Wright, M. H., Paape, D. , Storck, E. M., Serwa, R. A., Smith, D. F. and Tate, E. W. (2015) Global analysis of protein N-myristoylation and exploration of N-myristoyltransferase as a drug target in the neglected human pathogen Leishmania donovani. Chemistry and Biology, 22(3), pp. 342-354. (doi: 10.1016/j.chembiol.2015.01.003) (PMID:25728269) (PMCID:PMC4372256)
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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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Paape, Dr Daniel |
| Authors: | Wright, M. H., Paape, D., Storck, E. M., Serwa, R. A., Smith, D. F., and Tate, E. W. |
| Subjects: | Q Science > Q Science (General) |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | Chemistry and Biology |
| Publisher: | Cell Press |
| ISSN: | 1074-5521 |
| ISSN (Online): | 1879-1301 |
| Copyright Holders: | Copyright © 2014 The Authors |
| First Published: | First published in Chemistry and Biology 22(3):342-354 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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