Biochemical and Molecular Studies of Human Methenyltetrahydrofolate Synthetase

Jolivet, Jacques; Dayan, Alain; Beauchemin, M.; Chahla, Dounia; Mamo, Aline; Bertrand, Richard

doi:10.1634/theoncologist.1-4-248

Cited by 9 publications

(2 citation statements)

References 41 publications

(16 reference statements)

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“…Recently, we have demonstrated that the enzyme methenyltetrahydrofolate synthetase (MTHFS; EC 6.3.3.2) influences intracellular folate concentrations by accelerating rates of folate catabolism [8]. MTHFS catalyzes the ATPdependent conversion of 5-formylTHF to 5,10-methenylTHF (Reaction 1) [20][21][22]. 5-formylTHF(Glu n ) + MgATP → 5,10-methenylTHF(Glu n ) + MgADP (Reaction 1) 5-formylTHF does not participate directly in folate-dependent one-carbon transfer reactions, but is an inhibitor of various folate-dependent enzymes [23].…”

Section: Abbreviationsmentioning

confidence: 99%

Methenyltetrahydrofolate synthetase is a high-affinity catecholamine-binding protein

Anguera

2006

Archives of Biochemistry and Biophysics

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Recombinant mouse 5,10-methenyltetrahydrofolate synthetase (MTHFS) was expressed in Escherichia coli and shown to co-purify with a chromophore that had a lambda(max) at 320nm. The chromophore remained bound to MTHFS during extensive dialysis, but dissociated from MTHFS when its substrate, 5-formyltetrahydrofolate, was bound. The chromophore was identified as an oxidized catecholamine by mass spectrometry and absorption spectroscopy. Purified recombinant mouse MTHFS and rabbit liver MTHFS proteins were shown to bind oxidized N-acetyldopamine (NADA) tightly. The addition of NADA to cell culture medium accelerated markedly folate turnover and decreased both folate accumulation and total cellular folate concentrations in MCF-7 cells. Expression of the MTHFS cDNA in MCF-7 cells increased the concentration of NADA required to deplete cellular folate. The results of this study are the first to identify a link between catecholamines and one-carbon metabolism and demonstrate that NADA accelerates folate turnover and impairs cellular folate accumulation in MCF-7 cells.

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Section: Abbreviationsmentioning

confidence: 99%

Methenyltetrahydrofolate synthetase is a high-affinity catecholamine-binding protein

Anguera

2006

Archives of Biochemistry and Biophysics

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“…Since 5-formyl-THF acts as an inhibitor of other folate-dependent enzymes, 5-formyl-THF cyclo-ligase may also indirectly regulate several key metabolic processes, such as purine, pyrimidine and amino-acid biosynthesis (Stover & Schirch, 1991;Bertrand & Jolivet, 1989). Since all of these processes are required for cell growth and development, 5-formyl-THF cyclo-ligase has been suggested as a target for drug discovery (Jolivet et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Structure of 5-formyltetrahydrofolate cyclo-ligase fromBacillus anthracis(BA4489)

et al. 2007

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PDB Reference: 5-formyltetrahydrofolate cycloligase, 2jcb, r2jcbsf.Bacillus anthracis is a spore-forming bacterium and the causative agent of the disease anthrax. The Oxford Protein Production Facility has been targeting proteins from B. anthracis in order to develop high-throughput technologies within the Structural Proteomics in Europe project. As part of this work, the structure of 5-formyltetrahydrofolate cyclo-ligase (BA4489) has been determined by X-ray crystallography to 1.6 Å resolution. The structure, solved in complex with magnesium-ion-bound ADP and phosphate, gives a detailed picture of the proposed catalytic mechanism of the enzyme. Chemical differences from other cyclo-ligase structures close to the active site that could be exploited to design specific inhibitors are also highlighted.

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Structural and functional characterization of a 5,10‐methenyltetrahydrofolate synthetase from Mycoplasma pneumoniae (GI: 13508087)

et al. 2005

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Mycoplasma pneumoniae 5,10-methenyltetrahydrofolate synthetase [MTHFS; also known as 5-formyltetrahydrofolate cycloligase; Enzyme Commission (EC) 6.3.3.2] belongs to a large cycloligase protein family with 97 sequence homologues from bacteria to human. To help define the molecular (biochemical and biophysical) function of the M. pneumoniae MTHFS, we have previously determined its crystal structure at 2.2 A resolution (Chen et al., Proteins 2004;56:839-843). In this current study, activity assays confirmed the functionality of the recombinant protein, with K(m) = 165 microM for 5-formyltetrahydrofolate (5-FTHF) and K(m) = 166 microM for MgATP. The methenyltetrahydrofolate activity of M. pneumoniae MTHFS has a requirement for divalent metal ions with Mg2+ being most effective, and an absolute requirement for nucleoside 5'-triphosphates with adenosine triphosphate (ATP) being most effective. Crystallization in the presence of substrates (MgATP, with or without 5-FTHF) produced the complex structures of the protein with adenosine diphosphate (ADP) and phosphate at 2.2 A resolution; with ADP, phosphate, and 5-FTHF at 2.5 A resolution. These structures directly demonstrated that the role of Mg2+ in the reaction is to form the ATP--Mg2+-enzyme complex.

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Biochemical and Molecular Studies of Human Methenyltetrahydrofolate Synthetase

Cited by 9 publications

References 41 publications

Methenyltetrahydrofolate synthetase is a high-affinity catecholamine-binding protein

Methenyltetrahydrofolate synthetase is a high-affinity catecholamine-binding protein

Structure of 5-formyltetrahydrofolate cyclo-ligase fromBacillus anthracis(BA4489)

Structural and functional characterization of a 5,10‐methenyltetrahydrofolate synthetase from Mycoplasma pneumoniae (GI: 13508087)

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