title: Myristoyl-CoA:protein N-myristoyltransferase, an essential enzyme and potential drug target in kinetoplastid parasites.
abstract: Co-translational modification of eukaryotic proteins by N-myristoylation aids subcellular targeting and protein-protein interactions. The enzyme that catalyzes this process, N-myristoyltransferase (NMT), has been characterized in the kinetoplastid protozoan parasites, Leishmania and Trypanosoma brucei. In Leishmania major, the single copy NMT gene is constitutively expressed in all parasite stages as a 48.5-kDa protein that localizes to both membrane and cytoplasmic fractions. Leishmania NMT myristoylates the target acylated Leishmania protein, HASPA, when both are co-expressed in Escherichia coli. Gene targeting experiments have shown that NMT activity is essential for viability in Leishmania. In addition, overexpression of NMT causes gross changes in parasite morphology, including the subcellular accumulation of lipids, leading to cell death. This phenotype is more extreme than that observed in Saccharomyces cerevisiae, in which overexpression of NMT activity has no obvious effects on growth kinetics or cell morphology. RNA interference assays in T. brucei have confirmed that NMT is also an essential protein in both life cycle stages of this second kinetoplastid species, suggesting that this enzyme may be an appropriate target for the development of anti-parasitic agents.
authors.affiliation: Wellcome Trust Laboratories for Molecular Parasitology, Centre for Molecular Microbiology and Infection, Department of Biological Sciences, Imperial College of Science, Technology and Medicine, London SW7 2AZ, United Kingdom.
authors.forename: Helen P
authors.initials: HP
authors.lastname: Price
authors.forename: Malini R
authors.initials: MR
authors.lastname: Menon
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Panethymitaki
authors.forename: David
authors.initials: D
authors.lastname: Goulding
authors.forename: Paul G
authors.initials: PG
authors.lastname: McKean
authors.forename: Deborah F
authors.initials: DF
authors.lastname: Smith
mesh_terms: D000217:Acyltransferases / Q000737:chemistry* / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D016923:Cell Death; D002455:Cell Division; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D017353:Gene Deletion; D005816:Genetic Complementation Test; D015151:Immunoblotting; D007700:Kinetics; D007891:Leishmania / Q000378:metabolism; D008969:Molecular Sequence Data; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013347:Subcellular Fractions; D013997:Time Factors; D014345:Trypanosoma / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase