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Pathway Description
Pemetrexed Action Pathway
Homo sapiens
Drug Action Pathway
Created: 2023-06-09
Last Updated: 2023-10-25
Pemetrexed is an antifolate, it contains a pyrrolopyrimidine base within its structure that inhibits DNA synthesis and de novo biosynthesis of nucleotides. Once inside the cell via a folate transporter, it is converted to by folylpolyglutamate synthétase into its polyglutamate form. This new form is better retained in the cells and goes on to inhibit enzymes such as dihydrofolate reductase, thymidylate synthase and bifunctional purine biosynthesis protein (PURH). This drug is used to treat cancer specifically that of lung cancer or mesothelioma can be used in combination with pembrolizumab or cisplatin. It is not metabolized by much of the liver but excreted via the urine.
References
Pemetrexed Pathway References
Fuld AD, Dragnev KH, Rigas JR: Pemetrexed in advanced non-small-cell lung cancer. Expert Opin Pharmacother. 2010 Jun;11(8):1387-402. doi: 10.1517/14656566.2010.482560.
Pubmed: 20446853
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Pubmed: 17845983
Rollins KD, Lindley C: Pemetrexed: a multitargeted antifolate. Clin Ther. 2005 Sep;27(9):1343-82. doi: 10.1016/j.clinthera.2005.09.010.
Pubmed: 16291410
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Pubmed: 21876184
Chen MJ, Shimada T, Moulton AD, Cline A, Humphries RK, Maizel J, Nienhuis AW: The functional human dihydrofolate reductase gene. J Biol Chem. 1984 Mar 25;259(6):3933-43.
Pubmed: 6323448
Masters JN, Attardi G: The nucleotide sequence of the cDNA coding for the human dihydrofolic acid reductase. Gene. 1983 Jan-Feb;21(1-2):59-63. doi: 10.1016/0378-1119(83)90147-6.
Pubmed: 6687716
Yao R, Schneider E, Ryan TJ, Galivan J: Human gamma-glutamyl hydrolase: cloning and characterization of the enzyme expressed in vitro. Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10134-8. doi: 10.1073/pnas.93.19.10134.
Pubmed: 8816764
Yin D, Chave KJ, Macaluso CR, Galivan J, Yao R: Structural organization of the human gamma-glutamyl hydrolase gene. Gene. 1999 Oct 1;238(2):463-70. doi: 10.1016/s0378-1119(99)00362-5.
Pubmed: 10570974
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Pubmed: 15489334
Prasannan P, Pike S, Peng K, Shane B, Appling DR: Human mitochondrial C1-tetrahydrofolate synthase: gene structure, tissue distribution of the mRNA, and immunolocalization in Chinese hamster ovary calls. J Biol Chem. 2003 Oct 31;278(44):43178-43187. doi: 10.1074/jbc.M304319200. Epub 2003 Aug 22.
Pubmed: 12937168
Sugiura T, Nagano Y, Inoue T, Hirotani K: A novel mitochondrial C1-tetrahydrofolate synthetase is upregulated in human colon adenocarcinoma. Biochem Biophys Res Commun. 2004 Feb 27;315(1):204-11. doi: 10.1016/j.bbrc.2004.01.035.
Pubmed: 15013446
Mungall AJ, Palmer SA, Sims SK, Edwards CA, Ashurst JL, Wilming L, Jones MC, Horton R, Hunt SE, Scott CE, Gilbert JG, Clamp ME, Bethel G, Milne S, Ainscough R, Almeida JP, Ambrose KD, Andrews TD, Ashwell RI, Babbage AK, Bagguley CL, Bailey J, Banerjee R, Barker DJ, Barlow KF, Bates K, Beare DM, Beasley H, Beasley O, Bird CP, Blakey S, Bray-Allen S, Brook J, Brown AJ, Brown JY, Burford DC, Burrill W, Burton J, Carder C, Carter NP, Chapman JC, Clark SY, Clark G, Clee CM, Clegg S, Cobley V, Collier RE, Collins JE, Colman LK, Corby NR, Coville GJ, Culley KM, Dhami P, Davies J, Dunn M, Earthrowl ME, Ellington AE, Evans KA, Faulkner L, Francis MD, Frankish A, Frankland J, French L, Garner P, Garnett J, Ghori MJ, Gilby LM, Gillson CJ, Glithero RJ, Grafham DV, Grant M, Gribble S, Griffiths C, Griffiths M, Hall R, Halls KS, Hammond S, Harley JL, Hart EA, Heath PD, Heathcott R, Holmes SJ, Howden PJ, Howe KL, Howell GR, Huckle E, Humphray SJ, Humphries MD, Hunt AR, Johnson CM, Joy AA, Kay M, Keenan SJ, Kimberley AM, King A, Laird GK, Langford C, Lawlor S, Leongamornlert DA, Leversha M, Lloyd CR, Lloyd DM, Loveland JE, Lovell J, Martin S, Mashreghi-Mohammadi M, Maslen GL, Matthews L, McCann OT, McLaren SJ, McLay K, McMurray A, Moore MJ, Mullikin JC, Niblett D, Nickerson T, Novik KL, Oliver K, Overton-Larty EK, Parker A, Patel R, Pearce AV, Peck AI, Phillimore B, Phillips S, Plumb RW, Porter KM, Ramsey Y, Ranby SA, Rice CM, Ross MT, Searle SM, Sehra HK, Sheridan E, Skuce CD, Smith S, Smith M, Spraggon L, Squares SL, Steward CA, Sycamore N, Tamlyn-Hall G, Tester J, Theaker AJ, Thomas DW, Thorpe A, Tracey A, Tromans A, Tubby B, Wall M, Wallis JM, West AP, White SS, Whitehead SL, Whittaker H, Wild A, Willey DJ, Wilmer TE, Wood JM, Wray PW, Wyatt JC, Young L, Younger RM, Bentley DR, Coulson A, Durbin R, Hubbard T, Sulston JE, Dunham I, Rogers J, Beck S: The DNA sequence and analysis of human chromosome 6. Nature. 2003 Oct 23;425(6960):805-11. doi: 10.1038/nature02055.
Pubmed: 14574404
Gustafsson R, Jemth AS, Gustafsson NM, Farnegardh K, Loseva O, Wiita E, Bonagas N, Dahllund L, Llona-Minguez S, Haggblad M, Henriksson M, Andersson Y, Homan E, Helleday T, Stenmark P: Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor. Cancer Res. 2017 Feb 15;77(4):937-948. doi: 10.1158/0008-5472.CAN-16-1476. Epub 2016 Nov 29.
Pubmed: 27899380
Peri KG, Belanger C, Mackenzie RE: Nucleotide sequence of the human NAD-dependent methylene tetrahydrofolate dehydrogenase-cyclohydrolase. Nucleic Acids Res. 1989 Nov 11;17(21):8853. doi: 10.1093/nar/17.21.8853.
Pubmed: 2587219
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. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
Mahadeo K, Diop-Bove N, Shin D, Unal ES, Teo J, Zhao R, Chang MH, Fulterer A, Romero MF, Goldman ID: Properties of the Arg376 residue of the proton-coupled folate transporter (PCFT-SLC46A1) and a glutamine mutant causing hereditary folate malabsorption. Am J Physiol Cell Physiol. 2010 Nov;299(5):C1153-61. doi: 10.1152/ajpcell.00113.2010. Epub 2010 Aug 4.
Pubmed: 20686069
Shin DS, Min SH, Russell L, Zhao R, Fiser A, Goldman ID: Functional roles of aspartate residues of the proton-coupled folate transporter (PCFT-SLC46A1); a D156Y mutation causing hereditary folate malabsorption. Blood. 2010 Dec 9;116(24):5162-9. doi: 10.1182/blood-2010-06-291237. Epub 2010 Aug 30.
Pubmed: 20805364
Titus SA, Moran RG: Retrovirally mediated complementation of the glyB phenotype. Cloning of a human gene encoding the carrier for entry of folates into mitochondria. J Biol Chem. 2000 Nov 24;275(47):36811-7. doi: 10.1074/jbc.M005163200.
Pubmed: 10978331
Prasad PD, Ramamoorthy S, Leibach FH, Ganapathy V: Molecular cloning of the human placental folate transporter. Biochem Biophys Res Commun. 1995 Jan 17;206(2):681-7. doi: 10.1006/bbrc.1995.1096.
Pubmed: 7826387
Wong SC, Proefke SA, Bhushan A, Matherly LH: Isolation of human cDNAs that restore methotrexate sensitivity and reduced folate carrier activity in methotrexate transport-defective Chinese hamster ovary cells. J Biol Chem. 1995 Jul 21;270(29):17468-75. doi: 10.1074/jbc.270.29.17468.
Pubmed: 7615551
Moscow JA, Gong M, He R, Sgagias MK, Dixon KH, Anzick SL, Meltzer PS, Cowan KH: Isolation of a gene encoding a human reduced folate carrier (RFC1) and analysis of its expression in transport-deficient, methotrexate-resistant human breast cancer cells. Cancer Res. 1995 Sep 1;55(17):3790-4.
Pubmed: 7641195
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