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(Received for publication, February 28, 1996)
From the Human cytosolic folylpolyglutamate
synthetase (FPGS) was expressed in Escherichia coli
and purified to homogeneity. Tetrahydrofolate and dihydrofolate were
the most effective substrates, while 5-substituted folates were poor
substrates. Most pteroyldiglutamates were better substrates than
monoglutamates.
The human FPGS gene spans 12 kilobases and contains 15 exons and 14
introns. A single FPGS gene was located to chromosome region 9q34.1.
Four exon 1 variants were identified, each of which was spliced to exon
2. The exon 1 variant corresponding to the isolated cDNA contains
two ATG codons and multiple transcription start sites in this region
generates mitochondrial and cytosolic FPGS (Freemantle, S. J., Taylor,
S. M., Krystal, G., and Moran, R. G. (1995) J. Biol. Chem.
270, 9579-9584). Exons 1B and 1C, generated by alternate splicing in
intron 1, and exon 1A, which is 5 Chinese hamster ovary cell transfectants expressing FPGS activity in
the mitochondria contained normal mitochondrial and low cytosolic
folylpolyglutamate pools. Mitochondrial FPGS activity is required for
mitochondrial folate accumulation, while cytosolic FPGS activity is
needed for establishment of normal cytosolic folate pools. The
reconstructed FPGS gene restored normal cytosolic and mitochondrial
folate metabolism in hamster cells.
Volume 271, Number 22,
Issue of May 31, 1996
pp. 13077-13087
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
-glutamate Synthetase and Organization, Localization,
and Differential Splicing of Its Gene
,
,
,
and
Department of Nutritional
Sciences, University of California, Berkeley, California 94720 and the
§ Ahmanson Department of Pediatrics and Medical Birth
Defects Center, Cedars-Sinai Medical Center, UCLA, Los Angeles,
California 90048
to exon 1 and may encode an
additional mitochondrial isoform, are preceded by a number of potential
promoter sites.
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