Loading Pathway...
Error: Pathway image not found.
Hide
Pathway Description
Levoleucovorin Action Pathway
Homo sapiens
Drug Action Pathway
Created: 2023-06-11
Last Updated: 2023-10-25
Levoleucovorin is a folate analog, used to counter the adverse effects of folic acid antagonists. Commonly used in combination with chemotherapy and 5-fluorouracil to treat patients with colorectal cancer. Folic acid is necessary in order to produce purines, pyrimidines and methionine required for DNA synthesis and replication. Once transported into the mitochondria, levoleucovorin acts to inhibit serine hydroxymethyltransferase. Without this enzyme, this halts the DNA synthesis and replication process as 5,10-Methylene-THF cannot be made. 5,10 Methylene THF is an intermediate in many amino acid pathways, such as methionine synthesis. It is also used in thymidine synthesis which is a nucleoside needed for DNA replication.
References
Levoleucovorin Pathway References
Chuang VT, Suno M: Levoleucovorin as replacement for leucovorin in cancer treatment. Ann Pharmacother. 2012 Oct;46(10):1349-57. doi: 10.1345/aph.1Q677. Epub 2012 Oct 2.
Pubmed: 23032661
Zittoun J: Pharmacokinetics and in vitro studies of l-leucovorin. Comparison with the d and d,l-leucovorin. Ann Oncol. 1993;4 Suppl 2:1-5. doi: 10.1093/annonc/4.suppl_2.s1.
Pubmed: 8353099
Jardine LF, Ingram LC, Bleyer WA: Intrathecal leucovorin after intrathecal methotrexate overdose. J Pediatr Hematol Oncol. 1996 Aug;18(3):302-4. doi: 10.1097/00043426-199608000-00014.
Pubmed: 8689347
McEntee G, Minguzzi S, O'Brien K, Ben Larbi N, Loscher C, O'Fagain C, Parle-McDermott A: The former annotated human pseudogene dihydrofolate reductase-like 1 (DHFRL1) is expressed and functional. Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15157-62. doi: 10.1073/pnas.1103605108. Epub 2011 Aug 26.
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
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. doi: 10.1101/gr.2596504.
Pubmed: 15489334
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
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
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
Garrow TA, Brenner AA, Whitehead VM, Chen XN, Duncan RG, Korenberg JR, Shane B: Cloning of human cDNAs encoding mitochondrial and cytosolic serine hydroxymethyltransferases and chromosomal localization. J Biol Chem. 1993 Jun 5;268(16):11910-6.
Pubmed: 8505317
Chave KJ, Snell K, Sanders PG: Isolation and characterisation of human genomic sequences encoding cytosolic serine hydroxymethyltransferase. Biochem Soc Trans. 1997 Feb;25(1):53S. doi: 10.1042/bst025053s.
Pubmed: 9056951
Takeishi K, Kaneda S, Ayusawa D, Shimizu K, Gotoh O, Seno T: Nucleotide sequence of a functional cDNA for human thymidylate synthase. Nucleic Acids Res. 1985 Mar 25;13(6):2035-43. doi: 10.1093/nar/13.6.2035.
Pubmed: 2987839
Kaneda S, Nalbantoglu J, Takeishi K, Shimizu K, Gotoh O, Seno T, Ayusawa D: Structural and functional analysis of the human thymidylate synthase gene. J Biol Chem. 1990 Nov 25;265(33):20277-84.
Pubmed: 2243092
Hisatomi H, Tanemura H, Iizuka T, Katsumata K, Nagao K, Sumida H, Udagawa H, Hikiji K: Differential alternative splicing expressions of thymidylate synthase isoforms. Cancer Lett. 2003 Apr 25;193(2):127-31. doi: 10.1016/s0304-3835(03)00005-3.
Pubmed: 12706868
Highlighted elements will appear in red.
Highlight Compounds
Highlight Proteins
Enter relative concentration values (without units). Elements will be highlighted in a color gradient where red = lowest concentration and green = highest concentration. For the best results, view the pathway in Black and White.
Visualize Compound Data
Visualize Protein Data
Downloads
Settings