Global analysis of protein N-myristoylation and exploration of N-myristoyltransferase as a drug target in the neglected human pathogen Leishmania donovani

Chemistry & Biology
Megan H WrightEdward W Tate

Abstract

N-Myristoyltransferase (NMT) modulates protein function through the attachment of the lipid myristate to the N terminus of target proteins, and is a promising drug target in eukaryotic parasites such as Leishmania donovani. Only a small number of NMT substrates have been characterized in Leishmania, and a global picture of N-myristoylation is lacking. Here, we use metabolic tagging with an alkyne-functionalized myristic acid mimetic in live parasites followed by downstream click chemistry and analysis to identify lipidated proteins in both the promastigote (extracellular) and amastigote (intracellular) life stages. Quantitative chemical proteomics is used to profile target engagement by NMT inhibitors, and to define the complement of N-myristoylated proteins. Our results provide new insight into the multiple pathways modulated by NMT and the pleiotropic effects of NMT inhibition. This work constitutes the first global experimental analysis of protein lipidation in Leishmania, and reveals the extent of NMT-related biology yet to be explored for this neglected human pathogen.

References

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Citations

Dec 15, 2015·Current Opinion in Chemical Biology·Tao PengHoward C Hang
Aug 6, 2016·Scientific Reports·Adam J Roberts, Alan H Fairlamb
Feb 7, 2018·Frontiers in Immunology·Justyna SobocińskaKatarzyna Kwiatkowska
Aug 8, 2017·Molecular BioSystems·Fernanda NegrãoSelma Giorgio
Aug 22, 2018·Chembiochem : a European Journal of Chemical Biology·Nadine KaiserHerbert Waldmann
Oct 21, 2018·Molecular & Cellular Proteomics : MCP·Andrea Goya GrocinEdward W Tate
Feb 24, 2017·Critical Reviews in Biochemistry and Molecular Biology·Robert W B BrownDavid M Engman
Dec 26, 2018·Journal of Cellular Physiology·Yumin ZhaoShigui Chong
Feb 5, 2021·Expert Review of Proteomics·Paul W Denny, Karunakaran Kalesh
Jan 23, 2021·RSC Medicinal Chemistry·Anutthaman Parthasarathy, Karunakaran Kalesh
Jan 1, 2019·Molecular & Cellular Proteomics : MCP·Andrea Goya GrocinEdward W Tate
Sep 5, 2017·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Fernanda NegrãoSelma Giorgio
Nov 23, 2020·Current Opinion in Chemical Biology·Ana Losada de la LastraEdward W Tate
Jun 1, 2019·Experimental Parasitology·Andrés M AlonsoMaría M Corvi
Apr 7, 2021·Chemical Reviews·Kiall F SuazoMark D Distefano
Apr 20, 2020·Trends in Biochemical Sciences·Thierry MeinnelCarmela Giglione
Dec 19, 2019·Journal of Medicinal Chemistry·Anke HarupaAlexis Kaushansky
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Nov 2, 2018·ACS Infectious Diseases·Victoriano Corpas-LopezSusan Wyllie
Nov 16, 2021·PLoS Neglected Tropical Diseases·Douglas O EscrivaniPatrick G Steel

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Methods Mentioned

BETA
acylation
lipidation
pull-down
myristoylation
FCS
acetylation

Software Mentioned

PEAKS
Andromeda
Perseus
MaxQuant
SPIDER
PEAKS7

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