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N-myristoylation as a drug target in malaria: exploring the role of N-myristoyltransferase substrates in the inhibitor mode of action

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Title: N-myristoylation as a drug target in malaria: exploring the role of N-myristoyltransferase substrates in the inhibitor mode of action
Authors: Schlott, AC
Holder, AA
Tate, EW
Item Type: Journal Article
Abstract: Malaria continues to be a significant cause of death and morbidity worldwide, and there is a need for new antimalarial drugs with novel targets. We have focused as a potential target for drug development on N-myristoyl transferase (NMT), an enzyme that acylates a wide range of substrate proteins. The NMT substrates in Plasmodium falciparum include some proteins that are common to processes in eukaryotes such as secretory transport and others that are unique to apicomplexan parasites. Myristoylation facilitates a protein interaction with membranes that may be strengthened by further lipidation, and the inhibition of NMT results in incorrect protein localization and the consequent disruption of function. The diverse roles of NMT substrates mean that NMT inhibition has a pleiotropic and severe impact on parasite development, growth, and multiplication. To study the mode of action underlying NMT inhibition, it is important to consider the function of proteins upstream and downstream of NMT. In this work, we therefore present our current perspective on the different functions of known NMT substrates as well as compare the inhibition of cotranslational myristoylation to the inhibition of known targets upstream of NMT.
Issue Date: 13-Apr-2018
Date of Acceptance: 1-Nov-2017
URI: http://hdl.handle.net/10044/1/58350
DOI: https://dx.doi.org/10.1021/acsinfecdis.7b00203
ISSN: 2373-8227
Publisher: American Chemical Society
Start Page: 449
End Page: 457
Journal / Book Title: ACS Infectious Diseases
Volume: 4
Issue: 4
Copyright Statement: © 2018 American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Infectious Diseases, after peer review and technical editing by the publisher. To access the final edited and published work see https://dx.doi.org/10.1021/acsinfecdis.7b00203
Keywords: Science & Technology
Life Sciences & Biomedicine
Chemistry, Medicinal
Infectious Diseases
Pharmacology & Pharmacy
N-myristoyl transferase
NMT
acyl transferase
myristoylation
palmitoylation
post-translational modification
protein lipidation
chemical proteomics
DEPENDENT PROTEIN-KINASE
TRANSFER-RNA SYNTHETASES
PLASMODIUM-FALCIPARUM
PARASITE DEVELOPMENT
MICRONEME SECRETION
THERAPEUTIC TARGET
TOXOPLASMA-GONDII
GLIDING MOTILITY
ESSENTIAL GENES
GOLGI-COMPLEX
Publication Status: Published
Conference Place: United States
Online Publication Date: 2018-01-24
Appears in Collections:Chemistry
Biological and Biophysical Chemistry
Faculty of Natural Sciences