Molecular Target Validation of Aspartate Transcarbamoylase from Plasmodium falciparum by Torin 2.

ACS Infectious Diseases
Soraya S BoschCarsten Wrenger

Abstract

Malaria is a tropical disease that kills about half a million people around the world annually. Enzymatic reactions within pyrimidine biosynthesis have been proven to be essential for Plasmodium proliferation. Here we report on the essentiality of the second enzymatic step of the pyrimidine biosynthesis pathway, catalyzed by aspartate transcarbamoylase (ATC). Crystallization experiments using a double mutant ofPlasmodium falciparum ATC (PfATC) revealed the importance of the mutated residues for enzyme catalysis. Subsequently, this mutant was employed in protein interference assays (PIAs), which resulted in inhibition of parasite proliferation when parasites transfected with the double mutant were cultivated in medium lacking an excess of nutrients, including aspartate. Addition of 5 or 10 mg/L of aspartate to the minimal medium restored the parasites' normal growth rate. In vitro and whole-cell assays in the presence of the compound Torin 2 showed inhibition of specific activity and parasite growth, respectively. In silico analyses revealed the potential binding mode of Torin 2 to PfATC. Furthermore, a transgenic ATC-overexpressing cell line exhibited a 10-fold increased tolerance to Torin 2 compared with control cultures. Take...Continue Reading

References

Aug 20, 1976·Science·W Trager, J B Jensen
Jul 1, 1974·The American Journal of Clinical Nutrition·J M BaertlG G Graham
Dec 1, 1969·Analytical Biochemistry·L M Prescott, M E Jones
May 1, 1982·Molecular and Biochemical Parasitology·P ReyesH G Heidrich
Feb 14, 1995·Proceedings of the National Academy of Sciences of the United States of America·Y WuT E Wellems
Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Feb 28, 2002·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Alberto CanepaJonas Bergström
Aug 22, 2002·The Journal of Biological Chemistry·Jeffrey BaldwinMargaret A Phillips
Apr 16, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Caiping YaoRené H Levy
Jun 1, 1964·The American Journal of Clinical Nutrition·R G WHITEHEAD, R F DEAN
Apr 24, 2004·Antimicrobial Agents and Chemotherapy·Martin SmilksteinMichael Riscoe
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Mar 30, 2005·The Journal of Biological Chemistry·Jeffrey BaldwinMargaret A Phillips
Jun 14, 2005·Proceedings of the National Academy of Sciences of the United States of America·Jie WangEvan R Kantrowitz
Jul 26, 2005·FEMS Microbiology Reviews·Harry P de KoningRichard J S Burchmore
Aug 16, 2005·Trends in Molecular Medicine·Monika LöfflerH Anne Simmonds
Jan 20, 2006·Journal of Medicinal Chemistry·Woody ShermanRamy Farid
May 30, 2006·Proceedings of the National Academy of Sciences of the United States of America·Jun LiuDaniel E Goldberg
Jul 7, 2009·Annual Review of Microbiology·Akhil B Vaidya, Michael W Mather
Sep 3, 2009·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Kazuaki MatobaShigeharu Harada
Nov 27, 2009·Trends in Parasitology·Ingrid B MüllerCarsten Wrenger
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Mar 2, 2011·PloS One·Nikolaos PsychogiosDavid S Wishart
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Martyn D WinnKeith S Wilson
May 31, 2011·Current Topics in Medicinal Chemistry·María Belén CasseraVern L Schramm
Oct 21, 2011·Accounts of Chemical Research·William N Lipscomb, Evan R Kantrowitz
May 2, 2012·Proceedings of the National Academy of Sciences of the United States of America·Wenyue GuoEvan R Kantrowitz
Jul 10, 2013·Proceedings of the National Academy of Sciences of the United States of America·Kirsten K HansonMaria M Mota
Dec 10, 2013·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Alba Ruiz-RamosSantiago Ramón-Maiques
Jul 17, 2015·Science Translational Medicine·Margaret A PhillipsSusan A Charman
Nov 20, 2015·Journal of Chemical Theory and Computation·Edward HarderRichard A Friesner
Jun 5, 2016·Asian Pacific Journal of Tropical Medicine·Sudaratana R Krungkrai, Jerapan Krungkrai
Jul 6, 2016·Acta Crystallographica. Section F, Structural Biology Communications·Sergey LunevMatthew R Groves
Feb 25, 2018·Biochemical and Biophysical Research Communications·Sergey LunevMatthew R Groves

❮ Previous
Next ❯

Citations


❮ Previous
Next ❯

Related Concepts

Related Feeds

Antimalarial Agents (ASM)

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

Antimalarial Agents

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

Related Papers

Acta Crystallographica. Section F, Structural Biology Communications
Sergey LunevMatthew R Groves
Biochemical and Biophysical Research Communications
Sergey LunevMatthew R Groves
Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova
E G KostiukovaS N Mosolov
Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova
E V Malinina, I V Zabozlaeva
© 2021 Meta ULC. All rights reserved