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Pathway Description
Atovaquone Action Pathway
Plasmodium falciparum
Drug Action Pathway
Atovaquone is an hydroxynaphthoquinone antimicrobial indicated for the prevention and treatment of Pneumocystis jirovecii pneumonia (PCP) and for the prevention and treatment of Plasmodium falciparum malaria. Atovaquone is a highly lipophilic drug that closely resembles the structure [ubiquinone]. Its inhibitory effect being comparable to ubiquinone, atovaquone can act by selectively affecting mitochondrial electron transport and parallel processes such as ATP and pyrimidine biosynthesis in atovaquone-responsive parasites.
The mechanism of action against Pneumocystis carinii has not been fully elucidated. In Plasmodium species, the site of action appears to be the cytochrome bc1 complex (Complex III). Several metabolic enzymes are linked to the mitochondrial electron transport chain via ubiquinone. Inhibition of electron transport by atovaquone will result in indirect inhibition of these enzymes. The inhibition of the electron transport chain prevents the release of energy, therefore it inhibits nucleic acid and ATP synthesis. This eventually leads to cell death..
References
Atovaquone Pathway References
Winter RW, Kelly JX, Smilkstein MJ, Dodean R, Hinrichs D, Riscoe MK: Antimalarial quinolones: synthesis, potency, and mechanistic studies. Exp Parasitol. 2008 Apr;118(4):487-97. doi: 10.1016/j.exppara.2007.10.016. Epub 2007 Nov 7.
Pubmed: 18082162
Cushion MT, Collins M, Hazra B, Kaneshiro ES: Effects of atovaquone and diospyrin-based drugs on the cellular ATP of Pneumocystis carinii f. sp. carinii. Antimicrob Agents Chemother. 2000 Mar;44(3):713-9. doi: 10.1128/AAC.44.3.713-719.2000.
Pubmed: 10681344
Srivastava IK, Morrisey JM, Darrouzet E, Daldal F, Vaidya AB: Resistance mutations reveal the atovaquone-binding domain of cytochrome b in malaria parasites. Mol Microbiol. 1999 Aug;33(4):704-11. doi: 10.1046/j.1365-2958.1999.01515.x.
Pubmed: 10447880
Srivastava IK, Morrisey JM, Darrouzet E, Daldal F, Vaidya AB: Resistance mutations reveal the atovaquone-binding domain of cytochrome b in malaria parasites. Mol Microbiol. 1999 Aug;33(4):704-11. doi: 10.1046/j.1365-2958.1999.01515.x.
Pubmed: 10447880
Syafruddin D, Siregar JE, Marzuki S: Mutations in the cytochrome b gene of Plasmodium berghei conferring resistance to atovaquone. Mol Biochem Parasitol. 1999 Nov 30;104(2):185-94. doi: 10.1016/s0166-6851(99)00148-6.
Pubmed: 10593174
McFadden DC, Tomavo S, Berry EA, Boothroyd JC: Characterization of cytochrome b from Toxoplasma gondii and Q(o) domain mutations as a mechanism of atovaquone-resistance. Mol Biochem Parasitol. 2000 Apr 30;108(1):1-12. doi: 10.1016/s0166-6851(00)00184-5.
Pubmed: 10802314
Kazanjian P, Armstrong W, Hossler PA, Lee CH, Huang L, Beard CB, Carter J, Crane L, Duchin J, Burman W, Richardson J, Meshnick SR: Pneumocystis carinii cytochrome b mutations are associated with atovaquone exposure in patients with AIDS. J Infect Dis. 2001 Mar 1;183(5):819-22. doi: 10.1086/318835. Epub 2001 Feb 1.
Pubmed: 11181161
Kessl JJ, Lange BB, Merbitz-Zahradnik T, Zwicker K, Hill P, Meunier B, Palsdottir H, Hunte C, Meshnick S, Trumpower BL: Molecular basis for atovaquone binding to the cytochrome bc1 complex. J Biol Chem. 2003 Aug 15;278(33):31312-8. doi: 10.1074/jbc.M304042200. Epub 2003 Jun 5.
Pubmed: 12791689
Kessl JJ, Ha KH, Merritt AK, Lange BB, Hill P, Meunier B, Meshnick SR, Trumpower BL: Cytochrome b mutations that modify the ubiquinol-binding pocket of the cytochrome bc1 complex and confer anti-malarial drug resistance in Saccharomyces cerevisiae. J Biol Chem. 2005 Apr 29;280(17):17142-8. doi: 10.1074/jbc.M500388200. Epub 2005 Feb 17.
Pubmed: 15718226
Meshnick SR, Berry EA, Nett J, Kazanjian P, Trumpower B: The interaction of atovaquone with the P. carinii cytochrome bc1 complex. J Eukaryot Microbiol. 2001;Suppl:169S-171S. doi: 10.1111/j.1550-7408.2001.tb00505.x.
Pubmed: 11906048
Lehninger, A.L. Lehninger principles of biochemistry (4th ed.) (2005). New York: W.H Freeman.
Salway, J.G. Metabolism at a glance (3rd ed.) (2004). Alden, Mass.: Blackwell Pub.
Guo R, Gu J, Zong S, Wu M, Yang M: Structure and mechanism of mitochondrial electron transport chain. Biomed J. 2018 Feb;41(1):9-20. doi: 10.1016/j.bj.2017.12.001. Epub 2018 Mar 26.
Pubmed: 29673555
Acin-Perez R, Fernandez-Silva P, Peleato ML, Perez-Martos A, Enriquez JA: Respiratory active mitochondrial supercomplexes. Mol Cell. 2008 Nov 21;32(4):529-39. doi: 10.1016/j.molcel.2008.10.021.
Pubmed: 19026783
Schagger H, Cramer WA, von Jagow G: Analysis of molecular masses and oligomeric states of protein complexes by blue native electrophoresis and isolation of membrane protein complexes by two-dimensional native electrophoresis. Anal Biochem. 1994 Mar;217(2):220-30. doi: 10.1006/abio.1994.1112.
Pubmed: 8203750
Schagger H, Pfeiffer K: Supercomplexes in the respiratory chains of yeast and mammalian mitochondria. EMBO J. 2000 Apr 17;19(8):1777-83. doi: 10.1093/emboj/19.8.1777.
Pubmed: 10775262
Hayward JA, Rajendran E, Makota FV, Bassett BJ, Devoy M, Neeman T, van Dooren GG: Real-Time Analysis of Mitochondrial Electron Transport Chain Function in Toxoplasma gondii Parasites Using a Seahorse XFe96 Extracellular Flux Analyzer. Bio Protoc. 2022 Jan 5;12(1):e4288. doi: 10.21769/BioProtoc.4288. eCollection 2022 Jan 5.
Pubmed: 35118179
Bianchi C, Fato R, Genova ML, Parenti Castelli G, Lenaz G: Structural and functional organization of Complex I in the mitochondrial respiratory chain. Biofactors. 2003;18(1-4):3-9. doi: 10.1002/biof.5520180202.
Pubmed: 14695915
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
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