Folylpolyglutamate synthase, mitochondrial

Details

Name
Folylpolyglutamate synthase, mitochondrial
Synonyms
  • 6.3.2.17
  • Folylpoly-gamma-glutamate synthetase
  • FPGS
  • Tetrahydrofolate synthase
  • Tetrahydrofolylpolyglutamate synthase
Gene Name
FPGS
Organism
Humans
Amino acid sequence
>lcl|BSEQ0001396|Folylpolyglutamate synthase, mitochondrial
MSRARSHLRAALFLAAASARGITTQVAARRGLSAWPVPQEPSMEYQDAVRMLNTLQTNAG
YLEQVKRQRGDPQTQLEAMELYLARSGLQVEDLDRLNIIHVTGTKGKGSTCAFTECILRS
YGLKTGFFSSPHLVQVRERIRINGQPISPELFTKYFWRLYHRLEETKDGSCVSMPPYFRF
LTLMAFHVFLQEKVDLAVVEVGIGGAYDCTNIIRKPVVCGVSSLGIDHTSLLGDTVEKIA
WQKGGIFKQGVPAFTVLQPEGPLAVLRDRAQQISCPLYLCPMLEALEEGGPPLTLGLEGE
HQRSNAALALQLAHCWLQRQDRHGAGEPKASRPGLLWQLPLAPVFQPTSHMRLGLRNTEW
PGRTQVLRRGPLTWYLDGAHTASSAQACVRWFRQALQGRERPSGGPEVRVLLFNATGDRD
PAALLKLLQPCQFDYAVFCPNLTEVSSTGNADQQNFTVTLDQVLLRCLEHQQHWNHLDEE
QASPDLWSAPSPEPGGSASLLLAPHPPHTCSASSLVFSCISHALQWISQGRDPIFQPPSP
PKGLLTHPVAHSGASILREAAAIHVLVTGSLHLVGGVLKLLEPALSQ
Number of residues
587
Molecular Weight
64608.53
Theoretical pI
8.0
GO Classification
Functions
ATP binding / tetrahydrofolylpolyglutamate synthase activity
Processes
brain development / cell proliferation / folic acid metabolic process / folic acid-containing compound metabolic process / glutamate metabolic process / liver development / nucleobase-containing compound metabolic process / one-carbon metabolic process / organ regeneration / small molecule metabolic process / tetrahydrofolylpolyglutamate biosynthetic process / vitamin metabolic process / water-soluble vitamin metabolic process
Components
cytoplasm / cytosol / mitochondrial inner membrane / mitochondrial matrix / mitochondrion
General Function
Tetrahydrofolylpolyglutamate synthase activity
Specific Function
Catalyzes conversion of folates to polyglutamate derivatives allowing concentration of folate compounds in the cell and the intracellular retention of these cofactors, which are important substrates for most of the folate-dependent enzymes that are involved in one-carbon transfer reactions involved in purine, pyrimidine and amino acid synthesis. Unsubstituted reduced folates are the preferred substrates. Metabolizes methotrexate (MTX) to polyglutamates.
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Mitochondrion inner membrane
Gene sequence
>lcl|BSEQ0010491|Folylpolyglutamate synthase, mitochondrial (FPGS)
ATGCTCAATACCCTGCAGACCAATGCCGGCTACCTGGAGCAGGTGAAGCGCCAGCGGGGT
GACCCTCAGACACAGTTGGAAGCCATGGAACTGTACCTGGCACGGAGTGGGCTGCAGGTG
GAGGACTTGGACCGGCTGAACATCATCCACGTCACTGGGACGAAGGGGAAGGGCTCCACC
TGTGCCTTCACGGAATGTATCCTCCGAAGCTATGGCCTGAAGACGGGATTCTTTAGCTCT
CCCCACCTGGTGCAGGTTCGGGAGCGGATCCGCATCAATGGGCAGCCCATCAGTCCTGAG
CTCTTCACCAAGTACTTCTGGCGCCTCTACCACCGGCTGGAGGAGACCAAGGATGGCAGC
TGTGTCTCCATGCCCCCCTACTTCCGCTTCCTGACACTCATGGCCTTCCACGTCTTCCTC
CAAGAGAAGGTGGACCTGGCAGTGGTGGAGGTGGGCATTGGCGGGGCTTATGACTGCACC
AACATCATCAGGAAGCCTGTGGTGTGCGGAGTCTCCTCTCTTGGCATCGACCACACCAGC
CTCCTGGGGGATACGGTGGAGAAGATCGCATGGCAGAAAGGGGGCATCTTTAAGCAAGGT
GTCCCTGCCTTCACTGTGCTCCAACCTGAAGGTCCCCTGGCAGTGCTGAGGGACCGAGCC
CAGCAGATCTCATGTCCTCTATACCTGTGTCCGATGCTGGAGGCCCTCGAGGAAGGGGGG
CCGCCGCTGACCCTGGGCCTGGAGGGGGAGCACCAGCGGTCCAACGCCGCCTTGGCCTTG
CAGCTGGCCCACTGCTGGCTGCAGCGGCAGGACCGCCATGGTGCTGGGGAGCCAAAGGCA
TCCAGGCCAGGGCTCCTGTGGCAGCTGCCCCTGGCACCTGTGTTCCAGCCCACATCCCAC
ATGCGGCTCGGGCTTCGGAACACGGAGTGGCCGGGCCGGACGCAGGTGCTGCGGCGCGGG
CCCCTCACCTGGTACCTGGACGGTGCGCACACCGCCAGCAGCGCGCAGGCCTGCGTGCGC
TGGTTCCGCCAGGCGCTGCAGGGCCGCGAGAGGCCGAGCGGTGGCCCCGAGGTTCGAGTC
TTGCTCTTCAATGCTACCGGGGACCGGGACCCGGCGGCCCTGCTGAAGCTGCTGCAGCCC
TGCCAGTTTGACTATGCCGTCTTCTGCCCTAACCTGACAGAGGTGTCATCCACAGGCAAC
GCAGACCAACAGAACTTCACAGTGACACTGGACCAGGTCCTGCTCCGCTGCCTGGAACAC
CAGCAGCACTGGAACCACCTGGACGAAGAGCAGGCCAGCCCGGACCTCTGGAGTGCCCCC
AGCCCAGAGCCCGGTGGGTCCGCATCCCTGCTTCTGGCGCCCCACCCACCCCACACCTGC
AGTGCCAGCTCCCTCGTCTTCAGCTGCATTTCACATGCCTTGCAATGGATCAGCCAAGGC
CGAGACCCCATCTTCCAGCCACCTAGTCCCCCAAAGGGCCTCCTCACCCACCCTGTGGCT
CACAGTGGGGCCAGCATACTCCGTGAGGCTGCTGCCATCCATGTGCTAGTCACTGGCAGC
CTGCACCTGGTGGGTGGTGTCCTGAAGCTGCTGGAGCCCGCACTGTCCCAGTAG
Chromosome Location
9
Locus
9q34.1
External Identifiers
ResourceLink
UniProtKB IDQ05932
UniProtKB Entry NameFOLC_HUMAN
GenBank Protein ID292029
GenBank Gene IDM98045
GenAtlas IDFPGS
HGNC IDHGNC:3824
General References
  1. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. [Article]
  2. Humphray SJ, Oliver K, Hunt AR, Plumb RW, Loveland JE, Howe KL, Andrews TD, Searle S, Hunt SE, Scott CE, Jones MC, Ainscough R, Almeida JP, Ambrose KD, Ashwell RI, Babbage AK, Babbage S, Bagguley CL, Bailey J, Banerjee R, Barker DJ, Barlow KF, Bates K, Beasley H, Beasley O, Bird CP, Bray-Allen S, Brown AJ, Brown JY, Burford D, Burrill W, Burton J, Carder C, Carter NP, Chapman JC, Chen Y, Clarke G, Clark SY, Clee CM, Clegg S, Collier RE, Corby N, Crosier M, Cummings AT, Davies J, Dhami P, Dunn M, Dutta I, Dyer LW, Earthrowl ME, Faulkner L, Fleming CJ, Frankish A, Frankland JA, French L, Fricker DG, Garner P, Garnett J, Ghori J, Gilbert JG, Glison C, Grafham DV, Gribble S, Griffiths C, Griffiths-Jones S, Grocock R, Guy J, Hall RE, Hammond S, Harley JL, Harrison ES, Hart EA, Heath PD, Henderson CD, Hopkins BL, Howard PJ, Howden PJ, Huckle E, Johnson C, Johnson D, Joy AA, Kay M, Keenan S, Kershaw JK, Kimberley AM, King A, Knights A, Laird GK, Langford C, Lawlor S, Leongamornlert DA, Leversha M, Lloyd C, Lloyd DM, Lovell J, Martin S, Mashreghi-Mohammadi M, Matthews L, McLaren S, McLay KE, McMurray A, Milne S, Nickerson T, Nisbett J, Nordsiek G, Pearce AV, Peck AI, Porter KM, Pandian R, Pelan S, Phillimore B, Povey S, Ramsey Y, Rand V, Scharfe M, Sehra HK, Shownkeen R, Sims SK, Skuce CD, Smith M, Steward CA, Swarbreck D, Sycamore N, Tester J, Thorpe A, Tracey A, Tromans A, Thomas DW, Wall M, Wallis JM, West AP, Whitehead SL, Willey DL, Williams SA, Wilming L, Wray PW, Young L, Ashurst JL, Coulson A, Blocker H, Durbin R, Sulston JE, Hubbard T, Jackson MJ, Bentley DR, Beck S, Rogers J, Dunham I: DNA sequence and analysis of human chromosome 9. Nature. 2004 May 27;429(6990):369-74. [Article]
  3. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [Article]
  4. Chen L, Qi H, Korenberg J, Garrow TA, Choi YJ, Shane B: Purification and properties of human cytosolic folylpoly-gamma-glutamate synthetase and organization, localization, and differential splicing of its gene. J Biol Chem. 1996 May 31;271(22):13077-87. [Article]
  5. Freemantle SJ, Taylor SM, Krystal G, Moran RG: Upstream organization of and multiple transcripts from the human folylpoly-gamma-glutamate synthetase gene. J Biol Chem. 1995 Apr 21;270(16):9579-84. [Article]
  6. Garrow TA, Admon A, Shane B: Expression cloning of a human cDNA encoding folylpoly(gamma-glutamate) synthetase and determination of its primary structure. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9151-5. [Article]
  7. Taylor SM, Freemantle SJ, Moran RG: Structural organization of the human folypoly-gamma-glutamate synthetase gene: evidence for a single genomic locus. Cancer Res. 1995 Dec 15;55(24):6030-4. [Article]
  8. Osborne CB, Lowe KE, Shane B: Regulation of folate and one-carbon metabolism in mammalian cells. I. Folate metabolism in Chinese hamster ovary cells expressing Escherichia coli or human folylpoly-gamma-glutamate synthetase activity. J Biol Chem. 1993 Oct 15;268(29):21657-64. [Article]
  9. Lowe KE, Osborne CB, Lin BF, Kim JS, Hsu JC, Shane B: Regulation of folate and one-carbon metabolism in mammalian cells. II. Effect of folylpoly-gamma-glutamate synthetase substrate specificity and level on folate metabolism and folylpoly-gamma-glutamate specificity of metabolic cycles of one-carbon metabolism. J Biol Chem. 1993 Oct 15;268(29):21665-73. [Article]
  10. Lin BF, Huang RF, Shane B: Regulation of folate and one-carbon metabolism in mammalian cells. III. Role of mitochondrial folylpoly-gamma-glutamate synthetase. J Biol Chem. 1993 Oct 15;268(29):21674-9. [Article]
  11. Kim JS, Lowe KE, Shane B: Regulation of folate and one-carbon metabolism in mammalian cells. IV. Role of folylpoly-gamma-glutamate synthetase in methotrexate metabolism and cytotoxicity. J Biol Chem. 1993 Oct 15;268(29):21680-5. [Article]
  12. Nair JR, McGuire JJ: Submitochondrial localization of the mitochondrial isoform of folylpolyglutamate synthetase in CCRF-CEM human T-lymphoblastic leukemia cells. Biochim Biophys Acta. 2005 Oct 30;1746(1):38-44. Epub 2005 Sep 7. [Article]
  13. Leil TA, Endo C, Adjei AA, Dy GK, Salavaggione OE, Reid JR, Ames MM, Adjei AA: Identification and characterization of genetic variation in the folylpolyglutamate synthase gene. Cancer Res. 2007 Sep 15;67(18):8772-82. [Article]
  14. Tomsho JW, Moran RG, Coward JK: Concentration-dependent processivity of multiple glutamate ligations catalyzed by folylpoly-gamma-glutamate synthetase. Biochemistry. 2008 Aug 26;47(34):9040-50. doi: 10.1021/bi800406w. Epub 2008 Aug 2. [Article]
  15. Van Damme P, Lasa M, Polevoda B, Gazquez C, Elosegui-Artola A, Kim DS, De Juan-Pardo E, Demeyer K, Hole K, Larrea E, Timmerman E, Prieto J, Arnesen T, Sherman F, Gevaert K, Aldabe R: N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12449-54. doi: 10.1073/pnas.1210303109. Epub 2012 Jul 18. [Article]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB00142Glutamic acidapproved, nutraceuticalunknownDetails
DB00293Raltitrexedapproved, investigationalunknownantagonistDetails
DB00563MethotrexateapprovedunknownsubstrateDetails
DB06813Pralatrexateapproved, investigationalyessubstrateDetails