Slow-tight-binding inhibition of enoyl-acyl carrier protein reductase from Plasmodium falciparum by triclosan

The Biochemical Journal
Mili KapoorAvadhesha Surolia

Abstract

Triclosan is a potent inhibitor of FabI (enoyl-ACP reductase, where ACP stands for acyl carrier protein), which catalyses the last step in a sequence of four reactions that is repeated many times with each elongation step in the type II fatty acid biosynthesis pathway. The malarial parasite Plasmodium falciparum also harbours the genes and is capable of synthesizing fatty acids by utilizing the enzymes of type II FAS (fatty acid synthase). The basic differences in the enzymes of type I FAS, present in humans, and type II FAS, present in Plasmodium, make the enzymes of this pathway a good target for antimalarials. The steady-state kinetics revealed time-dependent inhibition of FabI by triclosan, demonstrating that triclosan is a slow-tight-binding inhibitor of FabI. The inhibition followed a rapid equilibrium step to form a reversible enzyme-inhibitor complex (EI) that isomerizes to a second enzyme-inhibitor complex (EI*), which dissociates at a very slow rate. The rate constants for the isomerization of EI to EI* and the dissociation of EI* were 5.49x10(-2) and 1x10(-4) s(-1) respectively. The K(i) value for the formation of the EI complex was 53 nM and the overall inhibition constant K(i)* was 96 pM. The results match well wit...Continue Reading

References

Jan 1, 1979·Methods in Enzymology·J W Williams, J F Morrison
Feb 12, 1974·Biochemistry·R S MulveyS Beychok
Jul 12, 1996·Biochimica Et Biophysica Acta·C O Rock, J E Cronan
Nov 14, 1996·Biochimica Et Biophysica Acta·M J SculleyW W Cleland
Nov 7, 1998·The Journal of Biological Chemistry·R J HeathC O Rock
Apr 14, 1999·Nature·C W LevyJ B Rafferty
Oct 16, 1999·The Journal of Biological Chemistry·A RoujeinikovaD W Rice
Dec 28, 1999·Journal of Molecular Biology·A RoujeinikovaD W Rice
May 29, 2000·Health Policy·R Cookson, P Dolan
Sep 29, 2000·The Journal of Biological Chemistry·R J HeathC O Rock
Nov 9, 2000·FEBS Letters·T FawcettA R Slabas
Nov 15, 2001·The Journal of Biological Chemistry·Gregory A KicskaVern L Schramm
Dec 12, 2001·Biochemical and Biophysical Research Communications·M KapoorN Surolia
Jan 22, 2002·FEBS Letters·Ramón Hurtado-GuerrreroDolores González-Pacanowska
Nov 21, 2002·Biochemical Society Transactions·H MarrakchiC O Rock

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Citations

Mar 1, 2007·Acta Crystallographica. Section D, Biological Crystallography·Stephen P MuenchDavid W Rice
Aug 30, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Elver OteroFelipe Otálvaro
Sep 16, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry· YogiaraJae-Gu Pan
Sep 15, 2010·Expert Opinion on Drug Delivery·Hisham R Ibrahim
Apr 22, 2008·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Anastasia KariotiDeniz Tasdemir
Nov 21, 2007·Progress in Lipid Research·N M Carballeira
Aug 25, 2009·IUBMB Life·Agam Prasad SinghAvadhesha Surolia
Mar 5, 2016·Journal of the American Chemical Society·Lorillee TallorinMichael D Burkart
Sep 13, 2012·Protein Science : a Publication of the Protein Society·Steffen Lindert, J Andrew McCammon
Apr 11, 2012·Chemical Biology & Drug Design·Tabish Qidwai, Feroz Khan
Feb 5, 2005·Analytical Biochemistry·Basil PerdicakisEric Jervis
Sep 24, 2004·Journal of Molecular Biology·Lakshmi Swarnamukhi PiduguKaza Suguna
Apr 7, 2015·Molecular and Biochemical Parasitology·Melanie J ShearsGeoffrey I McFadden
Nov 13, 2007·Biochemical and Biophysical Research Communications·Shailendra Kumar SharmaAvadhesha Surolia
Nov 11, 2008·Biochemical and Biophysical Research Communications·Tanushree BanerjeeAvadhesha Surolia
Feb 1, 2017·The Journal of Cell Biology·Melissa VosPatrik Verstreken
May 2, 2006·The Journal of Biological Chemistry·Yong-Mei ZhangCharles O Rock
Apr 10, 2013·Expert Review of Anti-infective Therapy·Juan M Belardinelli, Héctor R Morbidoni
Sep 5, 2020·European Journal of Medicinal Chemistry·Preeti RanaSrinivas Nanduri
Nov 2, 2020·Bioorganic & Medicinal Chemistry Letters· YogiaraJae-Gu Pan

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