Folate-binding triggers the activation of folylpolyglutamate synthetase 1 1Edited by I. Wilson

Sun, Xiao; Cross, Jennifer; Bognar, Andrew L.; Baker, Edward N.; Smith, Clyde A.

doi:10.1006/jmbi.2001.4815

Cited by 58 publications

(109 citation statements)

References 33 publications

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“…The crystal structure of human FPGS has not been solved, however, the structures of the Escherichia coli, Lactobacillus casei, and Mycobacterium tuberculosis proteins have been published (31)(32)(33)(34). Human FPGS has been successfully modeled to the structure of the L. casei protein using homology modeling algorithms (17).…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Genetic Variation in the Folylpolyglutamate Synthase Gene

Leil

Endo

Adjei³

et al. 2007

Cancer Research

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Folylpolyglutamate synthase (FPGS) catalyzes the polyglutamation of folic acid, methotrexate, and pemetrexed to produce highly active metabolites. To characterize genetic variation in the FPGS gene, FPGS, have resequenced the gene in four different ethnic populations. Thirty-four single nucleotide polymorphisms were identified including five nonsynonymous coding single nucleotide polymorphisms that altered the FPGS protein sequence: F13L and V22I polymorphisms in the mitochondrial isoform of FPGS, and R466/424C, A489/ 447V, and S499/457F polymorphisms, which exist in both the mitochondrial and cytosolic isoforms. When expressed in AuxB1 cells, the A447V cytosolic variant was functionally similar to the wild-type cytosolic (WT Cyt) allozyme, whereas the R424C and S457F cytosolic variants were reduced by f2-fold in protein expression compared with WT Cyt (P < 0.01). The intrinsic clearance of glutamate was reduced by 12.3-fold (R424C, P < 0.01) and 6.2-fold (S457F, P < 0.01), whereas the intrinsic clearance of methotrexate was reduced by 4.2-fold (R424C, P < 0.05) and 5.4-fold (S457F, P < 0.05) in these two cytosolic variants when compared with the WT Cyt isoform. Additionally, the in vitro enzyme velocity at saturating pemetrexed concentrations was reduced by 1.6-fold (R424C, P < 0.05) and 2.6-fold (S457F, P < 0.01) compared with WT Cyt. AuxB1 cells harboring these same cytosolic variant allozymes displayed significant increases in the EC 50 for folic acid and in the IC 50 values for both methotrexate and pemetrexed relative to the WT Cyt form of FPGS. These observations suggest that genetic variations in FPGS may alter the efficacy of antifolate therapy in cancer patients. [Cancer Res 2007;67(18):8772-82]

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Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Genetic Variation in the Folylpolyglutamate Synthase Gene

Leil

Endo

Adjei³

et al. 2007

Cancer Research

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“…The FPGS enzyme requires three substrates, ATP, tetrahydrofolate and glutamate molecules, which bind different sites on the FPGS molecule. The putative rice FPGS protein sequences contain all the previously reported functional motifs (Sun et al, 2001; Fig. S1).…”

Section: Fpgs Genes Are Differentially Expressed In Rice Tissuesmentioning

confidence: 81%

Folate Polyglutamylation is Required for Rice Seed Development

Anukul

Ramos

Mehrshahi

et al. 2010

Rice

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In plants, polyglutamylated folate forms account for a significant proportion of the total folate pool. Polyglutamylated folate forms are produced by the enzyme folylpolyglutamate synthetase (FPGS). The FPGS enzyme is encoded by two genes in rice, Os03g02030 and Os10g35940. Os03g02030 represents the major expressed form in developing seed. To determine the function of this FPGS gene in rice, a T-DNA knockout line was characterised. Disrupting Os03g02030 gene expression resulted in delayed seed filling. LC-MS/MS-based metabolite profiling revealed that the abundance of mono-and polyglutamylated folate forms was significantly decreased in seeds of the knockout line. RT-qPCR detected an increase in the transcript abundance of folate biosynthesis genes in seed of the knockout plant, whereas the folate deglutamating enzyme γ-glutamyl hydrolase mRNA level was reduced. Our study has uncovered a novel role for folate polyglutamylation during rice seed development and a potential feedback mechanism to maintain folate abundance.

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“…The mutations denoted as L7, L15, L44, and L51 are mutations found in L1210 cell lines selected for resistance to lometrexol (26), SSM marks three residues involved in substrate binding and catalysis with human FPGS by site-directed mutagenesis (27), H460tdx indicates a mutation found in a non-small cell lung cancer cell selected for resistant to tomudex (28). The positions of the mutations found in AUXB1, AUXB3, and V79ght1 cells (Table 1) are noted, as is the peptide marking the transition from the amino-terminal domain (circled N) and carboxyl-terminal domain (circled C) from the crystal structure of the L. casei FPGS (29,30). The A and B regions represent ␣ helices and ␤ strands in that structure.…”

Section: Fpgs Expression In Cho Auxb1 and Auxb1 Cells Stablymentioning

confidence: 99%

Mammalian Mitochondrial and Cytosolic Folylpolyglutamate Synthetase Maintain the Subcellular Compartmentalization of Folates

Lawrence

Titus

Ferguson

et al. 2014

Journal of Biological Chemistry

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Background: Folylpolyglutamates are in the cytosol and mitochondria and the enzyme that makes these compounds, folylpolyglutamate synthetase (FPGS) is in both compartments. Results: Folylpolyglutamates cannot traverse mitochondrial membranes in either direction. Conclusion: Subcellular isoforms of FPGS are required to establish and maintain subcellular folate compartmentalization and function. Significance: Mitochondrial folates are a separate metabolic pool not in equilibrium with cytosol.

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Folate-binding triggers the activation of folylpolyglutamate synthetase 1 1Edited by I. Wilson

Cited by 58 publications

References 33 publications

Identification and Characterization of Genetic Variation in the Folylpolyglutamate Synthase Gene

Identification and Characterization of Genetic Variation in the Folylpolyglutamate Synthase Gene

Folate Polyglutamylation is Required for Rice Seed Development

Mammalian Mitochondrial and Cytosolic Folylpolyglutamate Synthetase Maintain the Subcellular Compartmentalization of Folates

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