of serine to tetrahydropteroylglutamate (H4PteGlu), represents in the cell an important link between the breakdown of amino acids and the metabolism of folates [11].
Livers from deficient animals had significantly increased levels of radioactive 5-methyltetrahydropteroylglutamate detected after conjugase treatment of extracts and significantly decreased levels of radioactive tetrahydropteroylglutamate and formylated derivatives [12].

Gene context of tetrahydropteroyl mono-L-glutamate

We have also studied the polyglutamate specificity of methionine synthase, which is responsible for the conversion of CH3-H4PteGlu1 into H4PteGlu1 [13].
Methods for thymidylate synthase pharmacodynamics: serial biopsy, free and total TS, FdUMP and dUMP, and H4PteGlu and CH2-H4PteGlu assays [14].

References

Characterization of the pools of 5,10-methylenetetrahydrofolates and tetrahydrofolates in xenografts of human colon adenocarcinoma. Houghton, J.A., Williams, L.G., Radparvar, S., Houghton, P.J. Cancer Res. (1988) [Pubmed]
Crystal structure at 2.4 A resolution of E. coli serine hydroxymethyltransferase in complex with glycine substrate and 5-formyl tetrahydrofolate. Scarsdale, J.N., Radaev, S., Kazanina, G., Schirch, V., Wright, H.T. J. Mol. Biol. (2000) [Pubmed]
Cobalamin dependent methionine synthesis and methyl-folate-trap in human vitamin B12 deficiency. Sauer, H., Wilmanns, W. Br. J. Haematol. (1977) [Pubmed]
Primary structure and tetrahydropteroylglutamate binding site of rabbit liver cytosolic 5,10-methenyltetrahydrofolate synthetase. Maras, B., Stover, P., Valiante, S., Barra, D., Schirch, V. J. Biol. Chem. (1994) [Pubmed]
Folate-homocysteine interrelations: potential new markers of folate status. Lucock, M.D., Daskalakis, I., Schorah, C.J., Lumb, C.H., Oliver, M., Devitt, H., Wild, J., Dowell, A.C., Levene, M.I. Mol. Genet. Metab. (1999) [Pubmed]
Enzymatic activities of rat liver cytosol 10-formyltetrahydrofolate dehydrogenase. Cook, R.J., Wagner, C. Arch. Biochem. Biophys. (1995) [Pubmed]
Intracellular metabolism of 5-methyltetrahydrofolate and 5-formyltetrahydrofolate in a human breast-cancer cell line. Voeller, D.M., Allegra, C.J. Cancer Chemother. Pharmacol. (1994) [Pubmed]
Effect of vitamin B12 deficiency on phosphatidylethanolamine methylation in rat liver. Akesson, B., Fehling, C., Jägerstad, M. Br. J. Nutr. (1978) [Pubmed]
Identification of 10-formyltetrahydrofolate, tetrahydrofolate and 5-methyltetrahydrofolate as major reduced folate derivatives in rat bile. Shin, H.C., Shimoda, M., Kokue, E., Takahashi, Y. J. Chromatogr. (1993) [Pubmed]
Effect of nitrous oxide inactivation of vitamin B12 on the levels of folate coenzymes in rat bone marrow, kidney, brain, and liver. Wilson, S.D., Horne, D.W. Arch. Biochem. Biophys. (1986) [Pubmed]
l-Threonine aldolase, serine hydroxymethyltransferase and fungal alanine racemase. A subgroup of strictly related enzymes specialized for different functions. Contestabile, R., Paiardini, A., Pascarella, S., di Salvo, M.L., D'Aguanno, S., Bossa, F. Eur. J. Biochem. (2001) [Pubmed]
The metabolic consequences of vitamin B-12/methionine deficiency in rats. Davidson, G.E., Weir, D.G., Scott, J.M. Biochim. Biophys. Acta (1975) [Pubmed]
Folylpolyglutamates as substrates and inhibitors of folate-dependent enzymes. Matthews, R.G., Ghose, C., Green, J.M., Matthews, K.D., Dunlap, R.B. Adv. Enzyme Regul. (1987) [Pubmed]
Methods for thymidylate synthase pharmacodynamics: serial biopsy, free and total TS, FdUMP and dUMP, and H4PteGlu and CH2-H4PteGlu assays. Spears, C.P., Gustavsson, B.G. Adv. Exp. Med. Biol. (1988) [Pubmed]

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