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Pathway Description
Lamivudine Anti-viral Action Pathway
Homo sapiens
Drug Action Pathway
Created: 2021-12-05
Last Updated: 2023-10-25
Lamivudine is a reverse transcriptase inhibitor used to treat HIV and hepatitis B infections. It is
a nucleoside reverse transcriptase inhibitor (NRTI) that targets HIV infected cells in the body. When HIV infects a cell, the virus first binds and fuses with the cell, releasing its nucleocapsid containing its RNA and reverse transcriptase into the cytosol of the cell. The reverse transcriptase converts the viral RNA into viral DNA in the cytosol. The viral DNA goes to the nucleus through the nuclear pore complex where it undergoes the process of transcription. The new viral RNA formed from transcription is transported back to the cytosol through the nuclear pore complex and translation occurs to produce viral proteins. These viral proteins are assembled and new HIV viruses bud from the cell.
Lamivudine enters the cell via solute carrier family 22 member 2 and is converted into lamivudine monophosphate by deoxycytidine kinase. UMP-CMP kinase protein then converts lamivudine monophosphate into lamivudine diphosphate. The lamivudine diphosphate is metabolized to lamivudine triphosphate via nucleoside diphosphate kinase A or phosphoglycerate kinase 1.
Limuvudine triphosphate is an analog of deoxycytidine-5'-triphosphate (dCTP). Lamivudine triphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with its substrate, dCTP and by incorporation into viral DNA. Lamivudine triphosphate lacks the 3'-OH group which is needed to form the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation, therefore, once lamivudine triphosphate gets incorporated into DNA, this causes DNA chain termination, preventing the growth of viral DNA. Less viral proteins are therefore produced, and there is a reduction in new viruses being formed. Common side effects from taking lamivudine include headache, nausea, vomiting, diarrhea, weight loss, abdominal pain, fever, cough and nasal signs & symtpoms.
References
Lamivudine Anti-viral Pathway References
Andrade, C. H., Freitas, L. M., & Oliveira, V. de. (2011). Twenty-six years of HIV science: An overview of anti-HIV drugs metabolism. Brazilian Journal of Pharmaceutical Sciences, 47(2), 209–230. https://doi.org/10.1590/s1984-82502011000200003
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Ritter, James (2020). Rang and Dale’s Pharmacology (9th ed). Antiviral drugs. Retrieved from: https://www-clinicalkey-com.login.ezproxy.library.ualberta.ca/#!/browse/book/3-s2.0-C2016004202X
Taylor K, Fritz K, Parmar M: Lamivudine
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Michelson AM, Markham AF, Orkin SH: Isolation and DNA sequence of a full-length cDNA clone for human X chromosome-encoded phosphoglycerate kinase. Proc Natl Acad Sci U S A. 1983 Jan;80(2):472-6. doi: 10.1073/pnas.80.2.472.
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Michelson AM, Blake CC, Evans ST, Orkin SH: Structure of the human phosphoglycerate kinase gene and the intron-mediated evolution and dispersal of the nucleotide-binding domain. Proc Natl Acad Sci U S A. 1985 Oct;82(20):6965-9. doi: 10.1073/pnas.82.20.6965.
Pubmed: 2995995
Chottiner EG, Shewach DS, Datta NS, Ashcraft E, Gribbin D, Ginsburg D, Fox IH, Mitchell BS: Cloning and expression of human deoxycytidine kinase cDNA. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1531-5. doi: 10.1073/pnas.88.4.1531.
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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.
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Van Rompay AR, Johansson M, Karlsson A: Phosphorylation of deoxycytidine analog monophosphates by UMP-CMP kinase: molecular characterization of the human enzyme. Mol Pharmacol. 1999 Sep;56(3):562-9. doi: 10.1124/mol.56.3.562.
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